Yongping Bai

BACKGROUND: Angiogenesis is essential for the recovery of ischemic hearts with coronary artery disease (CAD). PGPC (1-palmitoyl-2-glutamyl-sn-glycero-3-phosphocholine) is a major phospholipid oxidation product in atherosclerotic lesions. Autophagy participates in angiogenesis. However, whether PGPC affects angiogenesis in ischemic hearts by regulating autophagy remains unclear. METHODS: Plasma PGPC concentrations were quantified and the effects of PGPC on angiogenesis were evaluated in cultured endothelial cells and in vivo using a subcutaneous Matrigel plug assay, as well as in hindlimb ischemia and myocardial infarction models in C57BL/6J mice. Autophagic flux and the expression and modification of proteins associated with autophagy and angiogenesis were also assessed. RESULTS: Plasma PGPC levels were increased in patients with CAD, and they were positively correlated with the severity of CAD and negatively correlated with coronary collateral artery formation. PGPC inhibited endothelial cell migration and tube formation. PGPC suppressed neovascularization in Matrigel plugs and reduced blood flow recovery in hindlimb ischemia. In a mouse model of myocardial infarction, PGPC attenuated angiogenesis in the ischemic myocardium. These proangiogenic effects induced by VEGFA (vascular endothelial growth factor A) in ischemic hearts were significantly inhibited by PGPC. Mechanistically, PGPC inhibited the expression of STX17 (syntaxin 17), a crucial molecule that controls autophagosomal–lysosomal fusion by promoting the acetylation and subsequent ubiquitination and degradation of STX17. PGPC upregulated the expression of NPC1 (NPC intracellular cholesterol transporter 1) through CD36 (cluster of differentiation 36). NPC1 not only promoted the acetylation and subsequent ubiquitination and degradation of STX17 through the recruitment of ACAT1 (acetyl-CoA acetyltransferase 1), but also competed with STX17 to bind VAMP8 (vesicle-associated membrane protein 8), leading to inhibition of the expression of eNOS (endothelial nitric oxide synthase), ERK1/2 (extracellular signal-regulated kinase 1/2), and nitric oxide production. Oxidized phospholipid-neutralizing antibody E06, STX17 overexpression, or silencing of NPC1 reversed the inhibitory effect of PGPC on angiogenesis by restoring autophagic flux. CONCLUSIONS: PGPC promotes the acetylation and subsequent ubiquitin-mediated degradation of STX17 by increasing NPC1, leading to a reduction in the level of STX17 associated with VAMP8, which inhibits autophagosomal–lysosomal fusion and angiogenesis. Targeting PGPC, NPC1, or STX17 may represent novel therapeutic approaches to promote angiogenesis in patients with CAD.

Peripheral arterial disease (PAD) is characterized by impaired angiogenesis, yet the molecular mechanisms linking metabolic dysregulation to epigenetic reprogramming in endothelial cells (ECs) remain poorly understood. Here, we identify hexokinase 2 (HK2) as a critical regulator of angiogenesis through histone lactylation in PAD. In clinical specimens and murine hindlimb ischemia (HLI) models, HK2 expression was significantly downregulated. Functional assays in hypoxia-serum starved (HSS) human umbilical vein ECs (HUVECs) demonstrated that HK2 overexpression rescued angiogenesis by enhancing proliferation, migration, tube formation, and pro-angiogenic protein expression (VEGFA), while HK2 knockdown suppressed these phenotypes. Mechanistically, HK2 deficiency selectively reduced histone H3 lysine 18 lactylation (H3K18la) among eight tested histone lactylation sites, and HK2 restoration under HSS restored H3K18la level. Exogenous lactate reversed angiogenic defects in HK2-knockdown HUVECs by elevating H3K18la, which directly activated VEGFA transcription, as shown by Chromatin Immunoprecipitation coupled with quantitative Polymerase Chain Reaction (ChIP-qPCR). Furthermore, Sirtuin 2 (SIRT2), as a de-lactylase, inhibition in HK2-knockdown HUVECs restored H3K18la, angiogenesis, and pro-angiogenic protein expression. In HLI mice, SIRT2 inhibitor treatment improved blood flow recovery, increased EC density, and upregulated H3K18la. Our findings establish HK2 as a metabolic-epigenetic nexus driving angiogenesis via lactate-dependent H3K18la modification and propose SIRT2 inhibition as a novel therapeutic strategy to bypass HK2 deficiency in PAD.

Background: Recent studies have established an association between traumatic brain injury (TBI) and cardiometabolic diseases (CMDs). However, the influence of TBI on the sequential progression from a healthy state to CMD, subsequent to cardiometabolic multimorbidity (CMM), and ultimately to mortality remains unclear. Methods: A total of 366,616 participants free of CMD at baseline were derived from the UK Biobank (UKB). CMM was defined as the co-occurrence of ≥2 CMD, including diabetes mellitus (DM), ischemic heart disease (IHD), and stroke. Cox proportional hazards models and multi-state models were utilized to evaluate the association of TBI with disease transitions from a healthy state to CMM and subsequent mortality. Results: During a median follow-up of 16.91 years, 54,224 participants developed at least one CMD, among whom 7,562 progressed to CMM. Furthermore, 32,785 cases of mortality were documented. In multi-state models, the hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) for transitions from a healthy state to IHD, DM, stroke, and mortality were 1.91(95% CI: 1.77–2.05), 1.89 (95% CI: 1.71–2.09), and 4.73 (95% CI: 4.39–5.09), respectively. For sequential transitions from IHD, DM, and stroke to CMM, the HRs (95% CIs) were 2.67 (95% CI: 2.34–3.04), 3.29 (95% CI: 2.78–3.89), and 1.41 (95% CI: 1.15–1.72), respectively. Additionally, in Cox proportional hazards models, the HRs (95% CIs) for incident CMM and mortality among individuals with TBI were 3.98 (95% CI: 3.63–4.36) and 2.57 (95% CI: 2.44–2.71), respectively. Conclusion: This study found that TBI was associated with increased risk of progression from a healthy state to CMD, and subsequently to CMM and mortality, highlighting the importance of comprehensive management of TBI in cardiometabolic health. What is Known; What the Study Adds: What is Known: Traumatic brain injury (TBI) is associated with an elevated risk of developing multiple cardiometabolic diseases (CMDs). What the Study Adds: This study performed a systematic analysis of the relationships between TBI and multiple CMDs, providing valuable clinical references for the prevention and management of the onset and progression of cardiometabolic diseases and cardiometabolic multimorbidity (CMM) among patients with TBI.

Vascular stiffness, a hallmark of aging and cardiovascular disease, involves vascular smooth muscle cell (VSMC) senescence and extracellular matrix (ECM) dysregulation. This study investigates the role of fibulin‐1 (Fbln1) in these processes. Plasma proteomic profiling identified dysregulated proteins in vascular stiffness pedigrees. Fbln1 knockout mice and dual vascular stiffness models (natural aging and chronic angiotensin II [Ang II] infusion) were established. Phenotypic assessments included pulse wave velocity (PWV), histology, and molecular markers. Mechanistic investigations integrating DNA pull‐down assays, dual‐luciferase reporter assays, and RNA sequencing (RNA‐seq) were employed to dissect the transcriptional and signaling axis regulating Fbln1 expression and function. Elevated plasma Fbln1 correlated with hereditary vascular stiffness. Both aging and Ang II promote vascular stiffness, whereas Fbln1 knockdown ameliorates this phenotype by reducing PWV, reversing VSMC senescence, and attenuating collagen deposition. Zinc Finger Protein 384 (ZNF384) was identified as a transcriptional activator of Fbln1, which promoted VSMC senescence and collagen deposition via transforming growth factor‐beta (TGF‐β)/SMAD family member 3 (Smad3). Inhibiting TGF‐β/Smad3 signaling abolished Fbln1‐driven senescence and ECM remodeling. Fbln1 exacerbates vascular stiffness through ZNF384‐mediated transcriptional activation and TGF‐β/Smad3‐dependent ECM/senescence pathways. Targeting Fbln1 or its regulators may offer therapeutic strategies for age‐related vascular pathologies.

Objective: To assess the global burden and trends of ischemic heart disease (IHD) attributable to non-optimal temperature among younger and older populations using Global Burden of Disease 2021 data. Methods: We estimated temperature-attributable IHD burden (high, low, non-optimal) from 1990-2021 using deaths, Disability-adjusted life years (DALYs), age-standardized rates, and joinpoint regression, stratified by age, sex, region, and Socio-demographic Index. Decomposition analysis examined demographic contributions. Results: From 1990-2021, age-standardized mortality and disability rates declined globally, yet absolute numbers of deaths and DALYs, especially in older adults. The burden from low temperatures was disproportionately higher in older adults, with extreme disparities in Central Asia. Sex differences shifted with age, and burdens were consistently higher in lower SDI regions. Conclusions: Older adults bear a substantially greater IHD burden attributable to non-optimal temperature, highlighting the need for targeted prevention strategies. Export

The number of endothelial cells (ECs) decreases with aging; consequently, their function is impaired, which is a major cause of the mortality and morbidity of age-related ischemic diseases such as peripheral arterial disease (PAD). Growing evidence suggests that tryptophan metabolism dysfunction has been closely linked to age-related diseases and lifespan regulation across multiple species. In this study, we investigated whether tryptophan metabolism mediated vascular rarefaction and neovascularization impairment in aging. Fasting peripheral blood samples were collected from healthy volunteers, we found that the levels of indoleacrylic acid (IA), a metabolite primarily produced through gut microbial metabolism, were significantly lower in the elderly compared with the young. In both young and elderly PAD patients, lower IA levels were positively correlated with the PAD severity, risk of onset, and cardiovascular outcome, with larger correlation coefficients observed in the elderly patients. We established a hindlimb ischemia mouse model by ligating the femoral artery (FAL). A similar trend was observed between young and aged mice both non- and post-FAL. Supplementing aged mice with IA (50 mg·kg⁻¹·d⁻¹, i.g.) for 12 weeks was able to alleviate vascular dysfunction in aged mice. RNA-seq analysis revealed that IA activated the APLNR signaling pathway, alleviated ECs senescence, and enhanced their ability to respond to ischemia. These results provide new insights into the association between IA and vascular dysfunction, laying the theoretical foundation for the potential preventive and therapeutic roles of IA in age-related PAD.

Aging is characterized by progressive immunosenescence and inflammaging, in which impaired gut barrier and dysregulated mucosal immunity exacerbate systemi

This study investigated the relationship between plasma Interleukin‐17A (IL‐17A) and Interleukin‐17F (IL‐17F) levels and peripheral arterial disease (PAD), and explored the role of IL‐17F in neovascularization in a preclinical PAD model of aged mice. Using an enzyme‐linked immunosorbent assay, we found that plasma IL‐17A levels were similar in young and aged groups in both PAD patients and mice with hindlimb ischemia. In contrast, IL‐17F levels were elevated in the aged group. Spearman correlation analysis showed a positive correlation between IL‐17F levels and PAD severity, onset risk, and cardiovascular outcome. Under simulated ischemic conditions, IL‐17F induced endothelial cells (ECs) senescence and dysfunction in a dose‐dependent manner. In aged male and female mice following left femoral artery ligation, results from Doppler imaging, ischemia and motor scores, and histology indicated that neutralization of IL‐17F enhanced blood flow recovery, reduced ischemia scores, improved motor scores, and facilitated muscle regeneration and repair. Micro‐CT, whole‐mounting, and immunofluorescence staining results showed that neutralization of IL‐17F promoted neovascularization and inhibited ischemic hindlimb muscle ECs' senescence and dysfunction. This study reveals for the first time that higher IL‐17F levels were positively associated with PAD severity, onset risk, and cardiovascular outcome. Neutralization of IL‐17F promoted postischemic neovascularization in aged mice, suggesting it represented a promising therapeutic strategy for elderly PAD patients.

The tissue environment governs vascular remodeling, a key determinant of collateral circulation (CC) in ischemic disease, yet the mechanisms driving CC in adults remain unclear. Plasma profiling from patients with peripheral artery disease (PAD) and ischemic murine muscle revealed dysregulated lipid metabolism, including elevated APOA1 binding protein ( AIBP), with levels positively correlating with PAD severity. Myeloid cells enriched at CC sites increased AIBP expression postischemia. Genetic deletion of AIBP expanded CXCR4⁺ capillary endothelial cells ( CECs) with stemlike and proliferative properties that remodeled into functional collaterals, a process blocked by CXCR4 inhibition. Mechanistically, AIBP bound the endocytic receptor LRP2 to promote endothelial uptake of high-density lipoprotein (HDL)–associated miR-223, a repressor of CXCR4. Disruption of this AIBP–LRP2–HDL–miR-223 axis restored CXCR4 and rescued CC growth. These findings define a two-phase mechanism in which stemlike CECs first expand and then transition to arterial fates, establishing a therapeutic strategy for revascularization in ischemic vascular disease.

As we approach the mid‐21st century, more developing countries are progressing towards becoming developed nations. Advances in medical technology have resulted in the prolonged human lifespan and a sustained decline in birth rates, leading to a growing proportion of the population being aged 65 and above. The aging process is associated with organ function deterioration, increased risks of age‐related diseases, and a decrease in the quality of life for older adults. While there is ongoing debate about whether aging should be considered a disease or a natural physiological process, understanding the reasons for aging, identifying and measuring aging, and intervening in the aging process have become key topics in current medical research. Recent studies indicate that the rate of organ aging varies among individuals, with blood vessels being one of the organs that age first. Vascular aging increases the risk of cardiovascular diseases, overall mortality, and shortens lifespan. Therefore, in‐depth research on vascular aging is crucial for understanding its impact on vascular and multi‐organ function. In this review, we discuss the phenotypes caused by vascular aging, mechanisms of aging in various vascular cells, and potential therapeutic strategies for vascular aging.