Disturbed flow (DF) plays a critical role in the development and progression of cardiovascular disease (CVD). Hydrogen sulfide (H₂S) is involved in physiological processes within the cardiovascular system. However, its specific contribution to DF-induced vascular remodeling remains unclear. Here, we showed that the H₂S donor, NaHS suppressed DF-induced vascular remodeling in mice. Further experiments demonstrated that NaHS inhibited the proliferation and migration of vascular smooth muscle cells (VSMCs) induced by platelet-derived growth factor-BB (PDGF), as well as the autophagy triggered by DF and PDGF. Mechanistically, RNA-Seq results revealed that NaHS counteracted the PDGF-induced upregulation of lactate dehydrogenase B (LDHB). Overexpression of LDHB abolished the protective effect of NaHS on DF-induced vascular remodeling. Furthermore, LDHB interacted with vacuolar-type proton ATPase catalytic subunit A (ATP6V1A), leading to lysosomal acidification, a process that was attenuated by NaHS treatment. The residues of leucine (Leu) 57 in ATP6V1A and serine (Ser) 269 in LDHB are critical for their interaction. Notably, the expression of LDHB was found to be elevated in vascular tissues from patients with abdominal aortic aneurysms (AAA) and thoracic aortic aneurysms (TAA). These data identify a molecular mechanism by which H₂S attenuates DF-induced vascular remodeling by inhibiting LDHB and disrupting the interaction between LDHB and ATP6V1A, thereby impeding the autophagy process. Our findings provide insight that H₂S or targeting LDHB has therapeutic potential for preventing and treating vascular remodeling.

Vascular smooth muscle cell (VSMC) dysfunction is a critical pathological process in postinjury intima hyperplasia. This process is driven by the adherence and accumulation of platelet-derived extracellular vesicles (PEVs) released from activated platelets to VSMCs at the site of injured intima. However, the precise mechanism remains unclear. Thus, the present study aimed to investigate how PEVs adhere to VSMCs and facilitate VSMC dysfunction in postinjury intimal hyperplasia. Morphological results confirmed that PEVs led to VSMC dysfunction and intimal hyperplasia. Integrated single-cell and proteomic analysis revealed that increased secreted phosphoprotein 1 (SPP1) expression in VSMCs played a central role in this process, possibly by mediating PEV adhesion to VSMCs and activating the focal adhesion kinase (FAK)/phosphoinositide 3 kinase (PI3K)/protein kinase B (Akt) axis. In addition, integrin beta 3 (ITGβ3, CD61) on PEVs, with increased expression under pathological conditions, was predicted to interact with SPP1. Co-immunoprecipitation (Co-IP) analysis further confirmed that ITGβ3 interacted with SPP1, thereby activating the FAK/PI3K/AKT phosphorylation and promoting PEV adhesion. Of note, blocking ITGβ3 expression on PEVs reduced PEV adhesion and intimal hyperplasia. Thus, ITGβ3-SPP1-mediated PEV adhesion to VSMCs may be a novel mechanism in intimal hyperplasia, which proposed to be critical for vascular homeostasis.

Background: Low-density lipoprotein cholesterol (LDL-C) is considered an important risk factor for acute coronary syndrome (ACS). Recent studies have revealed high mortality in ACS patients with low LDL-C levels. However, the association between spontaneously very low LDL-C levels and the prognosis in ACS remains unknown. Methods: A total of 1882 consecutive statin-null ACS patients were analyzed and categorized into four groups according to their on-admission LDL-C level: very low <70 mg/dL, low 70–99 mg/dL, high 100–129 mg/dL, and very high ≥130 mg/dL. In-hospital mortality and 3-year mortality were assessed. Among them, 1009 patients were further grouped according to the hs-CRP value (<2 mg/L and ≥2 mg/L). Results: Over one-third of the patients had an initially lower LDL-C concentration. Higher in-hospital mortality (9.7%, 4.5%, 2.7%, and 3.5%, p = 0.001), long-term mortality (20.8%, 13.1%, 8.0%, and 7.8%, p < 0.001), and lower survival rate (KM: HR = 3.15, 95% CI 1.40–7.12, p < 0.001; Cox: HR = 2.09, 95% CI 1.30 to 3.36) were observed in the very low LDL-C group compared with other groups. Patients in the low LDL-C high CRP subgroup had the worst prognosis compared with other subgroups (in-hospital: 7.7%, 1.2%, 0.5%, and 4.3%, p = 0.031; long-term: 15.5%, 1.2%, 2.6%, and 9.4%, p = 0.018). Lower LDL-C levels were accompanied by higher CRP levels (p = 0.003). The CRP–LDL-C ratio had good predictive ability on short-term and long-term outcomes (AUC: 0.630 and 0.738). Conclusions: Spontaneously very low LDL-C level was independently associated with poor long-term survival in patients with ACS. Lower LDL-C level was related to higher CRP level, while the CRP–LDL-C ratio may be a potential risk prediction factor.

Background: Defined by the coexistence of at least two cardiovascular diseases, type 2 diabetes and suspected metabolic dysfunction-associated steatotic liver disease, cardiovascular–liver–metabolic multimorbidity (CLMM) is an emerging phenotype that is related to the cardiovascular–kidney–metabolic continuum yet distinct from it. By combining triglycerides, fasting glucose, HDL cholesterol and central adiposity, the modified cardiometabolic index (MCMI) summarizes these features in a single fasting-panel measure. Evidence to date has been confined to cross-sectional fatty-liver and self-reported outcomes; established lipid–glucose indices have not been compared head to head with MCMI for CLMM. Methods: We included 6124 CHARLS participants aged 45 years or older, free of CLMM in 2011 and with a 2015 health questionnaire. For the primary analysis, we assigned indeterminate follow-up outcomes (n = 1919) to non-CLMM; results from determinable-outcome and multiple-imputation analyses are presented beside the primary estimates, along with additional alternative assumptions. We used multivariable logistic regression, restricted cubic splines and paired ROC analyses. Exploratory analyses compared MCMI with 12 other indices. We also examined joint MCMI–CRP associations and interaction, subgroup, sensitivity and component-specific analyses, together with incremental models and bootstrap internal validation. Results: Over approximately four years, 619 participants (10.11%) fulfilled the surrogate-defined CLMM definition, with suspected MASLD documented in 93.4% of cases. A nonlinear association was observed (p < 0.001). The fully adjusted MCMI Q4-versus-Q1 odds ratio was 6.13 (95% CI 4.34–8.66) in the primary analysis, 6.67 (4.70–9.49) among participants with determinable outcomes and 5.69 (4.24–7.65) after multiple imputation of missing components, but 1.74 (1.49–2.02) if all indeterminate outcomes were assumed to be cases. Adjusting for baseline component count reduced the odds ratio from 6.38 to 3.22 (2.17–4.78) across the same 6064 participants. Per-SD odds ratios were 3.63 (3.01–4.37) for incident suspected MASLD versus 1.10 (1.00–1.21) for incident CVD. MCMI had an apparent AUC of 0.684 (0.664–0.705); differences from BMI and waist-to-height ratio were not statistically significant. After bootstrap optimism correction, the covariate model had AUCs of 0.697 with MCMI and 0.698 with BMI, and adding MCMI to separately modelled glucose, triglycerides, HDL cholesterol and waist circumference did not significantly improve model fit (p = 0.263). The high-MCMI/high-CRP group had an odds ratio of 3.29 (2.55–4.25) versus the double-low group, but interaction tests were not significant. Conclusions: MCMI was associated with incident surrogate-defined CLMM, yet much of the observed association appeared attributable to pre-existing component burden and to the LAP-based suspected MASLD component sharing inputs with MCMI, while its magnitude varied with the treatment of indeterminate outcomes. Its exploratory apparent discrimination was not significantly different from that of BMI or waist-to-height ratio. Interpretation remains limited by the lack of independent validation; the joint MCMI–CRP findings did not establish interaction or biological synergy.