‌Oxidative stress and insulin resistance (IR) are risk factors for cardiovascular and metabolic diseases (CVMDs). However, the interaction between the oxidative balance score (OBS, marker of oxidative stress), and the triglyceride-glucose index (TyG, IR surrogate), on CVMDs risk, remains largely unexplored. This cross-sectional, population-based study used data from the National Health and Nutrition Examination Survey (NHANES, 1999–2018), examining OBS and TyG. All exposures and outcomes were ascertained at the same time point; therefore, only associational relationships are reported. The primary outcome was the prevalence of four major CVMDs—cardiovascular disease (CVD), hypertension, type 2 diabetes mellitus (T2DM), and hyperlipidemia. Among 17,265 participants, the prevalence rates were 8.5

BACKGROUND:Myocardial ischemia/reperfusion (I/R) injury is a common and severe clinical complication in patients with ischemic heart disease after reperfusion therapy. Effective therapeutic strategies for myocardial I/R injury remain limited. Ferroptosis is a form of regulated cell death characterized by iron-dependent lipid peroxidation. However, the mechanisms underlying ferroptosis in myocardial I/R injury are not fully understood. METHODS:Transcriptomic data from patients with heart failure and cardiomyocytes undergoing ferroptosis were analyzed. Based on the screening results, TRIM28 (tripartite motif-containing 28) expression was evaluated in ferroptotic cardiomyocytes. Cardiac I/R injury models in mice and hypoxia/reoxygenation injury models in neonatal rat ventricular myocytes were established. To explore the function of TRIM28, we used adeno-associated virus serotype 9 to achieve cardiomyocyte-specific overexpression and generated tamoxifen-inducible cardiomyocyte-specific TRIM28 knockout mice. RNA sequencing, coimmunoprecipitation coupled with mass spectrometry, and ubiquitinome profiling were applied to elucidate the underlying mechanisms. Human heart samples from patients with ischemic heart disease were used to evaluate the expression of TRIM28 and its related signaling molecules. The Connectivity Map database was used to screen potential activators of TRIM28. RESULTS:We found that TRIM28 expression was downregulated in ferroptosis inducer-treated and hypoxia/reoxygenation-injured cardiomyocytes, as well as in I/R-injured mouse hearts. Cardiomyocyte-specific overexpression of TRIM28 protected the heart against I/R-induced ferroptosis, whereas its deficiency exacerbated myocardial I/R-induced ferroptotic injury. Mechanistically, TRIM28 functioned as an E3 ubiquitin ligase that directly bound to IRP2 (iron regulatory protein 2) and promoted K48-linked ubiquitination at the K877 site, leading to the downregulation of IRP2 and TFR1 (transferrin receptor 1), suppression of intracellular iron uptake, and consequent attenuation of cardiomyocyte ferroptosis. Furthermore, p55γ interacted with and upregulated TRIM28, thereby mitigating I/R-induced myocardial ferroptosis. Consistent with these findings, protein levels of TRIM28 and p55γ were decreased in heart samples from patients with ischemic heart disease, whereas IRP2 and TFR1 were increased. Last, we demonstrated that perhexiline inhibited I/R-induced myocardial ferroptosis by upregulating p55γ and TRIM28. CONCLUSIONS:Our study identifies TRIM28 as an essential E3 ubiquitin ligase of IRP2 and delineates that TRIM28-mediated inhibition of myocardial ferroptosis by targeting IRP2-TFR1 signaling protects the heart against I/R injury, indicating that targeting TRIM28 represents a promising therapeutic strategy for suppressing cardiomyocyte ferroptosis and I/R injury.

BACKGROUND:Peripheral artery disease is a severe ischemic vascular pathology without effective pharmacological approaches and improving angiogenesis to recover blood perfusion is a promising therapeutic strategy. Endothelial cells are the primary cell type contributing to angiogenesis in response to ischemia. However, the molecular mechanisms regulating ischemia-induced angiogenesis remain elusive. METHODS:We used a discovery-driven approach to identify elevated SRSF1 (serine/arginine splicing factor 1) expression in endothelial cells after ischemia. We used loss- and gain-of-function approaches to explore the role of SRSF1 in angiogenesis both in vivo and in vitro. A mouse model of hindlimb ischemia was used to evaluate ischemia-induced angiogenesis. We also investigated the mechanisms through transcriptome, enhanced crosslinking and immunoprecipitation sequencing, RNA pull-down, and chromatin immunoprecipitation-quantitative polymerase chain reaction analysis. RESULTS:Proteomic analyses identified endogenous SRSF1 accumulated in endothelial cells of the ischemic muscle and responded to hypoxia. Mice deficient in endothelial SRSF1 exhibited impaired blood flow recovery and impaired vasculature formation after hindlimb ischemia. Importantly, overexpression of SRSF1 enhanced blood flow recovery and angiogenesis after hindlimb ischemia. SRSF1 overexpression enhanced the angiogenic functions of human endothelial cells, promoting tube formation, sprouting capability, and cell migration, while SRSF1 knockdown suppressed these functions. Mechanistically, SRSF1 modulated the alternative splicing of ATF3 (activating transcription factor 3) by directly binding to ATF3 pre-mRNA (precursor messenger RNA), and SRSF1 overexpression elevated full-length ATF3 transcript at the expense of truncated ATF3Δzip2 transcript. ATF3 then bound directly to the KLF2 (Krüppel-like factor 2) promoter, suppressed KLF2 expression and downstream S1PR1 (sphingosine-1-phosphate receptor 1) signaling. Through upregulation of full-length ATF3 and downregulating KLF2-S1PR1 signaling, SRSF1 promoted endothelial tube formation and angiogenesis. In addition, alprostadil, the prostaglandin E1 analog, could activate the SRSF1 signaling to improve endothelial angiogenesis in vitro and in vivo. CONCLUSIONS:Our findings identified SRSF1 as a novel regulator of ischemia-induced angiogenesis that enhances endothelial angiogenic functions by regulating the ATF3-KLF2-S1PR1 pathway. These results suggest that modulation of endothelial SRSF1 may represent a promising therapeutic approach for treating ischemic vascular diseases.

Myocardial ischemia-reperfusion (I/R) injury is a prevalent cause of myocardial injury, involving a series of interconnected pathophysiological processes. However, there is currently no clinical therapy for effectively mitigating myocardial I/R injury. Here, we show that p85α protein levels increase in response to I/R injury through a comprehensive analysis of cardiac proteomics, and confirm this in the I/R-injured murine heart and failing human myocardium. Genetic inhibition of p85α in mice activates the Akt-GSK3β/Bcl-x(L) signaling pathway and ameliorates I/R-induced cardiac dysfunction, apoptosis, inflammation, and mitochondrial dysfunction. p85α silencing in cardiomyocytes alleviates hypoxia-reoxygenation (H/R) injury through activating the Akt-GSK3β/Bcl-x(L) signaling pathway, while its overexpression exacerbates the damage. Mechanistically, the interaction between MG53 and p85α triggers the ubiquitination and degradation of p85α, consequently enhancing Akt phosphorylation and ultimately having cardioprotective effects. Collectively, our findings reveal that substantial reduction of p85α and subsequently activated Akt signaling have a protective effect against cardiac I/R injury, representing an important therapeutic strategy for mitigating myocardial damage.

Background: Exploratory studies have shown that remote ischemic conditioning (RIC) has the potential to lower blood pressure (BP). We investigated whether chronic RIC reduces BP for hypertension. Methods: This is a multicenter, randomized, double-blind, parallel-controlled trial. Patients with an office BP of 130/80 to 160/100 mm Hg and a 24-hour average BP ≥125/75 mm Hg not on antihypertensive medications were recruited. After a 1-week compliance screening phase, they were randomly assigned in a 1:1 ratio to receive RIC or sham RIC twice daily for 4 weeks. The primary efficacy outcome was the change in 24-hour average systolic BP from baseline to 4 weeks. Safety events were assessed over the study period. Results: Ninety-five participants were randomly allocated to the RIC (n=49) and sham RIC (n=46) groups. In the intention-to-treat analysis, the reduction in 24-hour average systolic BP was greater in the RIC group than the sham RIC group (−4.6±9.5 versus −0.9±6.8 mm Hg; baseline-adjusted between-group mean difference: −3.6 mm Hg [95% CI, −6.9 to −0.3 mm Hg]; adjusted P =0.035). The per-protocol analysis showed that 24-hour average systolic BP reduced −5.9±8.6 mm Hg in the RIC group and −0.7±6.7 mm Hg in the sham RIC group (baseline-adjusted between-group mean difference: −5.2 mm Hg [95% CI, −8.5 to −1.9 mm Hg]; adjusted P =0.002). No major adverse events were reported in both groups. Conclusions: RIC is safe in patients with mild hypertension and may lower BP in the absence of antihypertensive medications. However, the effects of RIC on clinical outcomes in these patients require further investigation. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04915313.

Aims Regulated necrosis (necroptosis) and apoptosis are important biological features of myocardial infarction, ischaemia-reperfusion (I/R) injury, and heart failure. However, the molecular mechanisms underlying myocardial necroptosis remain elusive. Ischaemic preconditioning (IPC) is the most powerful intrinsic cardioprotection against myocardial I/R injury. In this study, we aimed to determine whether IPC suppresses I/R-induced necroptosis and the underlying molecular mechanisms. Methods and results We generated p55 gamma transgenic and knockout mice and used ligation of left anterior descending coronary artery to produce an in vivo I/R model. The effects of p55 gamma and its downstream molecules were subsequently identified using mass spectroscopy and co-immunoprecipitation and pulldown assays. We found that p55 gamma expression was down-regulated in failing human myocardium caused by coronary heart disease as well as in I/R mouse hearts. Cardiac-specific p55 gamma overexpression ameliorated the I/R-induced necroptosis. In striking contrast, p55 gamma deficiency (p55 gamma(-/-)) and cardiac-specific deletion of p55 gamma (p55 gamma(c-KO)) worsened I/R-induced injury. IPC up-regulated p55 gamma expression in vitro and in vivo. Using reporter and chromatin immunoprecipitation assays, we found that Hif1 alpha transcriptionally regulated p55 gamma expression and mediated the cardioprotection of IPC. IPC-mediated suppression of necroptosis was attenuated in p55 gamma(-/-) and p55 gamma(c-KO) hearts. Mechanistically, p55 gamma overexpression decreased the protein levels of RIP3 rather than the mRNA levels, while p55 gamma deficiency increased the protein abundance of RIP3. IPC attenuated the I/R-induced up-regulation of RIP3, which was abolished in p55 gamma-deficient mice. Up-regulation of RIP3 attenuated the p55 gamma- or IPC-induced inhibition of necroptosis in vivo. Importantly, p55 gamma directly bound and degraded RIP3 in a ubiquitin-dependent manner. We identified MG53 as the E3 ligase that mediated the p55 gamma-induced degradation of RIP3. In addition, we also found that p55 gamma activated the RISK pathway during IPC. Conclusions Our findings reveal that activation of the MG53-RIP3 signal pathway by p55 gamma protects the heart against I/R-induced necroptosis and underlies IPC-induced cardioprotection.

Background: The myocardial protective effects of activating the PI3K/Akt pathway have been documented, however, the impact of p85α, which is a regulatory subunit of class IA PI3K, on myocardial injury remains elusive.Methods: A mouse model of myocardial ischemia-reperfusion (I/R) injury and the model of hypoxia/reoxygenation (H/R) in cardiomyocytes were utilized. The role of p85α in myocardial injury was investigated through genetic depletion of p85α in mice, overexpression mediated by adenovirus, and knockdown using siRNA in cardiomyocytes. Transcriptomic analysis, immunoprecipitation assays, and western blots were applied to examine the molecular mechanisms of p85α.Findings: A comprehensive analysis of cardiac proteomics in response to I/R injury showed an elevation in the expression of p85α, which was further validated both in vivo and in vitro and in failing human myocardium. Transcriptome and functional studies revealed that genetic inhibition of p85α in mice resulted in improved cardiac function and the suppression of apoptosis, inflammation, and mitochondrial dysfunction induced by I/R. In vitro, reducing the levels of p85α in cardiomyocytes alleviated H/R injury, while its overexpression exacerbated the damage. Further investigation uncovered that downregulating p85α improved mitochondrial function through upregulating the expression of ERRα and PGC-1α, and activated the Akt-GSK3β/Bcl-x(L) signaling pathway, leading to protection against I/R injury. Mechanistically, the interaction between MG53 and p85α triggered ubiquitination and degradation processes for p85α, consequently enhancing Akt phosphorylation and ultimately exerting cardioprotective effects.Interpretation: Overall, our study demonstrates that substantial reduction of p85α has a protective effect against cardiac I/R injury. Our findings suggest that inhibition of p85α may provide a therapeutic strategy for mitigating myocardial damage.Funding: This study was funded by the National Nature Science Foundation of China (82030010 and U22A20268 to C.-M.C.).Declaration of Interest: The authors declare no conflict of interest.Ethical Approval: This study was approved by the Ethics Committee of Fuwai Hospital (IORG0003571). And all procedures involving human participants conformed to the ethical guidelines of the 1975 Declaration of Helsinki. The animal experiments were conducted in accordance with the guidelines outlined in the Guide for the Care and Use of Laboratory Animals (NIH Publication No. 86-23, revised 2011) and received approval from the Animal Care Committee of Capital Medical University.

Pyroptosis is a kind of programmed cell death mediated by the gasdermin protein, including the classical pathway that depends on caspase-1 and the non-classical pathway that depends on caspase-4, -5, and 11, accompanied by the release of a large number of inflammatory factors. Atherosclerosis, myocardial ischemia, heart failure and other cardiovascular diseases are closely related to inflammatory response. Pyroptosis, as a highly pro-inflammatory cell death, is also widely involved in the occurrence and development of the cardiovascular diseases, and plays an important role in these diseases.

PI3K-Akt信号通路在细胞增殖和代谢中发挥了重要作用,并且PI3K-Akt信号通路在心脏保护机制——缺血预适应和缺血后适应中发挥重要作用.本文通过分析PI3K分子和Akt分子以及PI3K-Akt信号通路对心脏和血管生理性和病理性的影响,旨在了解其在心血管疾病中的作用.