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Abstract Background Thoracic aortic dissection (TAD) is an irreversible cardiovascular disorder with high mortality and morbidity. However, the molecular mechanisms remain elusive. Thus, identifying an effective therapeutic target to prevent TAD is especially critical. The purpose of this study is to elucidate the potential mechanism of inflammation and vascular smooth muscle cell (VSMCs) phenotypic switch in β-aminopropionitrile fumarate (BAPN)-induced TAD. Methods A mouse model of TAD induced by BAPN and IL-1β -stimulated HVSMCs in vivo and in vitro models, respectively. ACE2 Knockdown mice treated with BAPN or without, and the TAD mouse model was treated with or without AAV-ACE2. Transthoracic ultrasound was conducted for assessment the maximum internal diameter of the thoracic aorta arch. RNA sequencing analysis was performed to recapitulate transcriptome profile changes. Western blot were used to detect the expression of MMP2, MMP9, ACE2, SIRT3, OPN, SM22α and other inflammatory markers. The circulating levels of ACE2 was measured by ELISA assay. Histological changes of thoracic aorta tissues were assessed by H&E, EVG and IHC analysis. Results We found that circulating levels of and the protein levels of ACE2 were increased in the TAD mouse model and in patients with TAD. For further evidence, ACE2 deficiency decelerated the formation of TAD. However, overexpression of ACE2 aggravated BAPN-induced aortic injury and VSMCs phenotypic switch via lowered SIRT3 expression and elevated inflammatory cytokine expression. Conclusion ACE2 deficiency prevented the development of TAD by inhibiting inflammation and VSMCs phenotypic switch in a SIRT3-dependent manner, suggesting that the ACE2/SIRT3 signaling pathway played a pivotal role in the pathological process of TAD and might be a potential therapeutical target.

Background: Aortic dissection (AD) is a critical emergency in cardiovascular disease. AD occurs only in specific sites of the aorta, and the variation of shear stress in different aortic segments is a possible cause not reported. This study investigated the key molecules involved in shear stress-induced AD through quantitative bioinformatic analysis of a public RNA sequencing database and clinical tissue sample validation. Methods: Gene expression data from the GSE153434, GSE147026, and GSE52093 datasets were downloaded from the Gene Expression Omnibus. Next, differently expressed genes (DEGs) in each dataset were identified and integrated to identify common AD DEGs. STRING, Cytoscape, and MCODE were used to identify hub genes and crucial clustering modules, and Connectivity Map (CMap) was used to identify positive and negative agents. The same procedure was performed for the GSE160611 dataset to obtain shear stress-induced human aortic endothelial cell (HAEC) DEGs. After the integration of these two DEGs sets to identify shear stress-associated hub DEGs in AD, Gene Ontology Enrichment Analysis was performed. The common chemokine receptors and ligands in AD were identified by analyzing AD's three RNA sequencing datasets. Their origin was verified by analyzing AD single-cell sequencing data and validated by immunoblotting and immunofluorescence. Results: We identified 100 down-regulated and 50 up-regulated AD common DEGs. Enrichment results showed that common DEGs were closely related to blood vessel morphogenesis, muscle structure development, muscle tissue development, and chemotaxis. Among those DEGs, MYC, CCL2, and SPP1 are the three molecules with the highest degree. A crucial cluster of 15 genes was identified using MCODE, which contained inflammation-related genes with elevated expression and muscle cell-related genes with decreased expression, and CCL2 is central to immune-related genes. CMap confirmed MEK inhibitors and ALK inhibitors as possible therapeutic agents for AD. Moreover, 366 shear stress-associated DEGs in HAEC were identified in the GSE160611 dataset. After taking the intersection, we identified five shear stress-associated hub DEGs in AD (ANGPTL4, SNAI2, CCL2, GADD45B, and PROM1), and the enrichment analysis indicated they were related to the endothelial cell apoptotic process. Chemokine CCL2 was the molecule with a high degree in both DEG sets. Besides CCL2, CXCL5 was the only chemokine ligand differentially expressed in the three datasets. Additionally, immunoblotting confirmed the increased expression of CCL2 and CXCL5 in clinical tissue samples. Further research at the single-cell level revealed that CCL2 has multiple origins, and CXCL5 is macrophage-derived. Conclusion: Through integrative analysis, we identified core common AD DEGs and possible therapeutic agents based on these DEGs. We elucidated that the chemokine CCL2 and CXCL5-mediated “Endothelial-Monocyte-Neutrophil” axis may contribute to the development of shear stress-induced AD. These findings provide possible therapeutic targets for the prevention and treatment of AD.

Doxorubicin (DOX) chemotherapy in cancer patients increases the risk of the occurrence of cardiac dysfunction and even results in congestive heart failure. Despite the great progress of pathology in DOX-induced cardiomyopathy, the underlying molecular mechanisms remain elusive. Here, we investigate the protective effects and the underlying mechanisms of melatonin in DOX-induced cardiomyopathy. Our results clearly show that oral administration of melatonin prevented the deterioration of cardiac function caused by DOX treatment, which was evaluated by left ventricular ejection fraction and fractional shortening as well as cardiac fibrosis. The ejection fraction and fractional shortening in the DOX group were 49.48% and 25.5%, respectively, while melatonin treatment increased the ejection fraction and fractional shortening to 60.33 and 31.39 in wild-type mice. Cardiac fibrosis in the DOX group was 3.97%, while melatonin reduced cardiac fibrosis to 1.95% in wild-type mice. Sirt3 is a mitochondrial deacetylase and shows protective effects in diverse cardiovascular diseases. Therefore, to test whether Sirt3 is a key factor in protection, Sirt3 knockout mice were used, and it was found that the protective effects of melatonin in DOX-induced cardiomyopathy were partly abolished. Further analysis revealed that Sirt3 and its downstream molecule TFEB were downregulated in response to DOX treatment, while melatonin administration was able to significantly enhance the expressions of Sirt3 and TFEB. Our in vitro study demonstrated that melatonin enhanced lysosomal function by increasing the Sirt3-mediated increase at the TFEB level, and the accumulation of autolysosomes induced by DOX treatment was attenuated. Thus, autophagic flux disrupted by DOX treatment was restored by melatonin supplementation. In summary, our results demonstrate that melatonin protects the heart against DOX injury by the restoration of autophagic flux via the activation of the Sirt3/TFEB signaling pathway.

The incidence of type 2 diabetes mellitus (T2DM) has been increasing globally, and T2DM patients are at an increased risk of major cardiac events such as myocardial infarction (MI). Nevertheless, the molecular mechanisms underlying MI injury in T2DM remain elusive. Ubiquitin-specific protease 10 (USP10) functions as a NICD1 (Notch1 receptor) deubiquitinase that fine-tunes the essential myocardial fibrosis regulator Notch signaling. Follistatin-like protein 1 (FSTL1) is a cardiokine with proven benefits in multiple pathological processes including cardiac fibrosis and insulin resistance. This study was designed to examine the roles of FSTL1/USP10/Notch1 signaling in MI-induced cardiac dysfunction in T2DM. High-fat-diet-treated, 8-week-old C57BL/6J mice and db/db T2DM mice were used. Intracardiac delivery of AAV9-FSTL1 was performed in T2DM mice following MI surgery with or without intraperitoneal injection of crenigacestat (LY3039478) and spautin-1. Our results demonstrated that FSTL1 improved cardiac function following MI under T2DM by reducing serum lactate dehydrogenase (LDH) and myocardial apoptosis as well as cardiac fibrosis. Further in vivo studies revealed that the protective role of FSTL1 against MI injury in T2DM was mediated by the activation of USP10/Notch1. FSTL1 protected cardiac fibroblasts (CFs) against DM-MI-induced cardiofibroblasts injury by suppressing the levels of fibrosis markers, and reducing LDH and MDA concentrations in a USP10/Notch1-dependent manner. In conclusion, FSTL1 treatment ameliorated cardiac dysfunction in MI with co-existent T2DM, possibly through inhibition of myocardial fibrosis and apoptosis by upregulating USP10/Notch1 signaling. This finding suggests the clinical relevance and therapeutic potential of FSTL1 in T2DM-associated MI and other cardiovascular diseases.

ObjectOur goal was to assess the implant depth of a Venus-A prosthesis during transcatheter aortic valve replacement (TAVR) when the areas of eccentric calcification were distributed in different sections of the aortic valve.MethodsA total of 53 patients with eccentric calcification of the aortic valve who underwent TAVR with a Venus-A prosthesis from January 2018 to November 2019 were retrospectively analyzed. The patients were divided into three groups (A, B, and C) according to the location of the eccentric calcification, which was determined by preprocedural computerized tomography angiography (CTA) images. The prosthesis release process and position were evaluated by contrast aortography during TAVR, and the differences in valve implant depths were compared among the three groups. The effects of different aortic root structures and procedural strategies on prosthesis implant depth were analyzed.ResultsEleven patients had eccentric calcification in region A; 19 patients, in region B; and 23 patients, in region C. The patients with eccentric calcification in region B had a higher risk of prosthesis migration (10.5% upward and 21.1% downward), and the position of the prosthesis after TAVR in group B was the deepest among the three groups. When eccentric calcification was located in region A or C, the prosthesis was released at the standard position with more stability, and the location of the prosthesis was less deep after TAVR (region A: 4.12 ± 3.4 mm; region B: 10.2 ± 5.3 mm; region C: 8.4 ± 4.0 mm; region A vs. region B, P = 0.0004; region C vs. region B; and P = 0.0360). In addition, the left ventricular outflow tract (LVOT) (P = 0.0213) and aortic root angulation (P = 0.0263) also had a significant effect on implant depth in the aortic root structure of the patients. The prosthesis size was 28.3 ± 2.4 in the deep implant group and 26.4 ± 2.0 in the appropriate implant group (P = 0.0068).ConclusionThe implant depth of the Venus-A prosthesis is closely related to the distribution of eccentric calcification in the aortic valve during TAVR. Surgeons should adjust the surgical strategy according to aortic root morphology to prevent prosthesis migration.

Myocardial ischemia/reperfusion injury is a common clinical problem and can result in severe cardiac dysfunction. Previous studies have demonstrated the protection of electroacupuncture against myocardial ischemia/reperfusion injury. However, the role of X-box binding protein I (XBP1) signaling pathway in the protection of electroacupuncture was still elusive. Thus, we designed this study and demonstrated that electroacupuncture significantly improved cardiac function during myocardial ischemia/reperfusion injury and reduced cardiac infarct size. Electroacupuncture treatment further inhibited cardiac injury manifested by the decrease of the activities of serum lactate dehydrogenase and creatine kinase-MB. The results also revealed that electroacupuncture elevated the expressions of XBP1, glucose-regulated protein 78 (GRP78), Akt, and Bcl-2 and decreased the Bax and cleaved Caspase 3 expressions. By using the inhibitor of XBP1 in vitro, the results revealed that suppression of XBP1 expression could markedly increase the activities of lactate dehydrogenase and creatine kinase-MB and cell apoptosis, thus exacerbating stimulated ischemia/reperfusion-induced H9c2 cell injury. Compared with stimulated ischemia/reperfusion group, inhibition of XBP1 inhibited the downstream GRP78 and Akt expressions during stimulated ischemia/reperfusion injury. Collectively, our data demonstrated that electroacupuncture treatment activated XBP1/GRP78/Akt signaling to protect hearts from myocardial ischemia/reperfusion injury. These findings revealed the underlying mechanisms of electroacupuncture protection against myocardial ischemia/reperfusion injury and may provide novel therapeutic targets for the clinical treatment of myocardial ischemia/reperfusion injury.

Abstract Background Myocardial ischemia/reperfusion (MI/R) injury imposes devastating cardiovascular sequelae in particular cardiac dysfunction as a result of restored blood flow. However, the mechanism behind MI/R injury remains elusive. Mitochondrial ubiquitin ligase (MITOL/MARCH5) is localized at the mitochondria‐ER contact site and may be activated in response to a variety of pathophysiological processes, such as apoptosis, mitochondrial injury, ER stress, hypoxia, and reactive oxygen species (ROS) generation. Irisin as a cleaved product of fibronectin type III domain‐containing protein 5 (FNDC5) displays cardioprotection in diverse cardiac diseases. Methods This study was designed to examine the role of irisin and MITOL in MI/R injury. Male C57BL/6J mice (8‐10‐week‐old) were administered adenovirus MITOL shRNA through intracardiac injection followed by MI/R surgery through ligation and release the slipknot of cardiac left anterior descending coronary artery. Results Our results showed that irisin improved myocardial function in the face of MI/R injury as evidenced by reduced myocardial infarct size, apoptotic rate, serum lactate dehydrogenase (LDH), ROS generation, and malondialdehyde (MDA) levels as well as lessened ER stress injury. Moreover, our results indicated that protective role of irisin was mediated by upregulation of MITOL. Irisin also protected H9c2 cells against simulated I/R through negating ER stress, apoptosis, ROS and MDA levels, as well as facilitating superoxide dismutase (SOD) by way of elevated MITOL expression. Conclusions To this end, our data favored that irisin pretreatment protects against MI/R injury, ER stress, ROS production, and mitochondrial homeostasis through upregulation of MITOL. These findings depicted the therapeutic potential of irisin and MITOL in the management of MI/R injury in patients with ST‐segment elevation.

During operations, surgical mesh is commonly fixed on tissues through fasteners such as sutures and staples. Attributes of surgical mesh include biocompatibility, flexibility, strength, and permeability, but sutures and staples may cause stress concentration and tissue damage. Here, we show that the functions of surgical mesh can be significantly broadened by developing a family of materials called hydrogel-mesh composites (HMCs). The HMCs retain all the attributes of surgical mesh and add one more: adhesion to tissues. We fabricate an HMC by soaking a surgical mesh with a precursor, and upon cure, the precursor forms a polymer network of a hydrogel, in macrotopological entanglement with the fibers of the surgical mesh. In a surgery, the HMC is pressed onto a tissue, and the polymers in the hydrogel form covalent bonds with the tissue. To demonstrate the concept, we use a poly(N-isopropylacrylamide) (PNIPAAm)/chitosan hydrogel and a polyethylene terephthalate (PET) surgical mesh. In the presence a bioconjugation agent, the chitosan and the tissue form covalent bonds, and the adhesion energy reaches above 100 J·m-2. At body temperature, PNIPAAm becomes hydrophobic, so that the hydrogel does not swell and the adhesion is stable. Compared with sutured surgical mesh, the HMC distributes force over a large area. In vitro experiments are conducted to study the application of HMCs to wound closure, especially on tissues under high mechanical stress. The performance of HMCs on dynamic living tissues is further investigated in the surgery of a sheep. [ABSTRACT FROM AUTHOR]

Abstract Background The purpose of this study was to examine the value of Xpert MTB/RIF assay and detection of additional Mycobacterium tuberculosis complex (MTBC) species antigens from intestinal tissue samples in differentiating intestinal tuberculosis (ITB) from Crohn’s disease (CD). Methods Several clinical specimens of intestinal tissue obtained by either endoscopic biopsy or surgical excision were used for mycobacteriologic solid cultures,Xpert MTB/RIF assays, immunohistochemistry, and histological examinations. Four antigens (38KDa, ESAT-6, MPT64, and Ag85 complex) of MTBC in the intestinal tissue were detected by immunohistochemical analysis. Results The study included 42 patients with ITB and 46 with CD. Perianal lesions and longitudinal ulcers were more common in patients with CD, while caseating granuloma and annular ulcers were more common in patients with ITB. The positive rate of MTBC detected by Xpert MTB/RIF in intestinal tissues of patients with ITB was 33.33%, which was significantly higher than that in patients with CD and that detected using acid-fast staining smears. It was also higher than that detected by tissue MTBC culture, but the difference was not statistically significant. The positive MPT64 expression rate in patients with ITB was 40.48%, which was significantly higher than that observed in patients with CD. The sensitivity of parallelly combined detection of tuberculosis protein MPT64 and Xpert MTB/RIF in diagnosing ITB was 50.0%. Conclusions The detection of Xpert MTB/RIF in intestinal tissue is a rapid and useful method for establishing an early diagnosis of ITB. The detection of MTBC using Xpert MTB/RIF and MPT64 antigen in intestinal tissues has a definitive value in the differential diagnosis ofITB and CD. The combination of these two methods can improve the detection sensitivity.