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Pulmonary arterial hypertension (PAH) is characterized by the severe obstruction of the small pulmonary arteries and concomitant high pulmonary arterial pressure, resulting in progressive right ventricular failure. Previously, we demonstrated that long-term interleukin (IL)-33 administration in mice induces severe occlusive medial hypertrophy of pulmonary arteries (PA) in the lungs, which is mediated by group 2 innate lymphoid cells (ILC2s). In response to IL-33, ILC2s accumulate around the blood vessels and produce IL-5, leading to perivascular eosinophil recruitment. In this study, we characterized IL-33-induced medial hypertrophy of PA. We demonstrated that long-term IL-33 administration causes an increase in right ventricular pressure. In IL-33-deficient mice, medial hypertrophy of PA mediated by eggs of Schistosoma mansoni was attenuated, accompanied by a partial reduction in ILC2s, eosinophils, and CD4 + T cells. In addition, proteomic analysis revealed dramatic changes in the urine samples from mice treated with IL-33 or S. mansoni eggs. Resistin-like alpha (RELMα), a pulmonary hypertension-related molecule, was commonly detected in the urine in both treatments. Large amounts of RELMα were observed in the lungs of the IL-33-treated mice. These observations suggest that IL-33-induced medial hypertrophy of PA is a useful model for studying the mechanism underlying the development of PAH and finding biomarkers to indicate the onset of PAH., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Masashi Ikutani reports financial support was provided by Hiroshima University. Shoichi Shimizu reports financial support was provided by University of Occupational and Environmental Health, Japan. Koki Okada reports financial support was provided by Hiroshima University. Koshi Imami reports financial support was provided by RIKEN. Tadakatsu Inagaki reports financial support was provided by National Cerebral and Cardiovascular Center Research Institute. Yoshikazu Nakaoka reports financial support was provided by National Cerebral and Cardiovascular Center Research Institute. Yoshio Osada reports financial support was provided by University of Occupational and Environmental Health, Japan. Susumu Nakae reports financial support was provided by Hiroshima University., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Calcification is common in chronic vascular disease, yet its role in pulmonary hypertension due to left heart disease is unknown. Here, we probed for the role of runt-related transcription factor-2 (RUNX2), a master transcription factor in osteogenesis, and its regulation by the HIPPO pathway transcriptional coactivator with PDZ-binding motif (TAZ) in the osteogenic reprogramming of pulmonary artery smooth muscle cells and vascular calcification in patients with pulmonary hypertension due to left heart disease. We similarly examined its role using an established rat model of pulmonary hypertension due to left heart disease induced by supracoronary aortic banding., Methods: Pulmonary artery samples were collected from patients and rats with pulmonary hypertension due to left heart disease. Genome-wide RNA sequencing was performed, and pulmonary artery calcification assessed. Osteogenic signalling via TAZ and RUNX2 was delineated by protein biochemistry. In vivo , the therapeutic potential of RUNX2 or TAZ inhibition by CADD522 or verteporfin was tested in the rat model., Results: Gene ontology term analysis identified significant enrichment in ossification and osteoblast differentiation genes, including RUNX2 , in pulmonary arteries of patients and lungs of rats with pulmonary hypertension due to left heart disease. Pulmonary artery calcification was evident in both patients and rats. Both TAZ and RUNX2 were upregulated and activated in pulmonary artery smooth muscle cells of patients and rats. Co-immunoprecipitation revealed a direct interaction of RUNX2 with TAZ in pulmonary artery smooth muscle cells. TAZ inhibition or knockdown decreased RUNX2 abundance due to accelerated RUNX2 protein degradation rather than reduced de novo synthesis. Inhibition of either TAZ or RUNX2 attenuated pulmonary artery calcification, distal lung vascular remodelling and pulmonary hypertension development in the rat model., Conclusion: Pulmonary hypertension due to left heart disease is associated with pulmonary artery calcification that is driven by TAZ-dependent stabilisation of RUNX2, causing osteogenic reprogramming of pulmonary artery smooth muscle cells. The TAZ-RUNX2 axis may present a therapeutic target in pulmonary hypertension due to left heart disease., Competing Interests: Conflict of interest: N. Nambiar Veetil reports support for the present manuscript from the German Centre for Cardiovascular Research (DZHK) Young Scientist Doctoral Scholarship and German Society for Cardiology (DGK) (Otto-Hess Doctoral Scholarship). J. Voelkl reports support for the present manuscript from Austrian Science Fund (FWF) (grant number P34724-BBL). J. Grune reports support for the present manuscript from the DZHK, the German Research Foundation (DFG) (CRC-1470 A04, CRC-1425), Corona-Stiftung, DynAge Freie Universität Berlin, the DGK, Corona-Stiftung, dt. Stiftung für Herzforschung and Charité 3R. W.M. Kuebler reports support for the present manuscript from the DFG, DZHK and German Ministry of Education and Research (BMBF); outside the submitted work; W.M. Kuebler reports consulting fees from Bayer AG, Germany, and a leadership role as Chair of Publications Committee for American Physiological Society. The remaining authors have nothing to disclose., (Copyright ©The authors 2024. For reproduction rights and permissions contact permissions@ersnet.org.)

The pathogenesis of pulmonary arterial hypertension (PAH) is closely linked to the abnormal proliferation of pulmonary artery smooth muscle cells. Studies have demonstrated that microRNAs play pivotal roles in the progression of pulmonary hypertension. We found that microRNA-637 (miR-637) and microRNA-661 (miR-661) are expressed at low levels in the serum of PAH patients. Moreover, the overexpression of miR-637 or miR-661 inhibited human pulmonary artery smooth muscle cell (HPASMC) proliferation and migration in hypoxic culture. Mechanistically, we overexpressed these two microRNAs in HPASMCs, and the RNA-sequencing (RNA-seq) results demonstrated that TRIM29 mRNA was suppressed, indicating that TRIM29 is a substrate. TRIM29 accumulates in the serum of patients with PAH and promotes cell proliferation and migration by activating AKT/mTOR signalling. In addition, overexpression of miR-637 or miR-661 reversed TRIM29-mediated HPASMC proliferation and migration. This study revealed that miR-637 and miR-661 are able to inhibit the proliferation ability of HPASMCs under hypoxic conditions through targeting TRIM29, suggesting that the microRNA-637/661/TRIM29 axis may act as a target for PAH treatment., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: Pulmonary arterial hypertension (PAH) is characterized by lipid accumulation and mitochondrial dysfunction. This study was designed to investigate the effects of hypoxia-inducible factor-1α (HIF-1α) on fatty acid uptake and mitophagy in PAH., Methods: Peripheral blood samples were obtained from PAH patients. Human pulmonary arterial smooth muscle cells and rat cardiac myoblasts H9c2 were subjected to hypoxia treatment. Male Sprague-Dawley rats were treated with monocrotaline (MCT). Right ventricular systolic pressure (RVSP), right ventricular hypertrophy index (RVHI), pulmonary artery remodeling, and lipid accumulation were measured. Cell proliferation and ROS accumulation were assessed. Mitochondrial damage and autophagosome formation were observed. Co-immunoprecipitation was performed to verify the interaction between HIF-1α and CD36/PI3K p85α., Results: HIF-1α, CD36, Parkin, and PINK1 were upregulated in PAH samples. HIF-1α knockdown or PI3K p85α knockdown restricted the expression of HIF-1α, PI3K p85α, Parkin, PINK1, and CD36, inhibited hPASMC proliferation, promoted H9c2 cell proliferation, reduced ROS accumulation, and suppressed mitophagy. CD36 knockdown showed opposite effects to HIF-1α knockdown, which were reversed by palmitic acid. The HIF-1α activator dimethyloxalylglycine reversed the inhibitory effect of Parkin knockdown on mitophagy. In MCT-induced rats, the HIF-1α antagonist 2-methoxyestradiol (2ME) reduced RVSP, RVHI, pulmonary artery remodeling, lipid accumulation, and mitophagy. Recombinant CD36 abolished the therapeutic effect of 2ME but inhibited mitophagy. Activation of Parkin/PINK1 by salidroside (Sal) promoted mitophagy to ameliorate the pathological features of PAH-like rats, and 2ME further enhanced the therapeutic outcome of Sal., Conclusion: PI3K p85α/HIF-1α induced CD36-mediated fatty acid uptake and Parkin/PINK1-dependent mitophagy to accelerate the progression of experimental PAH., Competing Interests: Declarations Ethics approval and consent to participate This study was approved by The IRB of Third Xiangya Hospital, Central South University (2020-S109), and written informed consent was obtained from each participant. The usage of the clinical samples was performed in accordance with the Declaration of Helsinki. All animal procedures were approved by the Animal Welfare Ethics Committee of the Third Xiangya Hospital, Central South University (2020sydw0211), and these experiments were in accordance with the ARRIVE guidelines. Consent for publication Written informed consent was obtained, and participants knew and agreed with the usage of their samples. Competing interests The authors have no conflict of interest to declare., (© 2024. The Author(s).)

Vitamin D (vitD) deficiency is frequently observed in patients with pulmonary arterial hypertension (PAH) and, in these patients, low levels of vitD correlate with worse prognosis. The aim of this study was to examine the expression and the antiproliferative role of vitD receptor (VDR) and its signalling pathway in the human pulmonary vasculature. VDR presence and expression was analyzed in lungs, pulmonary artery smooth muscle cells (PASMC) and endothelial cells (PAEC) from controls and PAH-patients. VDR expression and VDR-target genes were examined in PASMC treated with calcitriol. The antiproliferative effect of 48 h-calcitriol was studied in PASMC by MTT and BrdU assays. VDR is expressed in PASMC. It is downregulated in lungs and in PASMC, but not in PAEC, from PAH-patients compared to non-hypertensive controls. Calcitriol strongly upregulated VDR expression in PASMC and the VDR target genes KCNK3 (encoding TASK1), BIRC5 (encoding survivin) and BMP4. Calcitriol produced an antiproliferative effect which was diminished by silencing or by pharmacological inhibition of survivin or BMPR2, but not of TASK1. In conclusion, the expression of VDR is low in PAH-patients and can be rescued by calcitriol. VDR exerts an antiproliferative effect in PASMC by modulating survivin and the BMP signalling pathway., Competing Interests: Declarations Competing interests The authors declare no competing interests. Ethical approval Research using human samples were approved by the Ethics Committee of the Getafe Hospital (Madrid, Spain), Ciberes Biobank (Barcelona, Spain) and French institutional Ethics Committee (Protocol N8CO-08-003, ID RCB: 2008-A00485-50). Informed consent was obtained in all cases. Human explanted lung tissues from non-PAH subjects were obtained from non-tumor lung areas of the resection specimens from patients undergoing surgery for lung carcinoma or discarded for lung transplantation. The donor lungs included in this study were thoroughly reviewed by a pathologist. PAH samples were obtained from lung transplantation., (© 2024. The Author(s).)

Background: Mitochondrial dysfunction, characterized by impaired lipid metabolism and heightened reactive oxygen species generation, results in lipid peroxidation and ferroptosis. Ferroptosis is an inflammatory mode of cell death that promotes complement activation and macrophage recruitment. In pulmonary arterial hypertension (PAH), pulmonary arterial endothelial cells exhibit cellular phenotypes that promote ferroptosis. Moreover, there is ectopic complement deposition and inflammatory macrophage accumulation in the pulmonary vasculature. However, the effects of ferroptosis inhibition on these pathogenic mechanisms and the cellular landscape of the pulmonary vasculature are incompletely defined., Methods: Multiomics and physiological analyses evaluated how ferroptosis inhibition-modulated preclinical PAH. The impact of adeno-associated virus 1-mediated expression of the proferroptotic protein ACSL (acyl-CoA synthetase long-chain family member) 4 on PAH was determined, and a genetic association study in humans further probed the relationship between ferroptosis and pulmonary hypertension., Results: Ferrostatin-1, a small-molecule ferroptosis inhibitor, mitigated PAH severity in monocrotaline rats. RNA-sequencing and proteomics analyses demonstrated ferroptosis was associated with PAH severity. RNA-sequencing, proteomics, and confocal microscopy revealed complement activation and proinflammatory cytokines/chemokines were suppressed by ferrostatin-1. In addition, ferrostatin-1 combatted changes in endothelial, smooth muscle, and interstitial macrophage abundance and gene activation patterns as revealed by deconvolution RNA-sequencing. Ferroptotic pulmonary arterial endothelial cell damage-associated molecular patterns restructured the transcriptomic signature and mitochondrial morphology, promoted the proliferation of pulmonary artery smooth muscle cells, and created a proinflammatory phenotype in monocytes in vitro. Adeno-associated virus 1- Acsl4 induced an inflammatory PAH phenotype in rats. Finally, single-nucleotide polymorphisms in 6 ferroptosis genes identified a potential link between ferroptosis and pulmonary hypertension severity in the Vanderbilt BioVU repository., Conclusions: Ferroptosis promotes PAH through metabolic and inflammatory mechanisms in the pulmonary vasculature., Competing Interests: K.W. Prins received grant funding from Bayer unrelated to this article. The other authors report no conflicts.

Background: Unveiling pro-proliferation genes involved in crosstalk between pulmonary artery endothelial cells and pulmonary artery smooth muscle cells (PASMCs) are important to improving the therapeutic outcome of pulmonary hypertension (PH). Although growing studies have shown that super-enhancers (SEs) play a pivotal role in pathological and physiological processes, the SE-associated genes in PH and their impact on PASMC proliferation remain largely unexplored., Methods and Results: We used serotype 5 adenovirus-associated virus to interfere with syndecan-4 and constructed an SU5416 combined with hypoxia-PH model. Chromatin immunoprecipitation sequencing analysis, chromatin immunoprecipitation quantitative polymerase chain reaction, and bioinformatics were used to confirm early growth response 1 was involved in regulating syndecan-4-associated SE in PASMCs. The effects of syndecan-4 and its underlying mechanisms were subsequently elucidated using Western blot, coimmunoprecipitation, and cell coculture assays. Herein, we identified a novel SE-associated gene, syndecan-4, in hypoxia-exposed PASMCs. Syndecan-4 was transcriptionally driven by early growth response 1 via an SE and was significantly overexpressed in hypoxic PASMCs and plasma from patients with PH. Mechanism studies revealed that syndecan-4 induces PASMC proliferation by interacting and regulating protein kinase C α ubiquitination. In addition, syndecan-4 was enriched in exosomes secreted from hypoxic PASMCs, which subsequently transported and led to pulmonary artery endothelial cell dysfunction. Syndecan-4 inhibition in hypoxia by serotype 5 adenovirus-associated virus treatment attenuated the pulmonary artery remodeling and development of PH in vivo., Conclusions: Taken together, our results demonstrate that an SE-driven syndecan-4 modulates crosstalk of PASMCs and pulmonary artery endothelial cells and promotes vascular remodeling via the protein kinase C α and exosome pathway, thus providing potential targets for the early diagnosis and treatment of hypoxic PH.

Aims: Chronic hypoxia causes detrimental structural alterations in the lung, which may cause pulmonary hypertension and are partially mediated by the endothelium. While its relevance for the development of hypoxia-associated lung diseases is well known, determinants controlling the initial adaptation of the lung endothelium to hypoxia remain largely unexplored., Methods and Results: We revealed that hypoxia activates the transcription factor nuclear factor of activated T-cells 5 (NFAT5) and studied its regulatory function in murine lung endothelial cells (MLECs). EC-specific knockout of Nfat5 (Nfat5(EC)-/-) in mice exposed to normobaric hypoxia (10% O2) for 21 days promoted vascular fibrosis and aggravated the increase in pulmonary right ventricular systolic pressure as well as right ventricular dysfunction as compared with control mice. Microarray- and single-cell RNA-sequencing-based analyses revealed an impaired growth factor-, energy-, and protein-metabolism-associated gene expression in Nfat5-deficient MLEC after exposure to hypoxia for 7 days. Specifically, loss of NFAT5 boosted the expression and release of platelet-derived growth factor B (Pdgfb)-a hypoxia-inducible factor 1 alpha (HIF1α)-regulated driver of vascular smooth muscle cell (VSMC) growth-in capillary MLEC of hypoxia-exposed Nfat5(EC)-/- mice, which was accompanied by intensified VSMC coverage of distal pulmonary arteries., Conclusion: Collectively, our study shows that early and transient subpopulation-specific responses of MLEC to hypoxia may determine the degree of organ dysfunction in later stages. In this context, NFAT5 acts as a protective transcription factor required to rapidly adjust the endothelial transcriptome to cope with hypoxia. Specifically, NFAT5 restricts HIF1α-mediated Pdgfb expression and consequently limits muscularization and resistance of the pulmonary vasculature., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Pulmonary hypertension, characterized by vascular remodeling, currently lacks curative therapeutic options. The dysfunction of pulmonary artery endothelial cells plays a pivotal role in the initiation and progression of pulmonary hypertension (PH). ErbB3 (human epidermal growth factor receptor 3), also recognized as HER3, is a member of the ErbB family of receptor tyrosine kinases., Methods: Microarray, immunofluorescence, and Western blotting analyses were conducted to investigate the pathological role of ErbB3. Blood samples were collected for biomarker examination from healthy donors or patients with hypoxic PH. The pathological functions of ErbB3 were further validated in rodents subjected to chronic hypoxia- and Sugen-induced PH, with or without adeno-associated virus-mediated ErbB3 overexpression, systemic deletion, or endothelial cell-specific ErbB3 knockdown. Primary human pulmonary artery endothelial cells and pulmonary artery smooth muscle cells were used to elucidate the underlying mechanisms., Results: ErbB3 exhibited significant upregulation in the serum, lungs, distal pulmonary arteries, and pulmonary artery endothelial cells isolated from patients with PH compared with those from healthy donors. ErbB3 overexpression stimulated hypoxia-induced endothelial cell proliferation, exacerbated pulmonary artery remodeling, elevated systolic pressure in the right ventricle, and promoted right ventricular hypertrophy in murine models of PH. Conversely, systemic deletion or endothelial cell-specific knockout of ErbB3 yielded opposite effects. Coimmunoprecipitation and proteomic analysis identified YB-1 (Y-box binding protein 1) as a downstream target of ErbB3. ErbB3 induced nuclear translocation of YB-1 and subsequently promoted hypoxia-inducible factor 1/2α transcription. A positive loop involving ErbB3-periostin-hypoxia-inducible factor 1/2α was identified to mediate the progressive development of this disease. MM-121, a human anti-ErbB3 monoclonal antibody, exhibited both preventive and therapeutic effects against hypoxia-induced PH., Conclusions: Our study reveals, for the first time, that ErbB3 serves as a novel biomarker and a promising target for the treatment of PH., Competing Interests: None.

Genetic backgrounds of patients with pulmonary arterial hypertension (PAH) were not fully investigated. A variant of c.14429G > A (p.Arg4810Lys) in the ring finger protein 213 gene (RNF213) was recently identified as a risk allele for poor treatment response and poor clinical prognosis in patients with PAH. However, the molecular mechanisms of the RNF213 p.Arg4810Lys variant in development of PAH are unknown. We investigated the underlying molecular mechanisms of RNF213-associated vasculopathy using an in vivo mouse model. RNF213 +/p.Arg4828Lys mice, harboring the heterozygous RNF213 p.Arg4828Lys variant corresponding to the p.Arg4810Lys variant in humans, were created using the CRISPR-Cas9 system to recapitulate the genetic status of PAH patients. RNF213 +/p.Arg4828Lys mice had a significant elevation of the right ventricular systolic pressure, hypertrophy of the right ventricle, and increased thickness of the pulmonary arterial medial wall compared with wild-type mice after 3 months of exposure to a hypoxic environment. C-X-C motif chemokine ligand 12 (CXCL12), a C-X-C chemokine receptor type 4 (CXCR4) ligand, was significantly elevated in the lungs of RNF213 +/p.Arg4828Lys mice, and PAH was ameliorated by the administration of a CXCR4 antagonist. CXCL12-CXCR4 is an angiogenic chemokine axis, and immunohistochemistry demonstrated an increase in CXCR4 in vimentin-positive spindle-shaped cells in adventitia and interstitial lesions in RNF213 +/p.Arg4828Lys mice and lung specimens from severe PAH patients with the RNF213 p.Arg4810Lys variant. We confirmed a cause-and-effect relationship between the RNF213 p.Arg4810Lys variant and PAH via the CXCL12-CXCR4 pathway. The findings in this study suggest that targeting this pathway might be a novel therapeutic strategy for RNF213-associated vasculopathy., (© 2024. The Author(s).)

Impaired pulmonary angiogenesis plays a pivotal role in the progression of pulmonary arterial hypertension (PAH) and patient mortality, yet the molecular mechanisms driving this process remain enigmatic. Our study uncovered a striking connection between mitochondrial dysfunction (MD), caused by a humanized mutation in the NFU1 gene, and severely disrupted pulmonary angiogenesis in adult lungs. Restoring the bioavailability of the NFU1 downstream target, lipoic acid (LA), alleviated MD and angiogenic deficiency and rescued the progressive PAH phenotype in the NFU1G206C model. Notably, significant NFU1 expression and signaling insufficiencies were also identified in idiopathic PAH (iPAH) patients' lungs, emphasizing this study's relevance beyond NFU1 mutation cases. The remarkable improvement in mitochondrial function of PAH patient-derived pulmonary artery endothelial cells (PAECs) following LA supplementation introduces LA as a potential therapeutic approach. In conclusion, this study unveils a novel role for MD in dysregulated pulmonary angiogenesis and PAH manifestation, emphasizing the need to correct MD in PAH patients with unrecognized NFU1/LA deficiency., (© 2024 Niihori et al.)

Objective: In our study, we aim to explore the structural differences between the aortic root and the pulmonary artery to better understand the process of pulmonary autograft dilatation during the Ross procedure., Materials and Methods: We studied twenty human fetuses (aged 14-36 weeks of gestation) and four adults (one female and three males, aged 30-45 years, mean age = 37 ± 16 years). Samples of aortic root and pulmonary artery were obtained through dissection. Histological examinations, including hematoxylin-eosin, Masson's trichrome, and orcein staining, as well as immunohistochemical technique with caldesmon staining, were performed. Microscopic counting was conducted to assess the number of elastic laminae and smooth muscle cells in each arterial wall. Statistical analyses were performed using R software. Means and standard deviations were used to present central tendencies and data dispersion for elastic laminae and smooth muscle., Results: Significant histological differences were observed between the aortic root and pulmonary artery in both adults and fetuses. In fetuses, no difference was found between the two vessels in terms of elastic laminae (p = 0.26) and smooth muscle cells (p = 0.69). However, in adults, significant differences were found for elastic laminae (p < 0.001) and smooth muscle cells (p < 0.001) between the aorta and pulmonary artery., Conclusions: The microscopic vascular structure impacts the mechanical properties of the pulmonary autograft wall and explains its observed dilatation remote from the Ross procedure due to wall stresses related to systemic pressure., (© 2024. The Author(s).)

Pulmonary hypertension (PH) is a progressive cardiopulmonary disease characterized by elevated pulmonary artery pressure and vascular remodeling, resulting in poor prognosis and increased mortality rates. Chemokine-like factor 1 (CKLF1) plays a significant role in inducing inflammation and cell proliferation, both of which are critical processes in the pathogenesis of various diseases. Dihydromyricetin (DMY) has garnered attention for its potent anti-inflammatory properties. This study evaluated the protective effects of DMY against PH, demonstrating that DMY treatment can mitigate pyroptosis in pulmonary artery endothelial cells (PAECs) and pulmonary artery smooth muscle cells (PASMCs) in vivo via the CKLF1/CCR5 axis. Results indicated significant improvements in hemodynamics, inflammatory responses, fibrosis, vascular remodeling, and right ventricular hypertrophy in PH rats following DMY treatment. Furthermore, the interaction between CKLF1 and CCR5 was investigated in CKLF1 -/- rats after PH induction. DMY was found to downregulate CKLF1 expression and the inflammatory response in the lungs, with its therapeutic efficacy diminished following CKLF1 knockdown. This study underscores the therapeutic potential of DMY in the management of PH and lays a foundation for future research and clinical applications., Competing Interests: Declaration of Competing Interest The author declares that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Pulmonary arterial hypertension (PAH) is a chronic and fatal disease characterized by pulmonary vascular remodeling, similar to the 'Warburg effect' observed in cancer, which is caused by reprogramming of glucose metabolism. Oroxylin A (OA), an active compound derived from Scutellaria baicalensis , which can inhibit glycolytic enzymes [hexokinase 2 (HK2), Lactate dehydrogenase (LDH), and pyruvate dehydrogenase kinase 1 (PDK1) by downregulating aerobic glycolysis to achieve the treatment of liver cancer. To the best of our knowledge, however, the impact of OA on PAH has not been addressed. Consequently, the present study aimed to evaluate the potential protective role and mechanism of OA against PAH induced by monocrotaline (MCT; 55 mg/kg). The mean pulmonary artery pressure (mPAP) was measured using the central venous catheter method; HE and Masson staining were used to observe pulmonary artery remodeling. Non‑targeted metabolomics was used to analyze the metabolic pathways and pathway metabolites in MCT‑PAH rats. Western Blot analysis was employed to assess the levels of glucose transporter 1 (Glut1), HK2), pyruvate kinase (PK), isocitrate dehydrogenase 2 (IDH2), pyruvate dehydrogenase kinase 1(PDK1), and lactate dehydrogenase (LDH) protein expression in both lung tissue samples from MCT‑PAH rats. The results demonstrated that intragastric administration of OA (40 and 80 mg/kg) significantly decreased mPAP from 43.61±1.88 mmHg in PAH model rats to 26.51±1.53 mmHg and relieve pulmonary artery remodeling. Untargeted metabolomic analysis and multivariate analysis indicated abnormal glucose metabolic pattern in PAH model rats, consistent with the Warburg effect. OA administration decreased this effect on the abnormal glucose metabolism. The protein levels of key enzymes involved in glucose metabolism were evaluated by western blotting, which demonstrated that OA could improve aerobic glycolysis and inhibit PAH by decreasing the protein levels of Glut1, HK2, LDH, PDK1 and increasing the protein levels of PK and IDH2. In conclusion, OA decreased MCT‑induced PAH in rats by reducing the Warburg effect.

Cardiac tamponade from ruptured intrathoracic organs can lead to sudden cardiac death. In rare circumstances, the pulmonary artery can be the source of hemopericardium. We describe a case of a 62-year-old woman with no significant past medical history, who presented with sudden unexpected death. A forensic autopsy revealed 500 ml of hemopericardium. Further dissection demonstrated a saccular aneurysm in the pulmonary artery trunk, along with the evidence of prior dissection, i.e., neointimal layer. Persistent ductus arteriosus (PDA) was also present. Pulmonary artery aneurysms (PAA) are rare and often associated with congenital heart disease (CHD). PDA is the most common CHD related to PAA. Secondary pulmonary hypertension makes the pulmonary artery vulnerable to medial degeneration and increases the risk of dissection and rupture. Careful inspection of the great vessels and congenital anomalies are essential in the forensic autopsies for sudden death investigation., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Pulmonary thrombotic arteriopathy (PTA) can be an incidental finding in lung resections performed for various indications. Historic studies largely examined PTA in autopsies. Thus, the prevalence in surgical samples, particularly in the modern era of lung cancer screening, is poorly defined. Detection of PTA in surgical samples may provide an opportunity for therapeutic intervention, but the impact of this finding on clinical management is unknown. We retrospectively examined consecutive lung surgical resections containing a report of incidental PTA between 2019 and 2022 in our institution. A retrospective chart review was performed to determine the history of systemic thromboembolism and clinical and radiographic follow-up. All slides were reviewed to morphologically characterize the vascular changes. Among 2930 pulmonary resections, 66 (2.3%) reportedly contained PTA. Twenty-four (36.4%) patients had a clinically recognized thromboembolic event either before or after surgical resection. Patients with clinically recognized thromboembolic disease were significantly more likely to have both acute and organized thrombi affecting large arteries. The presence of infarct, chronic hypertensive vasculopathy, or number of vessels with thrombi were not significantly associated with a clinically detected event. Reporting of incidental PTA led to clinical intervention in six patients and confirmed systemic thromboembolic disease in 2. Moreover, 2 patients with no further workup based on the incidental pathology findings subsequently developed pulmonary embolism. PTA is incidentally detected in 2.3% of surgical lung resections, and in two-thirds of cases, there is no clinical suspicion of thromboembolic disease. Pathologic reporting of PTA rarely led to clinical intervention, suggesting a need for improved communication of incidental pathology findings., Competing Interests: Conflicts of Interest and Source of Funding: L.M.S.: Consulting for Genentech, Lilly; Research support from Genentech, Bristol Myers Squibb. A.G. is supported by a fellowship grant from the Fonds de Recherche du Québec-Santé. For the remaining authors, none were declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The role of stress granules (SGs) in pulmonary arterial hypertension (PAH) is unknown. We hypothesized that SG formation contributes to abnormal vascular phenotypes, and cardiac and skeletal muscle dysfunction in PAH. Using the rat Sugen/hypoxia (SU/Hx) model of PAH, we demonstrate the formation of SG puncta and increased expression of SG proteins compared to control animals in lungs, right ventricles, and soleus muscles. Acetazolamide (ACTZ) treatment ameliorated the disease and reduced SG formation in all of these tissues. Primary pulmonary artery smooth muscle cells (PASMCs) from diseased animals had increased SG protein expression and SG number after acute oxidative stress and this was ameliorated by ACTZ. Pharmacologic inhibition of SG formation or genetic ablation of the SG assembly protein (G3BP1) altered the SU/Hx-PASMC phenotype by decreasing proliferation, increasing apoptosis and modulating synthetic and contractile marker expression. In human PAH lungs, we found increased SG puncta in pulmonary arteries compared to control lungs and in human PAH-PASMCs we found increased SGs after acute oxidative stress compared to healthy PASMCs. Genetic ablation of G3BP1 in human PAH-PASMCs resulted in a phenotypic switch to a less synthetic and more contractile phenotype. We conclude that increased SG formation in PASMCs and other tissues may contribute to PAH pathogenesis.

Background: Integrative multiomics can elucidate pulmonary arterial hypertension (PAH) pathobiology, but procuring human PAH lung samples is rare., Methods: We leveraged transcriptomic profiling and deep phenotyping of the largest multicenter PAH lung biobank to date (96 disease and 52 control) by integration with clinicopathologic data, genome-wide association studies, Bayesian regulatory networks, single-cell transcriptomics, and pharmacotranscriptomics., Results: We identified 2 potentially protective gene network modules associated with vascular cells, and we validated ASPN , coding for asporin, as a key hub gene that is upregulated as a compensatory response to counteract PAH. We found that asporin is upregulated in lungs and plasma of multiple independent PAH cohorts and correlates with reduced PAH severity. We show that asporin inhibits proliferation and transforming growth factor-β/phosphorylated SMAD2/3 signaling in pulmonary artery smooth muscle cells from PAH lungs. We demonstrate in Sugen-hypoxia rats that ASPN knockdown exacerbated PAH and recombinant asporin attenuated PAH., Conclusions: Our integrative systems biology approach to dissect the PAH lung transcriptome uncovered asporin as a novel protective target with therapeutic potential in PAH., Competing Interests: Drs Hong, Medzikovic, and Eghbali are coinventors of US provisional patent application 63/544,027, “Asporin in Pulmonary Hypertension.”

Aims: Pulmonary vascular and right ventricular (RV) remodelling processes are important for development and progression of pulmonary hypertension (PH). The current study analysed the functional role of the extra domain A-containing fibronectin (ED-A+ Fn) for the development of PH by comparing ED-A+ Fn knockout (KO) and wild-type (WT) mice as well as the effects of an antibody-based therapeutic approach in a model of monocrotaline (MCT)-induced PH, which will be validated in a model of Sugen 5416/hypoxia-induced PH., Methods and Results: PH was induced using MCT (PH mice). Sixty-nine mice were divided into the following groups: sham-treated controls (WT: n = 7; KO: n = 7), PH mice without specific treatment (WT: n = 12; KO: n = 10), PH mice treated with a dual endothelin receptor antagonist (macitentan; WT: n = 6; KO: n = 11), WT PH mice treated with the F8 antibody, specifically recognizing ED-A+ Fn, (n = 8), and WT PH mice treated with an antibody of irrelevant antigen specificity (KSF, n = 8). Compared to controls, WT&#95;PH mice showed a significant elevation of the RV systolic pressure (P = 0.04) and RV functional impairment including increased basal RV (P = 0.016) diameter or tricuspid annular plane systolic excursion (P = 0.008). In contrast, KO PH did not show such effects compared to controls (P = n.s.). In WT&#95;PH mice treated with F8, haemodynamic and echocardiographic parameters were significantly improved compared to untreated WT&#95;PH mice or those treated with the KSF antibody (P < 0.05). On the microscopic level, KO&#95;PH mice showed significantly less tissue damage compared to the WT&#95;PH mice (P = 0.008). Furthermore, lung tissue damage could significantly be reduced after F8 treatment (P = 0.04). Additionally, these findings could be verified in the Sugen 5416/hypoxia mouse model, in which F8 significantly improved echocardiographic, haemodynamic, and histologic parameters., Conclusion: ED-A+ Fn is of crucial importance for PH pathogenesis representing a promising therapeutic target in PH. We here show a novel therapeutic approach using antibody-mediated functional blockade of ED-A+ Fn capable of attenuating and partially reversing PH-associated tissue remodelling., Competing Interests: Conflict of interest: M.M. is an employee of Philochem AG (www.philochem.ch), daughter company of Philogen. M.F. obtained financial support from Philogen (www.philogen.com). A.B., P.C.S., and M.F. have transferred IP rights to Philogen (www.philogen.com) concerning antibody–cytokine fusions. D.N. is CEO and shareholder of Philogen (www.philogen.com), a company working on the discovery and development of targeted therapeutics, including antibody–cytokine fusions. The remaining co-authors did not declare any conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Induction of resistin-like molecule β (Relm-β) and mitofusin 2 (MFN2) mediated aberrant mitochondrial fission have been found to be involved in the pathogenesis of pulmonary arterial hypertension (PAH). However, the molecular mechanisms underlying Relm-β regulation of MFN2 therefore mitochondrial fission remain unclear. This study aims to address these issues. Primary cultured PASMCs and monocrotaline (MCT)-induced PAH rats were applied in this study. The results showed that Relm-β promoted cells proliferation in PASMCs, this was accompanied with the upregulation of USP18, Twist1 and miR-214, and downregulation of MFN2. We found that Relm-β increased USP18 expression which in turn raised Twist1 by suppressing its proteasome degradation. Elevation of Twist1 increased miR-214 expression and then reduced MFN2 expression and mitochondrial fragmentation leading to PASMCs proliferation. In vivo study, we confirmed that Relm-β was elevated in MCT-induced PAH rat model, and USP18/Twist1/miR-214/MFN2 axis was altered similar as in vitro. Targeting this cascade by Relm-β receptor inhibitor Calhex231, proteasome inhibitor MG-132, Twist1 inhibitor Harmine or miR-214 antagomiR prevented the development of pulmonary vascular remodeling and therefore PAH in MCT-treated rats. In conclusion, we demonstrate that Relm-β promotes PASMCs proliferation and vascular remodeling by activating USP18/Twist1/miR-214 dependent MFN2 reduction and mitochondrial fission, suggesting that this signaling pathway might be a promising target for management of PAH., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Phenotypic transformation of pulmonary artery smooth muscle cells (PASMCs) contributes to vascular remodeling in hypoxic pulmonary hypertension (PH). Recent studies have suggested that circular RNAs (circRNAs) may play important roles in the vascular remodeling of hypoxia-induced PH. However, whether circRNAs cause pulmonary vascular remodeling by regulating the phenotypic transformation in PH has not been investigated. Microarray and RT-qPCR analysis identified that circLMBR1, a novel circRNA, decreased in mouse lung tissues of the hypoxia-SU5416 PH model, as well as in human PASMCs and mouse PASMCs exposed to hypoxia. Overexpression of circLMBR1 in the Semaxinib (SU5416) mouse model ameliorated hypoxia-induced PH and vascular remodeling in the lungs. Notably, circLMBR1 was mainly distributed in the nucleus and bound to the splicing factor PUF60. CircLMBR1 suppressed the phenotypic transformation of human PASMCs and vascular remodeling by inhibiting PUF60 expression. Furthermore, we identified U2AF65 as the downstream regulatory factor of PUF60. U2AF65 directly interacted with the pre-mRNA of the contractile phenotype marker smooth muscle protein 22-α (SM22α) and inhibited its splicing. Meanwhile, hypoxia exposure increased the formation of the PUF60-U2AF65 complex, thereby inhibiting SM22α production and inducing the transition of human PASMCs from a contractile phenotype to a synthetic phenotype. Overall, our results verified the important role of circLMBR1 in the pathological process of PH. We also proposed a new circLMBR1/PUF60-U2AF65/pre-SM22α pathway that could regulate the phenotypic transformation and proliferation of human PASMCs. This study may provide new perspectives for the diagnosis and treatment of PH., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Pulmonary arterial hypertension (PAH) is a worldwide challenging disease characterized by progressive elevation of pulmonary artery pressure. The proliferation, migration and phenotypic transformation of pulmonary smooth muscle cells are the key steps of pulmonary vascular remodeling. Quercetin (3,3', 4', 5, 6-pentahydroxyflavone, Que) is a natural flavonol compound that has antioxidant, anti-inflammatory, anti-tumor and other biological activities. Studies have shown that Que has therapeutic effects on PAH. However, the effect of quercetin on pulmonary vascular remodeling in PAH and its mechanism remain unclear., Methods and Results: In vivo, PAH rats were constructed by intraperitoneal injection of monocrotaline (MCT) at 60 mg/kg. Human pulmonary artery smooth muscle cells (HPASMCs) were treated with platelet-derived growth factor BB (PDGF-BB) 20 ng/mL to construct PAH cell model in vitro. The results showed that in vivo studies, MCT could induce right ventricular wall hyperplasia, narrow the small and medium pulmonary artery cavity, up-regulate the expression of proliferating and migration-related proteins proliferating cell nuclear antigen (PCNA) and osteopontin (OPN), and down-regulate the expression of alpha-smooth muscle actin (α-SMA). Que reversed the MCT-induced results. This process works by down-regulating the transforming growth factor-β1 (TGF-β1)/ Smad2/3 signaling pathway. In vitro studies, Que had the same effect on PDGF-BB-induced proliferation and migration cell models., Conclusions: Que inhibits the proliferation, migration and phenotypic transformation of HPASMCs by down-regulating TGF-β1/Smad2/Smad3 pathway, thereby reducing right ventricular hyperplasia (RVH) and pulmonary vascular remodeling, providing potential pharmacological and molecular explanations for the treatment of PAH., (© 2024. The Author(s).)

Background: In chronic obstructive pulmonary disease (COPD), vascular alterations have been shown to contribute to hypoxia and pulmonary hypertension, but the independent contribution of small vessel abnormalities to mortality remains unclear., Methods: We quantified artery and vein dimensions on computed tomography (CT) down to 0.2 mm. Small vessel volumes (<1 mmᴓ) were normalized by body surface area. In 7903 current and former smokers of the COPDGene study (53.2% male) the independent contribution of small artery and small vein volume to all-cause mortality was tested in multivariable Cox models. Additionally, we calculated the 95 th percentile of small arteries and veins in 374 never smokers to create two groups: normal and high small artery or vein volume. We describe clinical, physiological and imaging characteristics of subjects with a high small artery and high small vein volume., Findings: Both high small artery and high small vein volumes were independently associated with mortality with an adjusted hazard ratio of 1.07 [1.01, 1.14] and 1.34 [1.21, 1.49] per mL/m 2 increase, respectively. In COPDGene, 447 (5.7%) had high small artery volume and 519 (9.1%) subjects had high small vein volume and both had more emphysema, more air trapping and more severe coronary calcium., Interpretation: In smokers, abnormally high volumes in small arteries and veins are both relevant for mortality, which urges investigations into the aetiology of small pulmonary vessels and cardiac function in smokers., Funding: Award Number U01-HL089897 and U01-HL089856 from the NHLBI. COPD Foundation with contributions from AstraZeneca, Boehringer Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, Siemens, and Sunovion., Competing Interests: Declaration of interests AK, EA, TV, EP: no conflicts relevant to this manuscript. DL and SH: the department of radiology of National Jewish Health received grant support from the NHLBI. PdJ: The Department of Radiology from the UMC Utrecht receives research support from Philips Healthcare. JPC: employee and shareholder of Thirona. LGE, HT: employee of Thirona., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Pyroptosis, inflammatory necrosis of cells, is a programmed cell death involved in the pathological process of diseases. Endoplasmic reticulum stress (ERS), as a protective stress response of cell, decreases the unfold protein concentration to inhibit the unfold protein agglutination. Whereas the relationship between endoplasmic reticulum stress and pyroptosis in pulmonary hypertension (PH) remain unknown. Previous evident indicated that circular RNA (circRNA) can participate in several biological process, including cell pyroptosis. However, the mechanism of circRNA regulate pyroptosis of pulmonary artery smooth muscle cells through endoplasmic reticulum stress still unclear. Here, we proved that circSSR1 was down-regulate expression during hypoxia in pulmonary artery smooth muscle cells, and over-expression of circSSR1 inhibit pyroptosis both in vitro and in vivo under hypoxic. Our experiments have indicated that circSSR1 could promote host gene SSR1 translation via m6A to activate ERS leading to pulmonary artery smooth muscle cell pyroptosis. In addition, our results showed that G3BP1 as upstream regulator mediate the expression of circSSR1 under hypoxia. These results highlight a new regulatory mechanism for pyroptosis and provide a potential therapy target for pulmonary hypertension., Methods: RNA-FISH and qRT-PCR were showed the location of circSSR1 and expression change. RNA pull-down and RIP verify the circSSR1 combine with YTHDF1. Western blotting, PI staining and LDH release were used to explore the role of circSSR1 in PASMCs pyroptosis., Results: CircSSR1 was markedly downregulated in hypoxic PASMCs. Knockdown CircSSR1 inhibited hypoxia induced PASMCs pyroptosis in vivo and in vitro. Mechanistically, circSSR1 combine with YTHDF1 to promote SSR1 protein translation rely on m6A, activating pyroptosis via endoplasmic reticulum stress. Furthermore, G3BP1 induce circSSR1 degradation under hypoxic., Conclusion: Our findings clarify the role of circSSR1 up-regulated parental protein SSR1 expression mediate endoplasmic reticulum stress leading to pyroptosis in PASMCs, ultimately promoting the development of pulmonary hypertension., (© 2024. The Author(s).)

Background: Pulmonary hypertension is a rare, progressive disorder that can lead to right ventricular hypertrophy, right heart failure, and even sudden death. N6-methyladenosine modification and the main methyltransferase that mediates it, methyltransferase-like (METTL) 3, exert important effects on many biological and pathophysiological processes. However, the role of METTL3 in pyroptosis remains unclear., Methods and Results: Here, we characterized the role of METTL3 and the underlying cellular and molecular mechanisms of pyroptosis, which is involved in pulmonary hypertension. METTL3 was downregulated in a pulmonary hypertension mouse model and in hypoxia-exposed pulmonary artery smooth muscle cell. The small interfering RNA-induced silencing of METTL3 decreased the m6A methylation levels and promoted pulmonary artery smooth muscle cell pyroptosis, mimicking the effects of hypoxia. In contrast, overexpression of METTL3 suppressed hypoxia-induced pulmonary artery smooth muscle cell pyroptosis. Mechanistically, we identified the phosphate and tension homology deleted on chromosome 10 (PTEN) gene as a target of METTL3-mediated m6A modification, and methylated phosphate and tension homology deleted on chromosome 10 mRNA was subsequently recognized by the m6A "reader" protein insulin-like growth factor 2 mRNA-binding protein 2, which directly bound to the m6A site on phosphate and tension homology deleted on chromosome 10 mRNA and enhanced its stability., Conclusions: These results identify a new signaling pathway, the METTL3/phosphate and tension homology deleted on chromosome 10/insulin-like growth factor 2 mRNA-binding protein 2 axis, that participates in the regulation of hypoxia-induced pyroptosis.

Background: Sympathetic hyperactivity plays an important role in the initiation and maintenance of pulmonary hypertension. Carotid baroreceptor stimulation (CBS) is an effective autonomic neuromodulation therapy. We aim to investigate the effects of CBS on hypoxia-induced pulmonary hypertension and its underlying mechanisms., Methods and Results: Rats were randomly assigned into 4 groups, including a Control-sham group (n=7), a Control-CBS group (n=7), a Hypoxia-sham group (n=10) and a Hypoxia-CBS group (n=10). Echocardiography, ECG, and hemodynamics examination were performed. Samples of blood, lung tissue, pulmonary arteries, and right ventricle were collected for the further analysis. In the in vivo study, CBS reduced wall thickness and muscularization degree in pulmonary arterioles, thereby improving pulmonary hemodynamics. Right ventricle hypertrophy, fibrosis and dysfunction were all improved. CBS rebalanced autonomic tone and reduced the density of sympathetic nerves around pulmonary artery trunks and bifurcations. RNA-seq analysis identified BDNF and periostin ( POSTN ) as key genes involved in hypoxia-induced pulmonary hypertension, and CBS downregulated the mRNA expression of BDNF and POSTN in rat pulmonary arteries. In the in vitro study, norepinephrine was found to promote pulmonary artery smooth muscle cell proliferation while upregulating BDNF and POSTN expression. The proliferative effect was alleviated by silence BDNF or POSTN ., Conclusions: Our results showed that CBS could rebalance autonomic tone, inhibit pulmonary arterial remodeling, and improve pulmonary hemodynamics and right ventricle function, thus delaying hypoxia-induced pulmonary hypertension progression. There may be a reciprocal interaction between POSTN and BDNF that is responsible for the underlying mechanism.

Background: G6PD (glucose-6-phosphate-dehydrogenase) is a key enzyme in the glycolytic pathway and has been implicated in the pathogenesis of cancer and pulmonary hypertension-associated vascular remodeling. Here, we investigated the role of an X-linked G6pd mutation (N126D polymorphism), which is known to increase the risk of cardiovascular disease in individuals from sub-Saharan Africa and many others with African ancestry, in the pathogenesis of pulmonary hypertension induced by a vascular endothelial cell growth factor receptor blocker used for treating cancer., Methods and Results: CRISPR-Cas9 genome editing was used to generate the G6pd variant (N126D; G6pd N126D ) in rats. A single dose of the vascular endothelial cell growth factor receptor blocker sugen-5416 (SU; 20 mg/kg in DMSO), which is currently in a Phase 2/3 clinical trial for cancer treatment, was subcutaneously injected into G6pd N126D rats and their wild-type littermates. After 8 weeks of normoxic conditions, right ventricular pressure and hypertrophy, pulmonary artery remodeling, the metabolic profile, and cytokine expression were assessed. Right ventricular pressure and pulmonary arterial wall thickness were increased in G6PD N126D +SU/normoxic rats. Simultaneously, levels of oxidized glutathione, inositol triphosphate, and intracellular Ca 2+ were increased in the lungs of G6PD N126D +SU/normoxic rats, whereas nitric oxide was decreased. Also increased in G6PD N126D +SU/normoxic rats were pulmonary levels of plasminogen activator inhibitor-1, thrombin-antithrombin complex, and expression of proinflammatory cytokines CCL3 (chemokine [C-C motif] ligand), CCL5, and CCL7., Conclusions: Our results suggest G6PD N126D increases inositol triphosphate-Ca 2+ signaling, inflammation, thrombosis, and hypertrophic pulmonary artery remodeling in SU-treated rats. This suggests an increased risk of vascular endothelial cell growth factor receptor blocker-induced pulmonary hypertension in those carrying this G6PD variant.

Pulmonary hypertension (PH) is a progressive cardiopulmonary disorder characterized by pulmonary vascular remodeling (PVR), primarily due to the excessive proliferation of pulmonary artery smooth muscle cells (PASMCs). This study aimed to investigate the role and molecular mechanism of SOX9 in hypoxic PH in rats. The findings revealed that SOX9 was upregulated in the pulmonary arteries and PASMCs of hypoxia-exposed rats. SOX9 knockdown inhibited hypoxia-induced proliferation and migration of PASMCs, reduced PVR, and subsequently alleviated hypoxia-induced PH in rats, suggesting that SOX9 plays a critical role in PH. Further investigation demonstrated that SOX9 interacted with DPP4, preventing its ubiquitin degradation in hypoxia-exposed PASMCs. DPP4 knockdown inhibited hypoxia-induced PASMC proliferation and migration, and administration of the DPP4 inhibitor sitagliptin (5 mg/kg) significantly reduced PVR and alleviated hypoxia-induced PH in rats, indicating that SOX9 contributes to PH by stabilizing DPP4. The results also showed that hypoxia induced YAP1 expression and dephosphorylation, leading to YAP1 nuclear localization. YAP1 knockdown promoted the degradation of HIF-1α in hypoxia-exposed PASMCs and inhibited hypoxia-induced proliferation and migration of PASMCs. Additionally, HIF-1α, as a transcription factor, promoted SOX9 expression by binding to the SOX9 promoter in hypoxia-exposed PASMCs. In conclusion, hypoxia promotes the proliferation and migration of PASMCs through the regulation of the YAP1/HIF-1α/SOX9/DPP4 signaling pathway, leading to PH in rats. These findings suggest that SOX9 may serve as a potential prognostic marker and therapeutic target for PH., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Pulmonary arterial hypertension (PAH) is a debilitating vascular disorder characterized by abnormal pulmonary artery smooth muscle cell (PASMC) proliferation and collagen synthesis, contributing to vascular remodeling and elevated pulmonary vascular resistance. This study investigated the critical role of 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase (ATIC) in cell proliferation and collagen synthesis in PASMCs in PAH. Here we show that ATIC levels are significantly increased in the lungs of monocrotaline (MCT)-induced PAH rat model, hypoxia-induced PAH mouse model, and platelet-derived growth factor (PDGF)-stimulated PASMCs. Inhibition of ATIC attenuated PDGF-induced cell proliferation and collagen I synthesis in PASMCs. Conversely, overexpression or knockdown of ATIC causes a significant promotion or inhibition of Ras and ERK activation, cell proliferation, and collagen synthesis in PASMCs. Moreover, ATIC deficiency attenuated Ras activation in the lungs of hypoxia-induced PAH mice. Furthermore, Ras inhibition attenuates ATIC overexpression- and PDGF-induced collagen synthesis and PASMC proliferation. Notably, we identified that transcription factors MYC, early growth response protein 1 (EGR1), and specificity protein 1 (SP1) directly binds to promoters of Atic gene and regulate ATIC expression. These results provide the first evidence that ATIC promotes PASMC proliferation in pulmonary vascular remodeling through the Ras signaling pathway. NEW & NOTEWORTHY Our findings highlight the important role of ATIC in the PASMC proliferation of pulmonary vascular remodeling through its modulation of the Ras signaling pathway and its regulation by transcription factors MYC, EGR1, and SP1. ATIC's modulation of Ras signal pathway represents a novel mechanism contributing to PAH development.

Pulmonary arterial hypertension (PAH) is an obstructive vasculopathy that, if not promptly treated, culminates in right heart failure. Therefore, pre-clinical studies are needed to support and optimize therapeutic approaches of PAH. Here, we explore a prospective function of sevoflurane in experimental PAH through regulating TRAF6. Monocrotaline (MCT)-induced PAH rats were subjected to sevoflurane inhalation and intratracheal instillation of lentivirus overexpressing TRAF6. Platelet-derived growth factor (PDGF)-treated pulmonary artery smooth muscle cells (PASMCs) were exposed to sevoflurane and genetically manipulated for TRAF6 overexpression. It was found that MCT and PDGF challenge upregulated the levels of TRAF6 in rat lung tissues and PASMCs, but sevoflurane treatment led to reduced TRAF6 expression. Sevoflurane inhalation in MCT-induced rats resulted in alleviative pulmonary vascular remodeling, mitigated right ventricular dysfunction and hypertrophy, improved mitochondrial function and dynamics, and inactivation of NF-κB pathway. In vitro studies confirmed that exposure to sevoflurane repressed PDGF-induced proliferation, migration, and phenotype switching of PASMCs, and suppressed mitochondrial dysfunction and NF-κB activation in PDGF-stimulated PASMCs. The beneficial impact of sevoflurane on pathological changes of lung and cell phenotype of PASMCs were reversed by overexpression of TRAF6. In summary, our study suggested the protective properties of sevoflurane in targeting PAH by downregulating TRAF6 expression, providing a novel avenue for the management of PAH., Competing Interests: Declaration of competing interest The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Sex differences are recognized in pulmonary hypertension. However, the progression of disease with regard to vascular lesion formation and circulating cytokines/chemokines is unknown. To determine whether vascular lesion formation, changes in hemodynamics, and alterations in circulating chemokines/cytokines differ between males and females, we used a progressive model of pulmonary arterial hypertension (PAH), Sugen/hypoxia, and analyzed cohorts of male and female rats at time points suggested to indicate worsening disease. Our analysis included echocardiography for hemodynamics, morphometry, immunofluoresecence, and chemokine/cytokine analysis of plasma at each time point in both sexes. We found that male rats had significantly increased Fulton index, compared with those for females at each time point, as well as increased medial artery thickening at 8 weeks of PAH. Furthermore, females exhibited fewer obliterative vascular lesions than males at our latest time point. Our data also show increased IL-4, granulocyte-macrophage colony-stimulating factor, IL-10, and macrophage interacting protein-1α that were not observed in females, whereas females were observed to have increased RANTES (whose name derives from Regulated upon Activation, Normal T Cell Expressed and Presumably Secreted) and CXCL-10 that were not found in males. Males also have increased infiltrating macrophages in vascular lesions, compared with females. We found that development of progressive PAH in hemodynamics, morphology, and chemokine/cytokine circulation differs significantly between males and females. These data suggest a macrophage-driven pathology in males, whereas there may be T cell protection from vascular damage in females with PAH.

Hypoxic pulmonary hypertension (HPH) is a pathophysiological syndrome in which pulmonary vascular pressure increases under hypoxic stimulation and there is an urgent need to develop emerging therapies for the treatment of HPH. LncRNA MIR210HG is a long non-coding RNA closely related to hypoxia and has been widely reported in a variety of tumor diseases. But its mechanism in hypoxic pulmonary hypertension is not clear. In this study, we identified for the first time the potential effect of MIR210HG on disease progression in HPH. Furthermore, we investigated the underlying mechanism through which elevated levels of MIR210HG promotes the transition from a contractile phenotype to a synthetic phenotype in PASMCs under hypoxia via activation of autophagy-dependent ferroptosis pathway. While overexpression of HIF-2α in PASMCs under hypoxia significantly reversed the phenotypic changes induced by MIR210HG knockdown. We further investigated the potential positive regulatory relationship between STAT3 and the transcription of MIR210HG in PASMCs under hypoxic conditions. In addition, we established both in vivo and in vitro models of HPH to validate the differential expression of specific markers associated with hypoxia. Our findings suggest a potential mechanism of LncRNA MIR210HG in the progression of HPH and offer potential targets for disease intervention and treatment., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Conduit pulmonary arterial stiffening and the resultant increase in pulmonary vascular impedance have emerged as an important underlying driver of pulmonary arterial hypertension (PAH). Given that matrix deposition is central to vascular remodeling, we evaluated the role of the collagen cross-linking enzyme lysyl oxidase like 2 (LOXL2) in this study. Human pulmonary artery smooth muscle cells (PASMCs) subjected to hypoxia showed increased LOXL2 secretion. LOXL2 activity and expression were markedly higher in primary PASMCs isolated from the pulmonary arteries of the rat Sugen 5416 + hypoxia (SuHx) model of severe pulmonary hypertension (PH). Similarly, LOXL2 protein and mRNA levels were increased in the pulmonary arteries (PA) and lungs of rats with PH (SuHx and monocrotaline (MCT) models). Pulmonary arteries (PAs) isolated from the rats with PH exhibited hypercontractility to phenylephrine and attenuated vasorelaxation elicited by acetylcholine, indicating severe endothelial dysfunction. Tensile testing revealed a significant increase in PA stiffness in PH. Treatment with PAT-1251, a novel small-molecule LOXL2 inhibitor, improved active and passive properties of the PA ex vivo. There was an improvement in right heart function as measured by right ventricular pressure volume loops in vivo with PAT-1251. Importantly, PAT-1251 treatment ameliorated PH, resulting in improved pulmonary artery pressures, right ventricular remodeling, and survival. Hypoxia-induced LOXL2 activation is a causal mechanism in pulmonary artery stiffening in PH and pulmonary artery mechanical and functional decline. LOXL2 inhibition with PAT-1251 could be a promising approach to improve pulmonary artery pressures, right ventricular elastance, cardiac relaxation, and survival in PAH. NEW & NOTEWORTHY Pulmonary arterial stiffening contributes to the progression of PAH and the deterioration of right heart function. This study shows that LOXL2 is upregulated in rat models of PH. LOXL2 inhibition halts pulmonary vascular remodeling and improves PA contractility, endothelial function, and PA pressure, resulting in prolonged survival. Thus, LOXL2 is an important mediator of PA remodeling and stiffening in PH and a promising target to improve PA pressures and survival in PH.

Pulmonary artery stenosis (PAS) often presents in children with congenital heart disease, altering blood flow and pressure during critical periods of growth and development. Variability in stenosis onset, duration, and severity result in variable growth and remodeling of the pulmonary vasculature. Computational fluid dynamics (CFD) models enable investigation into the hemodynamic impact and altered mechanics associated with PAS. In this study, a one-dimensional (1D) fluid dynamics model was used to simulate hemodynamics throughout the pulmonary arteries of individual animals. The geometry of the large pulmonary arteries was prescribed by animal-specific imaging, whereas the distal vasculature was simulated by a three-element Windkessel model at each terminal vessel outlet. Remodeling of the pulmonary vasculature, which cannot be measured in vivo, was estimated via model-fitted parameters. The large artery stiffness was significantly higher on the left side of the vasculature in the left pulmonary artery (LPA) stenosis group, but neither side differed from the sham group. The sham group exhibited a balanced distribution of total distal vascular resistance, whereas the left side was generally larger in the LPA stenosis group, with no significant differences between groups. In contrast, the peripheral compliance on the right side of the LPA stenosis group was significantly greater than the corresponding side of the sham group. Further analysis indicated the underperfused distal vasculature likely moderately decreased in radius with little change in stiffness given the increase in thickness observed with histology. Ultimately, our model enables greater understanding of pulmonary arterial adaptation due to LPA stenosis and has potential for use as a tool to noninvasively estimate remodeling of the pulmonary vasculature., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Bronchopulmonary dysplasia (BPD) is characterized by impaired lung alveolar and vascular growth. We investigated the hypothesis that neonatal exposure to hyperoxia leads to persistent BPD phenotype caused by decreased expression of liver kinase B1 (LKB1), a key regulator of mitochondrial function. We exposed mouse pups from Postnatal Day (P)1 through P10 to 21% or 75% oxygen. Half of the pups in each group received metformin or saline intraperitoneally from P1 to P10. Pups were killed at P4 or P10 or recovered in 21% O 2 until euthanasia at P21. Lung histology and morphometry, immunofluorescence, and immunoblots were performed to detect changes in lung structure and expression of LKB1; downstream targets AMPK, PGC-1α, and electron transport chain (ETC) complexes; and Notch ligands Jagged 1 and delta-like 4. LKB1 signaling and in vitro angiogenesis were assessed in human pulmonary artery endothelial cells (exposed to 21% or 95% O 2 for 36 hours. Levels of LKB1, phosphorylated AMPK, PGC-1α, and ETC complexes were decreased in lungs at P10 and P21 in hyperoxia. Metformin increased LKB1, phosphorylated AMPK, PGC-1α, and ETC complexes at P10 and P21 in pups exposed to hyperoxia. Radial alveolar count was decreased, and mean linear intercept increased in pups exposed to hyperoxia at P10 and P21; these were improved by metformin. Lung capillary density was decreased in hyperoxia at P10 and P21 and was increased by metformin. In vitro angiogenesis was decreased in human pulmonary artery endothelial cells by 95% O 2 and was improved by metformin. Decreased LKB1 signaling may contribute to decreased alveolar and vascular growth in a mouse model of BPD.

In pulmonary hypertension (PHTN), a metabolic shift to aerobic glycolysis promotes a hyperproliferative, apoptosis-resistant phenotype in pulmonary arterial smooth muscle cells (PASMCs). Enhanced glycolysis induces extracellular acidosis, which can activate proton-sensing membrane receptors and ion channels. We previously reported that activation of the proton-gated cation channel acid-sensing ion channel 1a (ASIC1a) contributes to the development of hypoxic PHTN. Therefore, we hypothesize that enhanced glycolysis and subsequent acidification of the PASMC extracellular microenvironment activate ASIC1a in hypoxic PHTN. We observed decreased oxygen consumption rate and increased extracellular acidification rate in PASMCs from chronic hypoxia (CH)-induced PHTN rats, indicating a shift to aerobic glycolysis. In addition, we found that intracellular alkalization and extracellular acidification occur in PASMCs following CH and in vitro hypoxia, which were prevented by the inhibition of glycolysis with 2-deoxy-d-glucose (2-DG). Inhibiting H + transport/secretion through carbonic anhydrases, Na + /H + exchanger 1, or vacuolar-type H + -ATPase did not prevent this pH shift following hypoxia. Although the putative monocarboxylate transporter 1 (MCT1) and -4 (MCT4) inhibitor syrosingopine prevented the pH shift, the specific MCT1 inhibitor AZD3965 and/or the MCT4 inhibitor VB124 were without effect, suggesting that syrosingopine targets the glycolytic pathway independent of H + export. Furthermore, 2-DG and syrosingopine prevented enhanced ASIC1a-mediated store-operated Ca 2+ entry in PASMCs from CH rats. These data suggest that multiple H + transport mechanisms contribute to extracellular acidosis and that inhibiting glycolysis-rather than specific H + transporters-more effectively prevents extracellular acidification and ASIC1a activation. Together, these data reveal a novel pathological relationship between glycolysis and ASIC1a activation in hypoxic PHTN. NEW & NOTEWORTHY In pulmonary hypertension, a metabolic shift to aerobic glycolysis drives a hyperproliferative, apoptosis-resistant phenotype in pulmonary arterial smooth muscle cells. We demonstrate that this enhanced glycolysis induces extracellular acidosis and activates the proton-gated ion channel, acid-sensing ion channel 1a (ASIC1a). Although multiple H + transport/secretion mechanisms are upregulated in PHTN and likely contribute to extracellular acidosis, inhibiting glycolysis with 2-deoxy-d-glucose or syrosingopine effectively prevents extracellular acidification and ASIC1a activation, revealing a promising therapeutic avenue.

Objectives: Hughes-Stovin syndrome (HSS) is a rare inflammatory condition defined as pulmonary artery aneurysms (PAA) associated with deep vein thrombosis. It is similar to vascular involvement of Behçet's syndrome (BS), but differs in the absence of typical skin-mucosal findings. Whether HSS is a distinct entity or a form fruste of BS is debated. We formally compared HSS cases retrieved from the literature to BS patients with PAI followed by a tertiary centre., Methods: A systemic literature search using 'Hughes Stovin syndrome' as the key word covering the period between 2000 and 2023 revealed 58 (43 M/15 F) case reports (PROSPERO: CRD42023413537). We identified 74 (62M/12 F) BS patients with PAI followed up in a tertiary centre in Turkey from 2000 until 2020. We evaluated two cohorts head-to-head in terms of demographic and clinical features., Results: BS and HSS patients were found to be comparable with regard to several demographic, clinical and histopathological features. However, PAA were significantly more frequent and isolated pulmonary artery thrombosis (PAT) less common in HSS than that found in BS. Moreover, patients with HSS were more likely to be treated with anti-coagulants and vascular or surgical interventions, whereas less likely to receive immunosuppressive treatment., Conclusions: Our study indicates that HSS is indeed an 'incomplete form of BS'. It can be considered as evidence supporting the notion that the vascular phenotype develops independently from skin-mucosa lesions and uveitis in BS. However, HSS has been described mainly focusing on aneurysms, overlooking the aspect of in-situ thrombosis.

Pulmonary hypertension (PH) is characterized by excessive proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs), in which inflammatory signaling caused by activation of the NF-κB pathway plays an important role. A20 is an important negative regulator of the NF-κB pathway, and zinc promotes the expression of A20 and exerts a protective effect against various diseases (e.g. COVID19) by inhibiting the inflammatory signaling. The role of A20 and intracellular zinc signaling in PH has been explored, but the extracellular zinc signaling is not well understood, and whether zinc has protective effects on PH is still elusive. Using inductively coupled plasma mass spectrometry (ICP-MS), we studied the alteration of trace elements during the progression of monocrotaline (MCT)-induced PH and found that serum zinc concentration was decreased with the onset of PH accompanied by abnormalities of other three elements, including copper, chromium, and magnesium. Zinc chloride injection with the dosage of 5 mg/kg intraperitoneally partially corrected this abnormality and inhibited the progression of PH. Zinc supplementation induced the expression of A20 in lung tissue and reduce the inflammatory responses. In vitro, zinc supplementation time-dependently upregulated the expression of A20 in PASMCs, therefore correcting the excessive proliferation and migration of cells caused by hypoxia. Using genetically encoded-FRET based zinc probe, we found that these effects of zinc ions are not achieved by entering cells, but most likely by activating cell surface zinc receptor (ZnR/GPR39). These results provide the first evidence of the effectiveness of zinc supplementation in the treatment of PH., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: As one of the most common traffic-related pollutants, diesel exhaust (DE) confers high risk for cardiovascular and respiratory diseases. However, its impact on pulmonary vessels is still unclear., Methods: To explore the effects of DE exposure on pulmonary vascular remodeling, our study analyzed the number and volume of small pulmonary vessels in the diesel engine testers (the DET group) from Luoyang Diesel Engine Factory and the controls (the non-DET group) from the local water company, using spirometry and carbon content in airway macrophage (CCAM) in sputum. And then we constructed a rat model of chronic DE exposure, in which 12 rats were divided into the DE group (6 rats with 16-week DE exposure) and the control group (6 rats with 16-week clean air exposure). During right heart catheterization, right ventricular systolic pressure (RVSP) was assessed by manometry. Macrophage migration inhibitory factor (MIF) in lung tissues and bronchoalveolar lavage fluid (BALF) were measured by qRT-PCR and ELISA, respectively. Histopathological analysis for cardiovascular remodeling was also performed., Results: In DET cohort, the number and volume of small pulmonary vessels in CT were positively correlated with CCAM in sputum (P<0.05). Rat model revealed that chronic DE-exposed rats had elevated RVSP, along with increased wall thickness of pulmonary small vessels and right the ventricle. What's more, the MIF levels in BALF and lung tissues were higher in DE-exposed rats than the controls., Conclusion: Apart from airway remodeling, DE also induces pulmonary vascular remodeling, which will lead to cardiopulmonary dysfunction., (© 2024. The Author(s).)

Background: Identifying and understanding the microstructural changes within the wall of the pulmonary artery (PA) is crucial for elucidating disease mechanisms and guiding treatment strategies. We assessed the utility of optical coherence tomography (OCT) in identifying such changes within segmental/subsegmental PAs and compared the morphological variations in WHO group 4 pulmonary hypertension associated with Behcet Disease (BD), Takayasu arteritis (TA) and chronic thromboembolic pulmonary hypertension (CTEPH). Idiopathic pulmonary arterial hypertension (IPAH) patients served as controls.Methods and Results: A total of 197 cross-sectional images were analyzed from 20 consecutive patients. BD patients exhibited lower %wall area and mean wall thickness (MWT) compared with CTEPH, TA and, IPAH patients. TA patients showed a notably higher %wall area, which was significant in IPAH and BD patients. Variations in %wall area measurements were observed across distinct cross-sectional segments of the PA within individual patients (22% in CTEPH, 19% in BD, 16% in TA, 23% in IPAH patients). Intravascular webs, bands, and thrombi were observed in BD and CTEPH patients. OCT provided clear delineation of vascular wall calcifications and adventitial vasa vasorum. No procedure-related complications were observed., Conclusions: PA involvement differs among the various etiologies of PH, with the PA being heterogeneously affected. OCT offers promise in elucidating microstructural vascular wall changes and providing insights into disease mechanisms and treatment effects.

Pulmonary arterial hypertension (PAH) is characterized by progressive increase of pulmonary vascular resistance and remodeling that result in right heart failure. Recessive mutations of EIF2AK4 gene (encoding general control nonderepressible 2 kinase, GCN2) are linked to heritable pulmonary veno-occlusive disease (PVOD) in patients but rarely in patients with PAH. The role of GCN2 kinase activation in the pathogenesis of PAH remains unclear. Here, we show that GCN2 was hyperphosphorylated and activated in pulmonary vascular endothelial cells (ECs) of hypoxic mice, monocrotaline-treated rats, and patients with idiopathic PAH. Unexpectedly, loss of GCN2 kinase activity in Eif2ak4-/- mice with genetic disruption of the kinase domain induced neither PVOD nor pulmonary hypertension (PH) but inhibited hypoxia-induced PH. RNA-sequencing analysis suggested endothelin-1 (Edn1) as a downstream target of GCN2. GCN2 mediated hypoxia-induced Edn1 expression in human lung ECs via HIF-2α. Restored Edn1 expression in ECs of Eif2ak4-/- mice partially reversed the reduced phenotype of hypoxia-induced PH. Furthermore, GCN2 kinase inhibitor A-92 treatment attenuated PAH in monocrotaline-treated rats. These studies demonstrate that GCN2 kinase activation mediates pulmonary vascular remodeling and PAH at least partially through Edn1. Thus, targeting GCN2 kinase activation is a promising therapeutic strategy for treatment of PAH in patients without EIF2AK4 loss-of-function mutations.

Background: Measurement of tumor markers from peripheral venous blood is an emerging tool to assist in the early diagnosis of lung cancer. Samples from the pulmonary artery and pulmonary artery wedge position (trans-pulmonary samples) are accessible via right-heart catheterization and, by virtue of their proximity to lung tumors, may increase diagnostic yield., Case Presentation: We report a case of a 64 year-old woman from whom trans-pulmonary samples were obtained and who was diagnosed 16 months later with recurrent metastatic small cell lung cancer. Carcinoembryonic antigen, cytokeratin fragment 21 - 1 (CYFRA), and human epididymis protein 4 (HE4) levels demonstrated increasing concentrations across the pulmonary circulation. These gradients exceeded the assays' coefficient of variation by several-fold. For CYFRA and HE4, pulmonary artery wedge concentrations exceeded peripheral venous levels by more than 10% and peripheral arterial levels were up to 8% higher than peripheral venous levels., Conclusions: Evaluating the feasibility and utility of trans-pulmonary tumor markers for lung cancer diagnosis in a larger cohort should be considered. The addition of a peripheral arterial sample to standard peripheral venous samples may be a more practical alternative., (© 2024. The Author(s).)

Takayasu's arteritis-pulmonary artery involvement (TA-PAI) is a chronic, progressive, inflammatory disease affecting the pulmonary artery and its branches. Patients typically present with non-specific respiratory symptoms, such as fever, dyspnea, and chest pain, leading to a high rate of misdiagnosis. The diagnosis of TA-PAI is currently based on the diagnostic criteria of aortitis and imaging evidence of pulmonary artery involvement. However, pulmonary artery involvement is not typically included in the diagnostic criteria for aortitis, which may lead to a significant underestimation of the diagnostic rate of TA-PAI, particularly in cases where pulmonary artery involvement is the only manifestation. This article reports the case of a 26-year-old female patient who presented with recurrent chest pain and fever. She was initially diagnosed with pneumonia in a foreign hospital but did not show significant improvement after four months of treatment. Eventually, she was diagnosed with pulmonary artery involvement in aortitis and was stabilized with hormones, immunosuppressive drugs, and pulmonary vascular intervention. By analyzing the clinical features and diagnostic and therapeutic approaches of this case, and reviewing the relevant literature, clinicians can improve their understanding of TA-PAI.

Background: Pulmonary hypertension (PH) is a major complication linked to adverse outcomes in heart failure with preserved ejection fraction (HFpEF), yet no specific therapies exist for PH associated with HFpEF (PH-HFpEF). We have recently reported on the role of skeletal muscle SIRT3 (sirtuin-3) in modulation of PH-HFpEF, suggesting a novel endocrine signaling pathway for skeletal muscle modulation of pulmonary vascular remodeling., Methods: Using skeletal muscle-specific Sirt3 knockout mice ( Sirt3 skm-/- ) and mass spectrometry-based comparative secretome analysis, we attempted to define the processes by which skeletal muscle SIRT3 defects affect pulmonary vascular health in PH-HFpEF., Results: Sirt3 skm-/- mice exhibited reduced pulmonary vascular density accompanied by pulmonary vascular proliferative remodeling and elevated pulmonary pressures. Comparative analysis of secretome by mass spectrometry revealed elevated secretion levels of LOXL2 (lysyl oxidase homolog 2) in SIRT3-deficient skeletal muscle cells. Elevated circulation and protein expression levels of LOXL2 were also observed in plasma and skeletal muscle of Sirt3 skm-/- mice, a rat model of PH-HFpEF, and humans with PH-HFpEF. In addition, expression levels of CNPY2 (canopy fibroblast growth factor signaling regulator 2), a known proliferative and angiogenic factor, were increased in pulmonary artery endothelial cells and pulmonary artery smooth muscle cells of Sirt3 skm-/- mice and animal models of PH-HFpEF. CNPY2 levels were also higher in pulmonary artery smooth muscle cells of subjects with obesity compared with nonobese subjects. Moreover, treatment with recombinant LOXL2 protein promoted pulmonary artery endothelial cell migration/proliferation and pulmonary artery smooth muscle cell proliferation through regulation of CNPY2-p53 signaling. Last, skeletal muscle-specific Loxl2 deletion decreased pulmonary artery endothelial cell and pulmonary artery smooth muscle cell expression of CNPY2 and improved pulmonary pressures in mice with high-fat diet-induced PH-HFpEF., Conclusions: This study demonstrates a systemic pathogenic impact of skeletal muscle SIRT3 deficiency in remote pulmonary vascular remodeling and PH-HFpEF. This study suggests a new endocrine signaling axis that links skeletal muscle health and SIRT3 deficiency to remote CNPY2 regulation in the pulmonary vasculature through myokine LOXL2. Our data also identify skeletal muscle SIRT3, myokine LOXL2, and CNPY2 as potential targets for the treatment of PH-HFpEF., Competing Interests: M.T.G. is a coinventor of patents and patent applications directed to the use of recombinant neuroglobin and heme-based molecules as antidotes for carbon monoxide poisoning, which have been licensed by Globin Solutions, Inc. M.T.G. is a shareholder, advisor, and director in Globin Solutions, Inc. M.T.G. is also coinventor on patents directed to the use of nitrite salts in cardiovascular diseases, which were previously licensed to United Therapeutics, and are now licensed to Globin Solutions and Hope Pharmaceuticals. M.T.G. is a principal investigator in an investigator-initiated research study with Bayer Pharmaceuticals to evaluate riociguat as a treatment for patients with sickle cell disease.

Pulmonary hypertension (PH) is a malignant pulmonary vascular disease with a poor prognosis. Although the development of targeted drugs for this disease has made some breakthroughs in recent decades, PH remains incurable. Therefore, innovative clinical treatment methods and drugs for PH are still urgently needed. DYZY01 is a new drug whose main ingredient is high-purity cannabidiol, a non-psychoactive constituent of cannabinoids that was demonstrated to have anti-inflammatory and anti-pyroptosis properties. Several recent studies have found cannabidiol could improve experimental PH, whereas the mechanistic effect of it warrants further investigation. Thus, this study aimed to investigate whether DYZY01 can treat PH by inhibiting inflammation and pyroptosis and to reveal its underlying mechanism. We established hypoxia and monocrotaline (MCT)-induced PH rat models in vivo and treated them with either DYZY01 (10,50 mg/kg/d) or Riociguat (10 mg/kg/d) by oral administration. The mean pulmonary arterial pressure (mPAP), right ventricular hypertrophy index (RVHI), and extent of vascular remodeling were measured. Meanwhile, the effect of DYZY01 on human pulmonary arterial endothelial cells (HPAECs) was assessed in vitro. The results indicated that DYZY01 significantly reduced mPAP and RVHI in PH rats and reversed the extent of pulmonary vascular remodeling. This improvement may have been achieved by reducing endothelial cell pyroptosis via inhibiting the NF-κB/NLRP3/Caspase-1 pathway. Furthermore, DYZY01 could improve endothelial vascular function, possibly by regulating the secretion of vasodilator factors and inhibiting the proliferation and migration of pulmonary endothelial cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

We previously reported pulmonary arterial remodelling and active endothelial-to-mesenchymal transition (EndMT) in smokers and patients with early chronic obstructive pulmonary disease (COPD). In the present study, we aimed to evaluate the role of different drivers of EndMT. Immunohistochemical staining for EndMT drivers, TGF-β1, pSMAD-2/3, SMAD-7, and β-catenin, was performed on lung resections from 46 subjects. Twelve were non-smoker-controls (NC), six normal lung function smokers (NLFS), nine patients with small-airway diseases (SAD), nine mild-moderate COPD-current smokers (COPD-CS) and ten COPD-ex-smokers (COPD-ES). Histopathological measurements were done using Image ProPlus softwarev7.0. We observed lower levels of total TGF-β1 (P<0.05) in all smoking groups than in the non-smoking control (NC). Across arterial sizes, smoking groups exhibited significantly higher (P<0.05) total and individual layer pSMAD-2/3 and SMAD-7 than in the NC group. The ratio of SAMD-7 to pSMAD-2/3 was higher in COPD patients compared with NC. Total β-catenin expression was significantly higher in smoking groups across arterial sizes (P<0.05), except for COPD-ES and NLFS groups in small and medium arteries, respectively. Increased total β-catenin was positively correlated with total S100A4 in small and medium arteries (r = 0.35, 0.50; P=0.02, 0.01, respectively), with Vimentin in medium arteries (r = 0.42, P=0.07), and with arterial thickness of medium and large arteries (r = 0.34, 0.41, P=0.02, 0.01, respectively). This is the first study uncovering active endothelial SMAD pathway independent of TGF-β1 in smokers, SAD, and COPD patients. Increased expression of β-catenin indicates its potential interaction with SMAD pathway, warranting further research to identify the deviation of this classical pathway., (© 2024 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Background: The interplay between intrauterine and early postnatal environments has been associated with an increased risk of cardiovascular diseases in adulthood, including pulmonary arterial hypertension (PAH). While emerging evidence highlights the crucial role of mitochondrial pathology in PAH, the specific mechanisms driving fetal-originated PAH remain elusive., Methods and Results: To elucidate the role of mitochondrial dynamics in the pathogenesis of fetal-originated PAH, we established a rat model of postnatal catch-up growth following intrauterine growth restriction (IUGR) to induce pulmonary arterial hypertension (PAH). RNA-seq analysis of pulmonary artery samples from the rats revealed dysregulated mitochondrial metabolic genes and pathways associated with increased pulmonary arterial pressure and pulmonary arterial remodeling in the RC group (postnatal catch-up growth following IUGR). In vitro experiments using pulmonary arterial smooth muscle cells (PASMCs) from the RC group demonstrated elevated proliferation, migration, and impaired mitochondrial functions. Notably, reduced expression of Mitofusion 2 (Mfn2), a mitochondrial outer membrane protein involved in mitochondrial fusion, was observed in the RC group. Reconstitution of Mfn2 resulted in enhanced mitochondrial fusion and improved mitochondrial functions in PASMCs of RC group, effectively reversing the Warburg effect. Importantly, Mfn2 reconstitution alleviated the PAH phenotype in the RC group rats., Conclusions: Imbalanced mitochondrial dynamics, characterized by reduced Mfn2 expression, plays a critical role in the development of fetal-originated PAH following postnatal catch-up growth after IUGR. Mfn2 emerges as a promising therapeutic strategy for managing IUGR-catch-up growth induced PAH., (© 2024. The Author(s).)

Cardiovascular involvement in Behçet's disease (BD) is considerably related to morbidity and mortality. However, the cardiovascular manifestation is sometimes difficult to distinguish from those of other causes. The suspicion of BD and proper treatment is pivotal in the management of BD. Histology demonstrates perivasculitis. Neutrophil seems to play an important role in the inflammation of BD. It is thought that inflammation causes venous thrombosis and arterial aneurysm. Characteristically, BD involves both arteries and veins of variable size in any region. Venous thrombosis needs immunosuppression, and inferior vena cava thrombosis and Budd-Chiari syndrome require intensive immunosuppressive therapy. Arterial involvement causes aneurysm which usually is treated by surgical or endovascular intervention with immunosuppression. Pulmonary artery aneurysm and cardiac involvement require multimodal managements., Competing Interests: The authors have no potential conflicts of interest to disclose., (© Copyright: Yonsei University College of Medicine 2024.)

A 46-year-old Japanese man was referred to our hospital because of a marked increase in his eosinophil count (22,870/μL) and elevated liver enzyme levels. Computed tomography (CT) showed thrombi measuring approximately 8 cm in both femoral veins. A liver biopsy revealed eosinophilic infiltration, hepatocyte necrosis, fibrosis, and multiple thrombi. We suspected acute liver injury and deep vein thrombosis associated with hypereosinophilic syndrome and initiated steroids and heparin treatment. Four days after starting treatment, the patient experienced sudden chest pain and cardiopulmonary arrest. CT revealed bilateral pulmonary artery thrombosis, and despite administration of a tissue plasminogen activator, the patient died.

Pulmonary hypertension (PH) is an incurable disease characterized by pulmonary vascular remodeling. Endothelial injury and inflammation are the key triggers of disease initiation. Recent findings suggest that STING (stimulator of IFN genes) activation plays a critical role in endothelial dysfunction and IFN signaling. Here, we investigated the involvement of STING in the pathogenesis of PH. Patients with PH and rodent PH model samples, a Sugen 5416/hypoxia PH model, and pulmonary artery endothelial cells (PAECs) were used to evaluate the hypothesis. We found that the cyclic guanosine monophosphate-AMP synthase-STING signaling pathway was activated in lung tissues from rodent PH models and patients with PH and in TNF-α-induced PAECs in vitro . Specifically, STING expression was significantly elevated in the endothelial cells in PH disease settings. In the Sugen 5416/hypoxia mouse model, genetic knockout or pharmacological inhibition of STING prevented the progression of PH. Functionally, knockdown of STING reduced the proliferation and migration of PAECs. Mechanistically, STING transcriptionally regulates its binding partner F2RL3 (F2R-like thrombin or trypsin receptor 3) through the STING-NF-κB axis, which activated IFN signaling and repressed BMPR2 (bone morphogenetic protein receptor 2) signaling both in vitro and in vivo . Further analysis revealed that F2RL3 expression was increased in PH settings and identified negative feedback regulation of F2RL3/BMPR2 signaling. Accordingly, a positive correlation of expression amounts between STING and F2RL3/IFN-stimulated genes was observed in vivo . Our findings suggest that STING activation in PAECs plays a critical role in the pathobiology of PH. Targeting STING may be a promising therapeutic strategy for preventing the development of PH.