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Zebrafish exhibit a robust ability to regenerate their hearts following injury, and the immune system plays a key role in this process. We previously showed that delaying macrophage recruitment by clodronate liposome (CL) treatment compromises neutrophil resolution and heart regeneration, even when the infiltrating macrophage number was restored within the first-week post injury (Lai et al., 2017). Here, we examined the molecular mechanisms underlying the cardiac repair of regenerative PBS-control hearts vs. non-regenerative CL-treated hearts. Bulk transcriptomic analyses revealed that CL-treated hearts exhibited disrupted inflammatory resolution and energy metabolism during cardiac repair. Temporal single-cell profiling of inflammatory cells in regenerative vs. non-regenerative conditions further identified heterogenous macrophages and neutrophils with distinct infiltration dynamics, gene expression, and cellular crosstalk. Among them, two residential macrophage subpopulations were enriched in regenerative hearts and barely recovered in non-regenerative hearts. Early CL treatment at 8 days or even 1 month before cryoinjury led to the depletion of resident macrophages without affecting the circulating macrophage recruitment to the injured area. Strikingly, these resident macrophage-deficient zebrafish still exhibited compromised neovascularization and scar resolution. Our results characterized the inflammatory cells of the zebrafish injured hearts and identified key resident macrophage subpopulations prerequisite for successful heart regeneration.

Gut microbiota and its metabolites, along with host metabolism of ʟ-carnitine, play a crucial role in cardiovascular disease (CVD) development, forming Trimethylamine-N-oxide (TMAO), an atherosclerosis risk factor. TMAO promotes the formation of atherosclerotic plaques and platelet aggregation potential, causing thrombosis. A high-fat diet and carnitine administration can accelerate CVD progression. Ginger (Zingiber officinale Roscoe) essential oil (GEO) and its bioactive compound citral have lipid lowering and anti-inflammatory effects, which may prevent CVD; however, their ability to prevent atherosclerosis through gut microbiota modulation remains to be elucidated. Furthermore, the Gubra Amylin NASH (GAN) diet is a palm oil-containing high-fat diet for inducing steatohepatitis; however, the study of the GAN diet in combination with ʟ-carnitine for inducing atherosclerosis in mouse model has not been investigated yet. We examined the CVD-protecting effect of GEO and citral against the formation of aortic atherosclerosis and linked them with changes in the gut microbiota and its metabolites in the ʟ-carnitine/GAN diet-treated apolipoprotein E-deficient (ApoE−/−) mouse model. GEO and citral demonstrated CVD protective function by alleviating aortic atherosclerotic lesions. They reduced blood sugar, improved insulin resistance, decreased plasma TMAO levels, and inhibited serum inflammatory cytokines, especially interleukin-1β. Moreover, they demonstrated their ability to modulate gut microbiota diversity and composition into a favourable direction. Collectively, GEO and citral may serve as potential prebiotics for CVD prevention by improving dysbiosis.

Epidemiological studies reveal that marijuana increases the risk of cardiovascular disease (CVD); however, little is known about the mechanism. Δ 9 -tetrahydrocannabinol (Δ 9 -THC), the psychoactive component of marijuana, binds cannabinoid receptor 1 (CB1/CNR1) in the vasculature and is implicated in CVD. A UK Biobank analysis found that cannabis is an independent risk factor for CVD. We found that marijuana smoking activated inflammatory cytokines implicated in CVD. In silico virtual screening identified genistein, a soybean isoflavone, as a putative CB1 antagonist. Human-induced pluripotent stem cell-derived endothelial cells (hiPSC-ECs) were used to model Δ 9 -THC induced inflammation and oxidative stress via NF-κB signaling. Knockdown of the CB1 receptor with siRNA, CRISPR interference (CRISPRi), and genistein attenuate the effects of Δ 9 -THC. In mice, genistein blocked Δ 9 -THC-induced endothelial dysfunction in wire myograph, reduced atherosclerotic plaque, and had minimal penetration of the central nervous system (CNS). Genistein is a peripherally restricted CB1 antagonist that attenuates Δ 9 -THC-induced atherosclerosis.

Background: The sino atrial node (SAN) is characterized by the microenvironment of pacemaker cardiomyocytes (PCs) encased with fibroblasts. An altered microenvironment leads to rhythm failure. Operable cell or tissue models are either generally lacking or difficult to handle. The biological process behind the milieu of SANs to evoke pacemaker rhythm is unknown. We explored how fibroblasts interact with PCs and regulate metabolic reprogramming and rhythmic activity in the SAN. Methods: Tbx18 (T-box transcription factor 18)-induced PCs and fibroblasts were used for cocultures and engineered tissues, which were used as the in vitro models to explore how fibroblasts regulate the functional integrity of SANs. RNA-sequencing, metabolomics, and cellular and molecular techniques were applied to characterize the molecular signals underlying metabolic reprogramming and identify its critical regulators. These pathways were further validated in vivo in rodents and induced human pluripotent stem cell-derived cardiomyocytes. Results: We observed that rhythmicity in Tbx18-induced PCs was regulated by aerobic glycolysis. Fibroblasts critically activated metabolic reprogramming and aerobic glycolysis within PCs, and, therefore, regulated pacemaker activity in PCs. The metabolic reprogramming was attributed to the exclusive induction of Aldoc (aldolase c) within PCs after fibroblast-PC integration. Fibroblasts activated the integrin-dependent mitogen-activated protein kinase-E2F1 signal through cell-cell contact and turned on Aldoc expression in PCs. Interruption of fibroblast-PC interaction or Aldoc knockdown nullified electrical activity. Engineered Tbx18-PC tissue sheets were generated to recapitulate the microenvironment within SANs. Aldoc-driven rhythmic machinery could be replicated within tissue sheets. Similar machinery was faithfully validated in de novo PCs of adult mice and rats, and in human PCs derived from induced pluripotent stem cells. Conclusions: Fibroblasts drive Aldoc-mediated metabolic reprogramming and rhythmic regulation in SANs. This work details the cellular machinery behind the complex milieu of vertebrate SANs and opens a new direction for future therapy.

The origin and fate of renal myofibroblasts is not clear after acute kidney injury (AKI). Here, we demonstrate that myofibroblasts were activated from quiescent pericytes (qPericytes) and the cell numbers increased after ischemia/reperfusion injury–induced AKI (IRI-AKI). Myofibroblasts underwent apoptosis during renal recovery but one-fifth of them survived in the recovered kidneys on day 28 after IRI-AKI and their cell numbers increased again after day 56. Microarray data showed the distinctive gene expression patterns of qPericytes, activated pericytes (aPericytes, myofibroblasts), and inactivated pericytes (iPericytes) isolated from kidneys before, on day 7, and on day 28 after IRI-AKI. Hypermethylation of the Acta2 repressor Ybx2 during IRI-AKI resulted in epigenetic modification of iPericytes to promote the transition to chronic kidney disease (CKD) and aggravated fibrogenesis induced by a second AKI induced by adenine. Mechanistically, transforming growth factor-β1 decreased the binding of YBX2 to the promoter of Acta2 and induced Ybx2 hypermethylation, thereby increasing α-smooth muscle actin expression in aPericytes. Demethylation by 5-azacytidine recovered the microvascular stabilizing function of aPericytes, reversed the profibrotic property of iPericytes, prevented AKI-CKD transition, and attenuated fibrogenesis induced by a second adenine-AKI. In conclusion, intervention to erase hypermethylation of pericytes after AKI provides a strategy to stop the transition to CKD.

Although atherosclerosis preferentially develops at arterial curvatures and bifurcations where disturbed flow (DF) activates endothelium, therapies targeting flow-dependent mechanosensing pathways in the vasculature are unavailable. Here, we provided experimental evidence demonstrating a previously unidentified causal role of DF-induced endothelial TXNDC5 (thioredoxin domain containing 5) in atherosclerosis. TXNDC5 was increased in human and mouse atherosclerotic lesions and induced in endothelium subjected to DF. Endothelium-specific Txndc5 deletion markedly reduced atherosclerosis in ApoE−/− mice. Mechanistically, DF-induced TXNDC5 increases proteasome-mediated degradation of heat shock factor 1, leading to reduced heat shock protein 90 and accelerated eNOS (endothelial nitric oxide synthase) protein degradation. Moreover, nanoparticles formulated to deliver Txndc5-targeting CRISPR-Cas9 plasmids driven by an endothelium-specific promoter (CDH5) significantly increase eNOS protein and reduce atherosclerosis in ApoE−/− mice. These results delineate a new molecular paradigm that DF-induced endothelial TXNDC5 promotes atherosclerosis and establish a proof of concept of targeting endothelial mechanosensitive pathways in vivo against atherosclerosis., Description, Targeting flow-sensitive TXNDC5, an ER protein driving endothelial dysfunction by destabilizing eNOS, lessens atherosclerosis.

Significance Vascular disease is a leading cause of human morbidity and mortality and current therapies mainly target systemic risk factors but not the diseased vasculature per se. We have devised a targeted nanomedicine approach engineering self-assembled polyelectrolyte complex micelles that target inflamed vascular endothelium and simultaneously encapsulate therapeutic nucleic acids. We showed that this targeted nanomedicine strategy effectively delivers therapeutic nucleotides to inflamed endothelium in vivo. The causal role of increased endothelial miR-92a in driving atherosclerosis is established by a new transgenic mouse line. We demonstrated that targeted polyelectrolyte complex micelles significantly enhance the anti–miR-92a therapy treating vascular complications in vivo., Vascular disease is a leading cause of morbidity and mortality in the United States and globally. Pathological vascular remodeling, such as atherosclerosis and stenosis, largely develop at arterial sites of curvature, branching, and bifurcation, where disturbed blood flow activates vascular endothelium. Current pharmacological treatments of vascular complications principally target systemic risk factors. Improvements are needed. We previously devised a targeted polyelectrolyte complex micelle to deliver therapeutic nucleotides to inflamed endothelium in vitro by displaying the peptide VHPKQHR targeting vascular cell adhesion molecule 1 (VCAM-1) on the periphery of the micelle. This paper explores whether this targeted nanomedicine strategy effectively treats vascular complications in vivo. Disturbed flow-induced microRNA-92a (miR-92a) has been linked to endothelial dysfunction. We have engineered a transgenic line (miR-92aEC-TG/Apoe−/−) establishing that selective miR-92a overexpression in adult vascular endothelium causally promotes atherosclerosis in Apoe−/− mice. We tested the therapeutic effectiveness of the VCAM-1–targeting polyelectrolyte complex micelles to deliver miR-92a inhibitors and treat pathological vascular remodeling in vivo. VCAM-1–targeting micelles preferentially delivered miRNA inhibitors to inflamed endothelial cells in vitro and in vivo. The therapeutic effectiveness of anti–miR-92a therapy in treating atherosclerosis and stenosis in Apoe−/− mice is markedly enhanced by the VCAM-1–targeting polyelectrolyte complex micelles. These results demonstrate a proof of concept to devise polyelectrolyte complex micelle-based targeted nanomedicine approaches treating vascular complications in vivo.

To perceive and integrate the environmental cues, cells and tissues sense and interpret various physical forces like shear, tensile, and compression stress. Mechanotransduction involves the sensing and translation of mechanical forces into biochemical and mechanical signals to guide cell fate and achieve tissue homeostasis. Disruption of this mechanical homeostasis by tissue injury elicits multiple cellular responses leading to pathological matrix deposition and tissue stiffening, and consequent evolution toward pro-inflammatory/pro-fibrotic phenotypes, leading to tissue/organ fibrosis. This review focuses on the molecular mechanisms linking mechanotransduction to fibrosis and uncovers the potential therapeutic targets to halt or resolve fibrosis.

BackgroundOnline video-based learning is more common in higher education. Investigating students' viewing behaviors while watching online video lectures is essential for instructors to understand their learning status so that the course content, structure, and media selection can be improved continuously. The current study identified the engagement level of the learners based on their online video-watching behaviors, and tested the correlation between the engagement level and learning outcome.MethodsThe action logs of watching online video lectures in 2020 Spring Pharmacology of the 4th-year medical students of the 6-year course and their feedbacks by questionnaires after each exam during the semester were provided anonymously. The data were analyzed and visualized for an efficient way to comprehend and interpret. To define the student's engagement level in his or her video-based learning journey, three viewing criteria, “Completion,” “Pausing,” and “Repeated watching” were identified. We evaluated the association between the engagement level and the students' learning outcomes, including their learning satisfaction, knowledge acquisition progresses based on assessment results, and the grades measured by the instructors.ResultsThe graphs and the charts demonstrate whether the students allocated enough time to finish the video lectures (completion), paused for a while, then resumed the video (pausing), or replayed the specific sections of video content (repeated watching). The engagement level with video lectures, evaluated by pre-defined thresholds for “Completion,” “Pausing,” and “Repeated watching” had a positive correlation with the learning outcomes.ConclusionsWe suggested that an engagement dashboard containing real-time visualized information on students' online video-watching behaviors can be developed to help instructors to monitor students' learning progress and improve teaching in a timely fashion. It can also help each student to re-feel the stimulation of peers, prompt self-monitoring, improve their learning attitudes and disciplines for better learning outcomes. This innovative way of assessing student's engagement during online video-based learning can also be used for quality assurance purposes.

Cardiovascular disease (CVD) is strongly associated with the gut microbiota and its metabolites, including trimethylamine-N-oxide (TMAO), formed from metaorganismal metabolism of ʟ-carnitine. Raw garlic juice, with allicin as its primary compound, exhibits considerable effects on the gut microbiota. This study validated the benefits of raw garlic juice against CVD risk via modulation of the gut microbiota and its metabolites. Allicin supplementation significantly decreased serum TMAO in ʟ-carnitine-fed C57BL/6 J mice, reduced aortic lesions, and altered the fecal microbiota in carnitine-induced, atherosclerosis-prone, apolipoprotein E-deficient (ApoE−/−) mice. In human subjects exhibiting high-TMAO production, raw garlic juice intake for a week reduced TMAO formation, improved gut microbial diversity, and increased the relative abundances of beneficial bacteria. In in vitro and ex vivo studies, raw garlic juice and allicin inhibited γ-butyrobetaine (γBB) and trimethylamine production by the gut microbiota. Thus, raw garlic juice and allicin can potentially prevent cardiovascular disease by decreasing TMAO production via gut microbiota modulation.

Diabetic cardiomyopathy (DC) is one of the major lethal complications in patients with diabetes mellitus (DM); however, no specific strategy for preventing or treating DC has been identified.This study aimed to investigate the effects of β-lapachone (Lap), a natural compound that increases antioxidant activity in various tissues, on DC and explore the underlying mechanisms.As an in vivo model, C57BL/6 mice were fed with the high-fat diet (HF) for 10 weeks to induce type 2 DM. Mice were fed Lap with the HF or after 5 weeks of HF treatment to investigate the protective effects of Lap against DC.In the two in vivo models, Lap decreased heart weight, increased heart function, reduced oxidative stress, and elevated mitochondrial content under the HF. In the in vitro model, palmitic acid (PA) was used to mimic the effects of an HF on the differentiated-cardiomyoblast cell line H9c2. The results demonstrated that Lap reduced PA-induced ROS production by increasing the expression of antioxidant regulators and enzymes, inhibiting inflammation, increasing mitochondrial activity, and thus reducing cell damage. Via the use of specific inhibitors and siRNA, the protective effects of Lap were determined to be mediated mainly by NQO1, Sirt1 and mitochondrial activity.Heart damage in DM is usually caused by excessive oxidative stress. This study showed that Lap can protect the heart from DC by upregulating antioxidant ability and mitochondrial activity in cardiomyocytes. Lap has the potential to serve as a novel therapeutic agent for both the prevention and treatment of DC.

Cerebral small vessel disease is one of the most common causes of cognitive decline and stroke. While several lines of evidence have established a relationship between inflammation and cerebrovascular pathology, the mechanistic link has not yet been elucidated. Recent studies suggest activation of immune mediators, including the soluble form of triggering receptor expressed on myeloid cells 2 (TREM2), may be critical regulators. In this study, we compared the plasma levels of soluble TREM2 and its correlations with neuroimaging markers and cerebral amyloid load in 10 patients with Alzheimer’s disease and 66 survivors of spontaneous intracerebral haemorrhage with cerebral amyloid angiopathy or hypertensive small vessel disease, two of the most common types of sporadic small vessel disease. We performed brain MRI and 11C-Pittsburgh compound B PET for all participants to evaluate radiological small vessel disease markers and cerebral amyloid burden, and 18F-T807 PET in a subgroup of patients to evaluate cortical tau pathology. Plasma soluble TREM2 levels were comparable between patients with Alzheimer’s disease and small vessel disease (P = 0.690). In patients with small vessel disease, plasma soluble TREM2 was significantly associated with white matter hyperintensity volume (P Our results indicate plasma soluble TREM2 is associated with white matter hyperintensity independent of amyloid and tau pathology. These findings highlight the potential utility of plasma soluble TREM2 as a strong predictive marker for small vessel disease-related white matter injury and hold clinical implications for targeting the innate immune response when treating this disease.

Genome-wide association studies (GWAS) have suggested new molecular mechanisms in vascular cells driving atherosclerotic diseases such as coronary artery disease (CAD) and ischemic stroke (IS). Nevertheless, a major challenge to develop new therapeutic approaches is to spatiotemporally manipulate these GWAS-identified genes in specific vascular tissues in vivo. YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif) have merged as critical transcriptional regulators in cells responding to biomechanical stimuli, such as in athero-susceptible endothelial cells activated by disturbed flow (DF). The molecular mechanisms by which DF activates while unidirectional flow (UF) inactivates YAP/TAZ remain incompletely understood. Recent studies demonstrated that DF and genetic predisposition (risk allele) of CAD/IS locus 1p32.2 converge to reduce phospholipid phosphatase 3 (PLPP3) expression in vascular endothelium. Restoration of endothelial PLPP3 in vivo, although remains challenging and unexplored, is hypothesized to reduce atherosclerosis. We devised a nanomedicine system integrating nanoparticles and Cdh5 promoter-driven plasmids to successfully restore PLPP3 expression in activated endothelium, resulting in suppressed YAP/TAZ activity and reduced DF-induced atherosclerosis in mice. Mechanistically, our studies discovered a molecular paradigm by which CAD/IS GWAS gene PLPP3 inactivates YAP/TAZ by reducing lysophosphatidic acid (LPA)-induced myosin II and ROCK in endothelium under UF. These results highlight a new mechanistic link between GWAS and YAP/TAZ mechano-regulation and moreover, establish a proof of concept of vascular wall-based therapies employing targeted nanomedicine to manipulate CAD/IS GWAS genes in vivo.

Obesity is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD). However, ‘obesity paradox’ is observed in patients with coronary artery disease while defining obesity by body mass index (BMI). The purpose of this study is to identify a better anthropometric parameter to predict cardiovascular events in patients with ASCVD. The study was conducted using the Taiwanese Secondary Prevention for patients with AtheRosCLErotic disease (T-SPARCLE) Registry. A total of 6,920 adult patients with stable ASCVD, enrolled from January 2010 to November 2014, were included, with a mean age of 65.9 years, 73.9% males, and a mean BMI of 26.3 kg/m2 at baseline. These patients were followed up for a median of 2.5 years. The study endpoint was the composite major adverse cardiovascular event (MACE), defined as cardiovascular death, nonfatal myocardial infarction or stroke, or cardiac arrest with resuscitation. Multivariable Cox proportional hazards regression showed a significant positive association between waist-to-BMI ratio and MACE (adjusted hazard ratio 1.69 per cm‧m2/kg increase in waist-to-BMI ratio, 95% CI 1.12–2.49, p = 0.01) after adjusting for potential risk factors and confounders. Traditional anthropometric parameters, such as BMI, weight, waist and waist-hip ratio, or newer waist-based indices, such as body roundness index and a body shape index, did not show any significant linear associations (p = 0.09, 0.30, 0.89, 0.54, 0.79 and 0.06, respectively). In the restricted cubic spline regression analysis, the positive dose–response association between waist-to-BMI ratio and MACE persisted across all the range of waist-to-BMI ratio. The positive dose–response association was non-linear with a much steeper increase in the risk of MACE for waist-to-BMI ratio > 3.6 cm‧m2/kg. In conclusion, waist-to-BMI ratio may function as a positive predictor for the risk of MACE in established ASCVD patients.

Background and objectivesLiver fibrosis (LF) occurs following chronic liver injuries. Currently, there is no effective therapy for LF. Recently, we identified thioredoxin domain containing 5 (TXNDC5), an ER protein disulfide isomerase (PDI), as a critical mediator of cardiac and lung fibrosis. We aimed to determine if TXNDC5 also contributes to LF and its potential as a therapeutic target for LF.DesignHistological and transcriptome analyses on human cirrhotic livers were performed. Col1a1-GFPTg, Alb-Cre;Rosa26-tdTomato and Tie2-Cre/ERT2;Rosa26-tdTomato mice were used to determine the cell type(s) where TXNDC5 was induced following liver injury. In vitro investigations were conducted in human hepatic stellate cells (HSCs). Col1a2-Cre/ERT2;Txndc5fl/fl (Txndc5cKO) and Alb-Cre;Txndc5fl/fl (Txndc5Hep-cKO) mice were generated to delete TXNDC5 in HSCs and hepatocytes, respectively. Carbon tetrachloride treatment and bile duct ligation surgery were employed to induce liver injury/fibrosis in mice. The extent of LF was quantified using histological, imaging and biochemical analyses.ResultsTXNDC5 was upregulated markedly in human and mouse fibrotic livers, particularly in activated HSC at the fibrotic foci. TXNDC5 was induced by transforming growth factor β1 (TGFβ1) in HSCs and it was both required and sufficient for the activation, proliferation, survival and extracellular matrix production of HSC. Mechanistically, TGFβ1 induces TXNDC5 expression through increased ER stress and ATF6-mediated transcriptional regulation. In addition, TXNDC5 promotes LF by redox-dependent JNK and signal transducer and activator of transcription 3 activation in HSCs through its PDI activity, activating HSCs and making them resistant to apoptosis. HSC-specific deletion of Txndc5 reverted established LF in mice.ConclusionsER protein TXNDC5 promotes LF through redox-dependent HSC activation, proliferation and excessive extracellular matrix production. Targeting TXNDC5, therefore, could be a potential novel therapeutic strategy to ameliorate LF.

To perceive and integrate the environmental cues, cells and tissues sense and interpret various physical forces like shear, tensile, and compression stress. Mechanotransduction involves the sensing and translation of mechanical forces into biochemical and mechanical signals to guide cell fate and achieve tissue homeostasis. Disruption of this mechanical homeostasis by tissue injury elicits multiple cellular responses leading to pathological matrix deposition and tissue stiffening, and consequent evolution toward pro-inflammatory/pro-fibrotic phenotypes, leading to tissue/organ fibrosis. This review focuses on the molecular mechanisms linking mechanotransduction to fibrosis and uncovers the potential therapeutic targets to halt or resolve fibrosis.

Epidemiological studies reveal that marijuana increases the risk of cardiovascular disease (CVD); however, little is known about the mechanism. Δ9-tetrahydrocannabinol (Δ9-THC), the psychoactive component of marijuana, binds to cannabinoid receptor 1 (CB1/CNR1) in the vasculature and is implicated in CVD. A UK Biobank analysis found that cannabis was an risk factor for CVD. We found that marijuana smoking activated inflammatory cytokines implicated in CVD. In silico virtual screening identified genistein, a soybean isoflavone, as a putative CB1 antagonist. Human-induced pluripotent stem cell-derived endothelial cells were used to model Δ9-THC-induced inflammation and oxidative stress via NF-κB signaling. Knockdown of the CB1 receptor with siRNA, CRISPR interference, and genistein attenuated the effects of Δ9-THC. In mice, genistein blocked Δ9-THC-induced endothelial dysfunction in wire myograph, reduced atherosclerotic plaque, and had minimal penetration of the central nervous system. Genistein is a CB1 antagonist that attenuates Δ9-THC-induced atherosclerosis.

Background Thoracic aortic aneurysm and dissection (TAAD) is a devastating but treatable disease if detected early. The clinical manifestations and genetic characteristics underlying TAAD patients in Taiwan, however, remain unclear. Methods We consecutively recruited patients referred for TAAD screening and/or management at a tertiary medical center in Taiwan. All patients received a comprehensive survey of the clinical manifestations and a genetic testing with a 29-gene next-generation sequencing (NGS) panel. Results Patients (n = 107) were referred for different reasons, and could be grouped into 4 categories: known aortic aneurysm or dissection (AoAD) (n = 57), Marfanoid features (n = 36), having family members of suspected AoAD (n = 11), and ectopic lens (n = 3). AoAD were confirmed in 73 (68.2%) of the entire cohort. Among all the clinical manifestations, skin striae distensae was the only physical sign that showed significant association with AoAD (p = 0.007 after adjusted). Disease-causing genes/variants were identified in 46 patients (43.0%); FBN1 was the most prevalent disease-causing gene, followed by TGFBR1, TGFBR2 and FBN2. A positive genetic testing was not only an independent predictor of AoAD (hazard ratio (HR) 3.468, 95% confidence interval (CI) [1.541–7.807], p = 0.003), but also had a higher chance of dissection among the patients with known dilated aorta (HR 4.552, 95% CI [1.578–13.135], p = 0.005). Conclusion The presence of skin striae distensae may serve as a clinical cue for physicians to search for AoAD in subjects who are at risk. The NGS panel test not only helps confirm the diagnosis, but also stratify the risk of dissection among patients with dilated aorta.

Renal fibrosis, a common pathological manifestation of virtually all types of chronic kidney disease (CKD), often results in diffuse kidney scarring and predisposes to end-stage renal disease. Currently, there is no effective therapy against renal fibrosis. Recently, our laboratory identified an ER-resident protein, thioredoxin domain containing 5 (TXNDC5), as a critical mediator of cardiac fibrosis. Transcriptome analyses of renal biopsy specimens from patients with CKD revealed marked TXNDC5 upregulation in fibrotic kidneys, suggesting a potential role of TXNDC5 in renal fibrosis. Employing multiple fluorescence reporter mouse lines, we showed that TXNDC5 was specifically upregulated in collagen-secreting fibroblasts in fibrotic mouse kidneys. In addition, we showed that TXNDC5 was required for TGF-β1-induced fibrogenic responses in human kidney fibroblasts (HKFs), whereas TXNDC5 overexpression was sufficient to promote HKF activation, proliferation, and collagen production. Mechanistically, we showed that TXNDC5, transcriptionally controlled by the ATF6-dependent ER stress pathway, mediated its profibrogenic effects by enforcing TGF-β signaling activity through posttranslational stabilization and upregulation of type I TGF-β receptor in kidney fibroblasts. Using a tamoxifen-inducible, fibroblast-specific Txndc5 knockout mouse line, we demonstrated that deletion of Txndc5 in kidney fibroblasts mitigated the progression of established kidney fibrosis, suggesting the therapeutic potential of TXNDC5 targeting for renal fibrosis and CKD.

Pulmonary fibrosis (PF) is a major public health problem with limited therapeutic options. There is a clear need to identify novel mediators of PF to develop effective therapeutics. Here we show that an ER protein disulfide isomerase, thioredoxin domain containing 5 (TXNDC5), is highly upregulated in the lung tissues from both patients with idiopathic pulmonary fibrosis and a mouse model of bleomycin (BLM)-induced PF. Global deletion of Txndc5 markedly reduces the extent of PF and preserves lung function in mice following BLM treatment. Mechanistic investigations demonstrate that TXNDC5 promotes fibrogenesis by enhancing TGFβ1 signaling through direct binding with and stabilization of TGFBR1 in lung fibroblasts. Moreover, TGFβ1 stimulation is shown to upregulate TXNDC5 via ER stress/ATF6-dependent transcriptional control in lung fibroblasts. Inducing fibroblast-specific deletion of Txndc5 mitigates the progression of BLM-induced PF and lung function deterioration. Targeting TXNDC5, therefore, could be a novel therapeutic approach against PF., Pulmonary fibrosis is a major public health problem with unclear mechanism and limited therapeutic options. Here the authors show that a fibroblast-enriched endoplasmic reticulum protein, TXNDC5, promotes pulmonary fibrosis by stabilizing TGFBR1 and show the potential of TXNDC5 as a therapeutic target against pulmonary fibrosis.

Cisplatin, despite its anti-cancer ability, exhibits severe testicular toxicities when applied systemically. Due to its wide application in cancer treatment, reduction of its damages to normal tissue is an imminent clinical need. Here we evaluated the effects of honokiol, a natural lipophilic polyphenol compound, on cisplatin-induced testicular injury. We showed in-vitro and in-vivo that nanosome-encapsulated honokiol attenuated cisplatin-induced DNA oxidative stress by suppressing intracellular reactive oxygen species production and elevating gene expressions of mitochondrial antioxidation enzymes. Nanosome honokiol also mitigated endoplasmic reticulum stress through down regulation of Bip-ATF4-CHOP signaling pathway. Additionally, this natural polyphenol compound diminished cisplatin-induced DNA breaks and cellular apoptosis. The reduced type I collagen accumulation in the testis likely attributed from inhibition of TGF&beta, 1, &alpha, SMA and ER protein TXNDC5 protein expression. The combinatorial beneficial effects better preserve spermatogenic layers and facilitate repopulation of sperm cells. Our study renders opportunity for re-introducing cisplatin to systemic anti-cancer therapy with reduced testicular toxicity and restored fertility.

Abnormal sarcolemmal Ca 2+ handling and impaired contractile function owing to sarcoplasmic reticulum/endoplasmic reticulum ATPase 2a (SERCA2a, encoded by ATP2A2 ) downregulation and/or dysfunction are pathognomonic hallmarks of heart failure (HF). There is, however, no clinically proven HF therapy that targets SERCA2a/ ATP2A2 dysregulation directly. Exploiting gene co-expression network analysis using an RNA sequencing dataset generated from human failing and non-failing left ventricular (LV) tissues, we identified long noncoding RNA lnc-SYNPO , transcribed from the 3’ untranslated region of SYNPO2 , as a potential regulator of SERCA2a/ ATP2A2 . Myocardial lnc-SYNPO was markedly upregulated during HF and its expression level showed a strong negative correlation (Pearson correlation coefficient=-0.60) with that of SERCA2a/ ATP2A2 in both mouse and human LV. Knockdown of lnc-SYNPO in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) increased, whereas overexpression of lnc-SYNPO reduced, SERCA2a/ ATP2A2 expression. In addition, lnc-SYNPO knockdown reversed endothelin-1 (ET-1) treatment-induced SERCA2a/ ATP2A2 downregulation, impaired Ca 2+ homeostasis and contractile dysfunction in hiPSC-CM. Mechanistically, the depletion of lnc-SYNPO, a chromatin-associated nuclear lncRNA, led to increased H3K4me3 and reduced H3K27me3 occupancy at SERCA2a/ ATP2A2 promoter. Chromatin isolation by RNA purification showed direct physical binding between lnc-SYNPO and the promoter of SERCA2a/ ATP2A2 . In addition, RNA pull-down assays showed that lnc-SYNPO binds to EZH2 and SUZ12, two core components of the polycomb repressor complex 2 (PRC2), suggesting that lnc-SYNPO represses SERCA2a/ ATP2A2 expression by recruiting PRC2 complex to the promoter of SERCA2a/ ATP2A2 , leading to epigenetic silencing of SERCA2a/ ATP2A2 . Taken together, these results unveiled a previously undiscovered epigenetic regulatory mechanism of SERCA2a/ ATP2A2 by lnc-SYNPO , contributing to impaired myocardial Ca 2+ homeostasis and contractile dysfunction observed with HF. Targeting lnc-SYNPO , therefore, could be a novel therapeutic approach to improve Ca 2+ homeostasis and contractile function in the failing human heart.

Rationale: Cardiac fibrosis plays a critical role in the pathogenesis of heart failure. Excessive accumulation of extracellular matrix (ECM) resulting from cardiac fibrosis impairs cardiac contractile function and increases arrhythmogenicity. Current treatment options for cardiac fibrosis, however, are limited, and there is a clear need to identify novel mediators of cardiac fibrosis to facilitate the development of better therapeutics. Exploiting coexpression gene network analysis on RNA sequencing data from failing human heart, we identified TXNDC5 (thioredoxin domain containing 5), a cardiac fibroblast (CF)–enriched endoplasmic reticulum protein, as a potential novel mediator of cardiac fibrosis, and we completed experiments to test this hypothesis directly. Objective: The objective of this study was to determine the functional role of TXNDC5 in the pathogenesis of cardiac fibrosis. Methods and Results: RNA sequencing and Western blot analyses revealed that TXNDC5 mRNA and protein were highly upregulated in failing human left ventricles and in hypertrophied/failing mouse left ventricle. In addition, cardiac TXNDC5 mRNA expression levels were positively correlated with those of transcripts encoding transforming growth factor β1 and ECM proteins in vivo. TXNDC5 mRNA and protein were increased in human CF (hCF) under transforming growth factor β1 stimulation in vitro. Knockdown of TXNDC5 attenuated transforming growth factor β1–induced hCF activation and ECM protein upregulation independent of SMAD3 (SMAD family member 3), whereas increasing expression of TXNDC5 triggered hCF activation and proliferation and increased ECM protein production. Further experiments showed that TXNDC5, a protein disulfide isomerase, facilitated ECM protein folding and that depletion of TXNDC5 led to ECM protein misfolding and degradation in CF. In addition, TXNDC5 promotes hCF activation and proliferation by enhancing c-Jun N-terminal kinase activity via increased reactive oxygen species, derived from NAD(P)H oxidase 4. Transforming growth factor β1–induced TXNDC5 upregulation in hCF was dependent on endoplasmic reticulum stress and activating transcription factor 6–mediated transcriptional control. Targeted disruption of Txndc5 in mice ( Txndc5 −/− ) revealed protective effects against isoproterenol-induced cardiac hypertrophy, reduced fibrosis (by ≈70%), and markedly improved left ventricle function; post-isoproterenol left ventricular ejection fraction was 59.1±1.5 versus 40.1±2.5 ( P Txndc5 −/− versus wild-type mice, respectively. Conclusions: The endoplasmic reticulum protein TXNDC5 promotes cardiac fibrosis by facilitating ECM protein folding and CF activation via redox-sensitive c-Jun N-terminal kinase signaling. Loss of TXNDC5 protects against β agonist–induced cardiac fibrosis and contractile dysfunction. Targeting TXNDC5, therefore, could be a powerful new therapeutic approach to mitigate excessive cardiac fibrosis, thereby improving cardiac function and outcomes in patients with heart failure.

The receptor for advanced glycation end products (RAGE) and its downstream pathways are involved in various inflammatory and immune responses. Importantly, there is soluble RAGE (sRAGE) that forms either by alternative splicing of RAGE messenger ribonucleic acid as the endogenous soluble form of RAGE (esRAGE) or by proteolytic cleavage of full-length RAGE protein. This study aimed to investigate the associations of the plasma levels of sRAGE and esRAGE in ischemic stroke (IS) patients with and without dementia. This cross-sectional study recruited patients with IS at a university medical center. Vascular dementia was defined as the scale of Clinical Dementia Ranking (CDR) ≥ 1. Standard enzyme-linked immunosorbent assay was used to measure the plasma concentration of sRAGE and esRAGE. From November 2014 to October 2015, a total of 172 IS patients (mean age: 72.1 ± 7.5 years, 64.5% male) were recruited, including 73 with CDR = 0, 63 with CDR = 0.5, and 36 with CDR ≥ 1. In univariate analysis, IS patients with dementia were older and had more diabetes mellitus, less atrial fibrillation, and higher post-stroke modified Rankin Scale scores than those without dementia. Plasma levels of sRAGE and esRAGE were significantly higher in IS patients with than those without dementia (1.44 ± 1.29 vs. 1.03 ± 0.48 and 0.39 ± 0.40 vs. 0.24 ± 0.13 ng/mL, both p