Vascular calcification is a highly regulated process in cardiovascular disease (CVD) and is strongly correlated with morbidity and mortality, especially in the adverse stage of vascular remodeling after coronary artery bypass graft surgery (CABG). However, the pathogenesis of vascular graft calcification, particularly the role of endothelial-smooth muscle cell interaction, is still unclear. To test how ECs interact with SMCs in artery grafts, single-cell analysis of wild-type mice is first performed using an arterial isograft mouse model and found robust cytokine-mediated signaling pathway activation and SMC proliferation, together with upregulated endothelial tripartite motif 35 (TRIM35) expression. Unexpectedly, severe SMC calcification in artery grafts is found in TRIM35 conditional endothelial knockout (cKO) mice. Calcified medium (comprising calcium chloride and beta-glycerophosphate)-induced calcium deposition in vitro is also found in SMCs cocultured with TRIM35 knockout endothelium. This extraordinary phenomenon is further confirmed to be induced by increased MMP10 secretion. Mechanistically, endothelial TRIM35 inhibits MMP10 expression and secretion by promoting K63-linked ubiquitination of RelB and maintaining its nuclear localization, consequently inhibiting nuclear transcription of MMP10 through the noncanonical NF-κB signaling pathway. Targeting MMP10 in situ in arterial isografts can effectively alleviate vascular calcification caused by conditional endothelial TRIM35 knockout. These findings demonstrated that TRIM35 inhibited vascular calcification during arterial isograft remodeling, a process that is driven by the aberrant secretion of endothelial MMP10. Targeting MMP10 pathway may be a potential therapeutic strategy for vascular calcification in vessel grafts.

Cardiovascular injury and repair rely on the coordinated recruitment,proliferation,and differentiation of multiple cell types.As a heterogeneous cell population defined by the cluster of differentiation 34(CD34)protein,CD34+cells have long been regarded as key targets for cardiovascular regeneration and repair.These cells exhibit pronounced heterogeneity and pluripotent differentiation potential.Under the regulation of specific microenvironmental signals,they can differentiate into multiple lineages,such as endothelial cells,smooth muscle cells,fibroblasts,and inflammatory cells,thereby contributing to endothelial repair,tissue fibrosis,and immune modulation.In cardiovascular disease,CD34+cells exert dual effects:they may facilitate tissue repair and regeneration while also potentially exacerbating pathological injury.Although CD34+cell therapies have shown therapeutic promise in cardiovascular diseases,their clinical translation still faces numerous challenges and bottlenecks.Here,current evidence on the sources,differentiation trajectories,and functional heterogeneity of CD34+cells is synthesized,and recent advances spanning basic research and clinical translation are summarized,with the aim of refining mechanistic understanding and informing the development of precise therapeutic strategies.

ABSTRACT Purpose Many studies investigated the one-single-direction relationship between arterial stiffness and chronic kidney dysfunction, particularly in patients with end-stage renal disease. The bidirectional relevance between kidney function decline and arterial stiffness in general population remains unknown. This study aimed to address the temporary relationship between arterial stiffness and renal function. Materials and Methods This large-scale observational study comprised one cross-sectional and one longitudinal population sample totalling 67,060 individuals aged over 18 years with brachial-ankle pulse wave velocity (baPWV) and estimated glomerular filtration rate (eGFR) measurements available. Associations with potential risk conditions were analysed using multiple regression analyses. Cox proportional model was used to investigate the association of arterial stiffness and incident chronic kidney disease (CKD). Cross-lagged path analysis was further conducted to analyze the temporal relationship between baPWV and eGFR. Results Multiple regression analyses showed that baPWV was inversely associated with eGFR. Compared with the lower baPWV tertile group, higher baPWV was a predictor of CKD risk, with increased HRs for three baPWV tertile groups [HR=2.17 (1.26-3.76), P for trend <0.05]. Accordingly, lower eGFR was significantly associated with higher arterial stiffness risk, even after full-adjusted [HR=1.21 (1.02-1.44), P for trend <0.05]. In the path analysis, the coefficient of the association between baseline baPWV and follow-up eGFR was lower than the effect of baseline eGFR for follow-up baPWV (−0.063 Vs. −0.077, P <0.001). Conclusions Decrease of eGFR appeared to aggravate arterial stiffness, which unravelling a new understanding of the role kidney dysfunction played in arterial stiffening.

RIPK1 is crucial in the inflammatory response. The process of vascular graft remodeling is also involved in endothelial inflammation, which can influence the behavior of smooth muscle cells. However, the role of endothelial RIPK1 in arterial bypass grafts remains unknown. Here, we established an arterial isograft mouse model in wild-type and endothelial RIPK1 conditional knockout mice. Progressive vascular remodeling and neointima formation occurred in the graft artery, showing SMC accumulation together with endothelial inflammatory adhesion molecule and cytokine expression. Endothelial RIPK1 knockout exacerbated graft stenosis by increasing secretion of N-Shh. Mechanistically, RIPK1 directly phosphorylated EEF1AKMT3 at Ser 26 , inhibiting its methyltransferase activity and global protein synthesis, which further attenuated N-Shh translation and secretion. Consistently, treatment with the Hedgehog pathway inhibitor GDC0449 markedly alleviated RIPK1 knockout–induced graft stenosis. Our results demonstrated that endothelial RIPK1 played a protective role in arterial bypass graft vascular remodeling, highlighting that targeting Hedgehog pathway may be an attractive strategy for graft failure in the future.

Background Electrolyte balance is an important factor to sustain the homeostasis of human body environment and in sepsis pathogenesis. Many current cohort-based studies have already revealed that electrolyte disorder may intensify sepsis and induce stroke. However, the corresponding randomized controlled trials did not show that electrolyte disorder in sepsis has a harmful effect on stroke. Objectives The aim of this study was to examine the association of genetically sepsis-derived electrolyte disorder with stroke risk using meta-analysis and Mendelian randomization. Results In four studies (182,980 patients), electrolyte disorders were compared with stroke incidence in patients with sepsis. The pooled odds ratio (OR) of stroke is 1.79 [95% confidence interval (CI): 1.23–3.06; p < 0.05], which shows a significant association between electrolyte disorder and stroke in sepsis patients. Furthermore, in order to evaluate the causal association between stroke risk and sepsis-derived electrolyte disorder, a two-sample Mendelian randomization (MR) study was conducted. The genetic variants extracted from a genome-wide association study (GWAS) of exposure data that are strongly associated with frequently used sepsis were used as instrumental variables (IVs). Based on the IVs’ corresponding effect estimates, we estimated overall stroke risk, cardioembolic stroke risk, and stroke induced by large/small vessels from a GWAS meta-analysis with 10,307 cases and 19,326 controls. As a final step to verify the preliminary MR results, we performed sensitivity analysis using multiple types of Mendelian randomization analysis. Conclusion Our study revealed the association between electrolyte disorder and stroke in sepsis patients, and the correlation between genetic susceptibility to sepsis and increased risk of cardioembolic stroke, hinting that cardiogenic diseases and accompanying electrolyte disorder interference in due course could help sepsis patients get more benefits in stroke prevention.

BackgroundGenetic risk factors substantially contributed to the development of coronary atherosclerosis. Genome-wide association study (GWAS) has identified many risk loci for coronary atherosclerosis, but the translation of these loci into therapeutic targets is limited for their location in non-coding regions. Here, we aimed to screen the potential coronary atherosclerosis pathogenic genes expressed though TWAS (transcriptome wide association study) and explore the underlying mechanism association.MethodsFour TWAS approaches (PrediXcan, JTI, UTMOST, and FUSION) were used to screen genes associated with coronary atherosclerosis. Enrichment analysis of TWAS-identified genes was applied through the Metascape website. The summary-data-based Mendelian randomization (SMR) analysis was conducted to provide the evidence of causal relationship between the candidate genes and coronary atherosclerosis. At last, the cell type-specific expression of the intersection genes was examined by using human coronary artery single-cell RNA-seq, interrogating the immune microenvironment of human coronary atherosclerotic plaque at different stages of maturity.ResultsWe identified 19 genes by at least three approaches and 1 gene (NBEAL1) by four approaches. Enrichment analysis enriching the genes identified at least by two TWAS approaches, suggesting that these genes were markedly enriched in asthma and leukocyte mediated immunity reaction. Further, the summary-data-based Mendelian randomization (SMR) analysis provided the evidence of causal relationship between NBEAL1 gene and coronary atherosclerosis, confirming the protecting effects of NBEAL1 gene and coronary atherosclerosis. At last, the single cell cluster analysis demonstrated that NBEAL1 gene has differential expressions in macrophages, plasma cells and endothelial cells.ConclusionOur study identified the novel genes associated with coronary atherosclerosis and suggested the potential biological function for these genes, providing insightful guidance for further biological investigation and therapeutic approaches development in atherosclerosis-related diseases.

Background Obstructive sleep apnea (OSA) and atrial fibrillation (AF) are epidemiologically correlated, but the causal relationship between them remains elusive. We aimed to explore the causal relationships between OSA and AF. Method Using both the Finnish biobank and publicly available genome-wide association study data (GWAS), we conducted a two-sample Mendelian randomization (MR) analysis to estimate the causal effect of OSA on AF, both in the primary analysis and replicated analysis. The inverse variance weighted MR was selected as the main method. To further test the independent causal effect of OSA on AF, we also performed multivariable MR (MVMR), adjusting for body mass index (BMI), hypertension, and coronary artery disease (CAD), respectively. Results In the primary analysis, OSA was significantly associated with the increased risk of AF (OR 1.21, 95% CI 1.11–1.32) and the replicated analysis showed consistent results (OR 1.17, 95% CI 1.05–1.30). Besides, there was no heterogeneity and horizontal pleiotropy observed both in the primary and replicated analysis. Further multivariable MR suggested that the causal relationships between OSA and AF exist independently of BMI and CAD. The MVMR result after the adjustment for hypertension is similar in magnitude and direction to the univariable MR. But it did not support a causal relationship between OSA and AF. Conclusion Our study found that genetically driven OSA causally promotes AF. This causal relationship sheds new light on taking effective measures to prevent and treat OSA to reduce the risk of AF.

The receptor interacting protein kinases 1/3 (RIPK1/3) have emerged as the key mediators in cell death pathways and inflammatory signaling, whose ubiquitination, phosphorylation, and inhibition could regulate the necroptosis and apoptosis effectually. Recently, more and more studies show great interest in the mechanisms and the regulator of RIPK1/3-mediated inflammatory response and in the physiopathogenesis of cardiovascular diseases. The crosstalk of autophagy and necroptosis in cardiomyocyte death is a nonnegligible conversation of cell death. We elaborated on RIPK1/3-mediated necroptosis, pathways involved, the latest regulatory molecules and therapeutic targets in terms of ischemia reperfusion, myocardial remodeling, myocarditis, atherosclerosis, abdominal aortic aneurysm, and cardiovascular transplantation, etc.

肥胖是一种脂肪组织过度积累的状态,其在全球范围内的流行已经成为了一个重大的公共卫生挑战.世界卫生组织报道,截至2016年,在全球范围内,18岁及以上的成年人中超重人数超过19亿,肥胖人数超过6.5亿(超重率为39％,肥胖率为13％),且全球肥胖流行率在1975至2016年间增长近3倍[1].体质指数(BMI)增高会增加与其相关的心脏代谢疾病的患病风险,如高血压、冠心病和2型糖尿病等[2].

The long noncoding RNA H19 was reported to associate with melanogenesis. However, it remains unknown whether H19 expression will be changed by UVB irradiation and whether H19 will regulate melanocytes melanogenesis by paracrine effects. Here, we analysed the expression changes of H19 irradiated by UVB in keratinocytes and explored the mechanism of melanogenesis stimulated by H19 through paracrine effects. First, after keratinocytes were exposed to UVB irradiation, expression of H19 and pro‐opiomelanocortin ( POMC ) was measured by qRT ‐ PCR . Also, α‐melanocyte‐stimulating hormone (α‐ MSH ) contents in cells supernatant were measured by ELISA . Then, H19 si RNA s were designed and transfected into keratinocytes by liposome. The expression changes of H19, POMC and α‐ MSH were detected. Besides, expression of p53 was detected by Western blot. After that, supernatant of keratinocytes with H19 si RNA s or negative control si RNA was cocultured with immortalized melanocyte line PIG 1. Expression levels of Mi TF , TYR , Rab27A, TYRP 2, FSCN 1 and MYO 5A in PIG 1 cells were detected by Western blot and qRT ‐ PCR . We found that H19 expression of keratinocytes cells decreased after UVB irradiation. However, the levels of POMC , α‐ MSH and p53 were upregulated in UVB ‐irradiated cells. Compared with the negative control, H19 si RNA s could significantly increase the expression of POMC , α‐ MSH and p53. After supernatant of keratinocytes transfected with H19 si RNA s was cocultured with PIG 1 cells, the levels of Mi TF , TYR and Rab27A were upregulated in PIG 1 cells. In conclusion, UVB ‐inhibited H19 may promote α‐ MSH secretion by p53 in keratinocytes and then regulate melanocytes melanogenesis through paracrine effects.