BackgroundMyocardial ischemia-reperfusion injury (MIRI) remains a therapeutic challenge with limited treatment options. Ferroptosis, characterized by lipid peroxidation, contributes significantly to MIRI pathogenesis. This study investigates whether dihydromyricetin (DHM), a bioactive flavonoid from Ampelopsis grossedentata, alleviates MIRI by inhibiting ferroptosis, and explores its cardioprotective mechanisms.MethodsA mouse myocardial I/R model was established in vivo by ligating the left anterior descending coronary artery for 30 min, followed by reperfusion for one or 7 days. Mice were pretreated with DHM (125 or 250 mg/kg, gavage) for 4 weeks, or with Fer-1 (10 mg/kg) for 1 week. In vitro, an OGD/R model was constructed using H9c2 cells, which were then treated with DHM (0–200 μM) or Fer-1 (10 μM). Potential targets were screened via network pharmacology. Target interaction was validated through biotin-pull-down, molecular docking, CETSA, and DARTS assays. Functional validation was performed using PPARα-knockdown and rescue cell lines.ResultsGSEA indicated significant activation of the ferroptosis pathway in MIRI, and cellular experiments confirmed that OGD/R induced a typical ferroptosis phenotype. DHM dose-dependently reversed OGD/R-induced ferroptosis-related alterations and ameliorated mitochondrial ultrastructural damage. In vivo, DHM pretreatment significantly reduced serum CK-MB levels, myocardial infarct size, and histopathological injury in I/R mice, while reversing cardiac ferroptosis marker changes. Mechanistically, network pharmacology identified seven overlapping targets, among which DHM specifically reversed the downregulation of PPARα. Biochemical assays and molecular docking confirmed that DHM directly binds to and stabilizes PPARα via the E286 site. Knockdown of PPARα markedly attenuated the anti-ferroptotic and cardioprotective effects of DHM, whereas PPARα rescue partially restored its function.ConclusionThis study demonstrates for the first time that DHM alleviates ischemia-reperfusion injury by directly targeting the E286 site of PPARα, upregulating its levels, and thereby suppressing cardiomyocyte ferroptosis. This finding reveals a novel mechanism underlying the cardioprotective effect of DHM and provides a new theoretical basis for targeting the PPARα-ferroptosis axis in MIRI intervention.

Background: Increasing evidence suggests a positive correlation between serum uric acid (SUA) levels and incident hypertension (IHT). However, few studies have focused on the sex-differential impact of SUA levels on IHT in populations with a normal body mass index (BMI). Methods: This study included participants without hypertension who had a BMI in the normal range (18.5–23.9 kg/m2). Sex-specific quartiles of SUA levels (Q1–Q4) were defined as: ≤180, 181–213, 214–249, and >249 μmol/L for females; ≤282, 283–324, 325–373, and >373 μmol/L for males. IHT was considered present when systolic blood pressure (SBP) was ≥140 mmHg or diastolic blood pressure (DBP) was ≥90 mmHg, or antihypertensive drugs were used. Cox proportional hazards models and mediation analysis were performed to estimate hazard ratios (HRs) and potential mediators in the relationship between sex-differential SUA levels and IHT. Results: This study included 24,538 participants, comprising 13,063 females and 11,475 males, with an IHT of 4.9% in females and 11.4% in males during 24 (12, 36) months. In the sex-stratified analysis, females exhibited higher unadjusted HRs for Q4 versus Q1 (HR = 3.487, 95% CI: 2.701–4.500; p < 0.001) compared to males (HR = 2.016, 95% CI: 1.719–2.365; p < 0.001). After adjustment for multiple variables, the HRs for females remained higher than those for males (2.237 [1.670–2.998] vs. 1.904 [1.601–2.265]); however, the magnitude of the difference was notably reduced. Mediation analysis indicated that the association between SUA levels and IHT was primarily driven by age (19.42%), low-density lipoprotein (LDL) cholesterol (10.90%), and triglycerides (10.46%) in females, and by BMI (9.94%), triglycerides (TG) (8.73%), serum creatinine (7.26%), and age (7.23%) in males. Conclusion: SUA levels among Chinese adults with a normal BMI range were positively associated with IHT, with an apparent stronger association in females than in males.

This study investigates the role of the deubiquitinating enzyme USP14 in alleviating doxorubicin (DOX)-induced cardiotoxicity (DIC), particularly concerning its mechanism of regulating pyroptosis through the stabilization of the mitochondrial protein SIRT3. Using in vivo and in vitro models, the research demonstrated that USP14 overexpression protects against DOX-induced cardiac damage by modulating pyroptosis. Silencing SIRT3 via siRNA revealed that SIRT3 is a key intermediary molecule in USP14-mediated regulation of pyroptosis. Notably, DOX exposure resulted in decreased USP14 expression, while its overexpression preserved mitochondrial function and reduced oxidative stress by stabilizing SIRT3. Immunoprecipitation confirmed that USP14 stabilizes SIRT3 through deubiquitination. These findings position USP14 as a promising therapeutic target for mitigating DOX-induced cardiotoxicity by stabilizing SIRT3 and maintaining mitochondrial integrity, suggesting potential novel strategies for cardio-protection in chemotherapy.

Background Aortic dissection (AD) is a lethal vascular disease with high mortality and morbidity. Though AD clinical pathology is well understood, its molecular mechanisms remain unclear. Specifically, gene expression profiling helps illustrate the potential mechanism of aortic dissection in terms of gene regulation and its modification by risk factors. This study was aimed at identifying the genes and molecular mechanisms in aortic dissection through bioinformatics analysis. Method Nine patients with AD and 10 healthy controls were enrolled. The gene expression in peripheral mononuclear cells was profiled through next-generation RNA sequencing. Analyses including differential expressed gene (DEG) via DEGseq, weighted gene coexpression network (WGCNA), and VisANT were performed to identify crucial genes associated with AD. The Database for Annotation, Visualization, and Integrated Discovery (DAVID) was also utilized to analyze Gene Ontology (GO). Results DEG analysis revealed that 1,113 genes were associated with AD. Of these, 812 genes were markedly reduced, whereas 301 genes were highly expressed, in AD patients. DEGs were rich in certain categories such as MHC class II receptor activity, MHC class II protein complex, and immune response genes. Gene coexpression networks via WGCNA identified 3 gene hub modules, with one positively and 2 negatively correlated with AD, respectively. Specifically, module 37 was the most strongly positively correlated with AD with a correlation coefficient of 0.72. Within module 37, five hub genes (AGFG1, MCEMP1, IRAK3, KCNE1, and CLEC4D) displayed high connectivity and may have clinical significance in the pathogenesis of AD. Conclusion Our analysis provides the possible association of specific genes and gene modules for the involvement of the immune system in aortic dissection. AGFG1, MCEMP1, IRAK3, KCNE1, and CLEC4D in module M37 were highly connected and strongly linked with AD, suggesting that these genes may help understand the pathogenesis of aortic dissection.

The above article, published online on 09 October 2021 in Wiley Online Library ( wileyonlinelibrary.com ), has been withdrawn by agreement between the journal Editor in Chief, Gening Jiang, and John Wiley & Sons Ltd. The withdrawal has been agreed because the authors have not responded to repeated attempts to contact them to correct and approve the article proofs for publication of the version of record.

The above article, published online on 09 October 2021 in Wiley Online Library ( wileyonlinelibrary.com ), has been withdrawn by agreement between the journal Editor in Chief, Gening Jiang, and John Wiley & Sons Ltd. The withdrawal has been agreed because the authors have not responded to repeated attempts to contact them to correct and approve the article proofs for publication of the version of record.

It remains obscure whether circulating aortic zinc (Zn) and copper (Cu) levels are associated with the progress of human abdominal aortic aneurysms (AAA). Therefore, we conducted a meta-analysis to explore this relationship. A literature search on circulating and aortic zinc and copper levels and AAA patients was conducted using online databases including PubMed, Embase, and Cochrane up to March 20, 2019. To compare Zn and Cu concentrations in AAA patients with those in aortic occlusive disease (AOD) patients or healthy aorta donors or healthy blood donors, pooled weighted mean difference (WMD) and its 95% confidence interval (CI) were calculated. Subgroup analysis, sensitivity analysis, and meta-regression analysis were applied to explain the heterogeneity and evaluate the robustness of combined results. A total of 10 cross-sectional studies, including 252 cases and 304 controls, were used for meta-analysis. We found that circulating zinc and Zn/Cu ratio in AAA patients were significantly lower [WMD (95%CI): − 2.23 (− 4.10, − 0.36); − 0.18 (− 0.31, − 0.05), respectively] than those in non-AAA patients. Similarly, aneurysmal aorta had significantly lower zinc levels and Zn/Cu ratio [WMD (95%CI): − 9.22 (− 15.37, − 3.07); − 6.46 (− 10.14, − 2.77), respectively] than those in control group. No difference in circulating or aortic copper levels was noted between AAA patients and control group [WMD (95%CI): - 0.24 (- 2.09, 1.61); 0.30 (- 0.01, 0.61) , respectively]. Our meta-analysis suggests that zinc levels and Zn-Cu ratio, but not copper levels, may influence aneurysmal progress of AAA.

ObjectiveTo assess the association of gene polymorphisms of angiotensinogen (AGT), the key factor in rennin‐angiotensin‐aldosterone system (RAAS), with high‐sensitivity C‐reactive protein (hs‐CRP) and coronary artery disease (CAD).MethodsThe current study recruited the patients who were hospitalized and assessed by coronary angiography for suspected CAD. The patients with documented CAD served as CAD group (n = 492) while the patients without documented CAD (n = 87) served as control group. We compared laboratory data and CAD risk factors between the two groups. Furthermore, we analyzed the association of AGT M235T, G217A, G152A, G‐6A, A‐20C genotypes with coronary artery stenosis and in‐stent restenosis.ResultsThere were significantly differences between two patient groups in sex, smoking history, diabetes mellitus, carotid atherosclerosis, lower limb arteriosclerosis, hs‐CRP, blood glucose, and the level of high‐density lipoprotein (HDL; P < 0.05). In CAD group, hs‐CRP levels increased with increasing number of coronary artery branches (1, 2, or ≥3; P < 0.01), and Gensini integral was positively correlated with hs‐CRP levels (r = 0.361, P < 0.01). Frequencies of genotype and allele distribution in individual angiotensinogen loci (M235T, G217A, G152A, G‐6A, A‐20C) did not differ in two patient groups. Following stratification of patients according to hs‐CRP levels (<1 mg/L, 1‐3 mg/L, and >3 mg/L), the distribution frequency of allele M235T was statistically different among the groups (P < 0.05).ConclusionIn CAD patients, M235T among several AGT gene polymorphisms is associated with elevated hs‐CRP levels with AGT C allele as the significant factor for patients with hs‐CRP level of more than 1 mg/L.

Background and objective: Percutaneous coronary intervention, despite being effective for coronary revascularization, causes in-stent restenosis due to neointimal hyperplasia in a large number of patients. The renin-angiotensin system is involved in neointimal hyperplasia. This study sought to evaluate seven gene polymorphisms of key renin-angiotensin system components, including angiotensinogen, angiotensin-converting enzyme and angiotensin II type 1a receptors, and their associations with in-stent restenosis in patients with coronary artery disease following coronary stenting. Methods and results: Three hundred and fifty-two patients undergoing coronary drug-eluting stent implantation were recruited. Seventy-five patients (21.3%) were diagnosed as restenosis by angiography. Genotyping for angiotensin-converting enzyme insertion/deletion demonstrated a significant association of angiotensin-converting enzyme DD genotype with the occurrence of restenosis. Direct DNA sequencing revealed no association of angiotensinogen (M235T, G217A, G152A, G-6A, and A-20C) or angiotensin II type I receptor A1166C polymorphisms with in-stent restenosis. However, angiotensin II type 1a A1166C polymorphism was significantly associated with increased susceptibility to restenosis in a subgroup of patients aged more than 60 years. Conclusion: Thus, our study suggests that genetic polymorphisms of angiotensin-converting enzyme insertion/deletion are associated with in-stent restenosis in coronary artery disease patients following coronary stenting.

BACKGROUND AND AIM:TGF-β1 has been previously reported to be involved in the pathogenesis of atherosclerosis. The aim of the present study was to assess whether functional gene polymorphisms of TGF-β1 and its key receptor TGF-β receptor type II (TGFBR2) contribute as risk factors to the onset and severity of atherosclerotic coronary artery disease (CAD). DESIGN AND METHODS:A total of 605 patients who underwent angiography for suspected CAD were prospectively recruited to this study. Coronary stenosis severity was assessed by the number of narrowed coronary vessels and the Gensini score. Among them, 502 patients had documented CAD, and 103 patients without documented CAD served as non-CAD controls. All patients were genotyped for one TGF-β1 polymorphism (rs1800470 (+T29C)) and two TGFBR2 polymorphisms (rs6785385 (-3779A/G), rs764522 (-1444C/G)) by polymerase chain reaction-restriction fragment length polymorphism and confirmed by direct sequencing. RESULTS:No significant difference in the frequency for either polymorphism was found between CAD and control patients. Neither TGFBR2 rs6785385 (-3779A/G) nor rs764522 (-1444C/G) gene polymorphisms were associated with the severity of CAD (P>0.05). In male CAD patients, polymorphisms at TGF-β1 rs1800470 (+T29C) were, however, associated with the severity of CAD. The T allele frequency was significantly and positively correlated with the number of narrowed coronary arteries (three or more vessels: 49.3%, two vessels: 44.1%, one vessel: 36.9%) (P=0.039). Gensini scores in patients with the TT, CT, and CC genotype were 34.33±2.23, 32.06±4.79, and 26.90±3.83, respectively (P<0.05). In multiple linear regression analysis, the T allele of TGF-β1 polymorphism was independently correlated with the Gensini score (β=0.131). CONCLUSION:TGF-β1 T29C gene polymorphism may be associated with severity of CAD in male patients. TGFBR2 polymorphisms may not determine the genetic susceptibility to CAD.

Background and Objective: Transforming growth factor beta 1 (TGF-β1) has been previously reported to be involved in pathogenesis of atherosclerosis. However, there are conflicting views about whether TGF-β1 is pro- or anti-atherogenic. The aim of the present study was to establish the contributions of TGF-β1 and its key receptor TGF-β receptor type II (TGFBR2) functional gene polymorphisms to the severity of atherosclerotic coronary artery disease (CAD). Methods and Results: Five hundred and three consecutive patients with angiographically documented CAD were prospectively enrolled in this study. Coronary stenosis severity was assessed by the number of coronary narrowed vessels and the Gensini-score. All patients were genotyped for two TGF-β1 polymorphisms [rs1800471 (+T29C), rs1800470 (+915G/C)] and two TGF BR2 polymorphisms [rs67855385 (-3779A/G), rs764522 (-1444C/G)] by the means of polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and then confirmed by direct sequencing. No association between TGF-β1 rs1800470 (+915G/C), TGF BR2 rs67855385 (-3779A/G) and rs764522 (-1444C/G) gene polymorphisms and the severity of CAD was observed (P>0.05). TGF-β1 rs1800471 (+T29C) polymorphism was also not significantly associated with severity of CAD in female patients. However, in male CAD patients, polymorphisms at rs1800471 (+T29C) were found to be associated with the severity of CAD. There was a significant difference of the T allele frequency in patients with different numbers of vessels involved (three or more vessels: 49.3%, two vessels: 44.1%, single vessel: 35.8%) (P=0.039). Gensini scores were 34.33 ± 2.23, 32.06 ± 4.7877, and 26.90 ± 3.83 in those with the TT, CT, and CC genotype respectively (P=0.045). By using multiple linear regression, adjusting for other risk factors such as gender, blood pressure, diabetes, history of smoking, and serum lipid levels, the T allele was still positively correlated with the Gensini score and number of vessels involved (β=0.034). Conclusion: Our findings suggest that TGF-β1 T29C gene polymorphism is associated with severity of CAD in Chinese populations.

Background and Objective: Coronary artery disease (CAD) represents the most important cause of sudden cardiac death. Percutaneous coronary intervention (PCI) is an effective technique for coronary revascularization but a considerable number of patients develop restenosis after stenting. Renin angiotensin system (RAS) plays an important role in restenosis by promoting neo-intimal hyperplasia. This study evaluateed the polymorphisms of the genes encoding key RAS components including angiotensinogen (AGT), angiotensin converting enzyme (ACE) and angiotensin type 1a (AT1a) receptor in relation to severity of coronary artery disease and in-stent restenosis after coronary stenting. Methods and Results: Five hundred and twenty six patients who underwent angiography due to suspected CAD were prospectively recruited to this study. Five single nucleotide polymorphisms (M235T, G217A, G152A, G-6A, A-20C) of AGT gene, ACE insertion/deletion (I/D) and AT1a A1166C polymorphisms were genotyped from genomic DNA with direct sequencing. Severity of coronary atherosclerosis was assessed by angiographic Gensini score. A subsequent coronary angiography was performed 6-9 months later for suspected restenosis for patients (N=273) who underwent coronary stent implantation. In-stent restenosis was evaluated by means of quantitative angiography. Forty-five patients (16.5%) revealed in-stent restenosis. Haplotypes were constructed after linkage disequilibrium analysis. In a multivariate analysis of angiographic restenosis, there was no significant association of the polymorphisms of AGT(M235T, G217A, G152A, G-6A, A-20C, ACE I/D, and AT1a A1166C with the occurrence of in-stent restenosis (P>0.05). However, in the CAD group, frequency of ACE D allele was significantly higher in patients with angiographically defined multi-vessel disease compared to patients with single vessel CAD ( p = 0.013). Additionally, a significant association was found between the frequency of D allele and severity of CAD assessed by the Gensini score (P=0.028). Conclusion: Genetic polymorphisms of RAS are not associated with in-stent restenosis after coronary stenting. However, the presence of the ACE I/D polymorphism is potentially associated with the severity of CAD.