Post-myocardial infarction (MI) healing is a moving sequence of injury, inflammatory clearance, resolution, vascular repair, and scar maturation. This review evaluates how extracellular vesicles (EVs), cell-derived nanovesicles, and engineered nanoparticles can be matched to these changing biological requirements. A critical narrative synthesis was organized around four approximate post-MI windows: minutes to 24 h, days 1–3, days 3–7, and after day 7. Representative mechanistic, rodent, porcine, and human studies were compared by target cell, cargo, material, release profile, route, quantitative delivery evidence, efficacy, and translational liability. Early oxidative and microvascular injury favors brief cytoprotection and vascular targeting; the inflammatory peak favors calibrated control of recruited leukocytes while preserving debris removal; resolution favors efferocytosis, reparative immune signaling, angiogenesis, and local immunomodulation; and later remodeling favors selective rather than global antifibrotic therapy. Directly generated nanovesicles and modified-mRNA lipid nanoparticles expand the design space. However, human evidence remains sparse, and most preclinical studies use fixed schedules, young non-comorbid rodents, qualitative biodistribution, and incompletely defined potency assays. A credible spatiotemporal product must demonstrate phase-dependent target availability, controlled exposure, target-cell cargo engagement, and reduced benefit or emerging harm with a deliberately mismatched schedule. Translation requires quantitative pharmacokinetics and biodistribution, route-specific safety, mechanism-linked potency, scalable manufacturing, and validation in reperfused comorbid large-animal models.
Li et al. identified C4B as a potential therapy target for calcific aortic valve stenosis using genetic and histological analyses. However, genetic target prioritization isn’t the same as pharmacological validation. Lifelong genetic differences in C4B may not replicate therapeutic inhibition effects, especially given the complex C4A/C4B locus. Increased C4B in calcified valves supports biological relevance but doesn’t prove causality. C4B is a promising candidate needing further functional and pharmacological validation.
Cardiovascular disease remains the leading cause of death worldwide, imposing significant morbidity and healthcare costs. While low serum high-density lipoprotein (HDL)-cholesterol levels have traditionally been linked to cardiovascular risk, most pharmacological interventions aimed at raising HDL-cholesterol levels have not consistently improved cardiovascular outcomes. Epidemiologic and genetic studies further suggest that circulating HDL-cholesterol levels may not directly determine cardiovascular risk, underscoring the complexity of HDL particles in cardiovascular health. HDL particles are dynamic, multifunctional complexes composed of diverse proteins and lipids, whose composition determines their cardioprotective properties. In cardiovascular disease, the composition of HDL particles is frequently remodeled, resulting in dysfunctional particles with impaired antioxidant, anti-inflammatory, and lipid transport functions. Consequently, the composition and functionality of HDL particles, rather than their cholesterol content, appear to be the primary determinants of their protective capacity. A deeper understanding of HDL particles' compositional changes in cardiovascular disease may guide therapies that restore their protective capacity, thus offering a more effective strategy to reduce cardiovascular risk. This review summarizes current knowledge on changes in the proteomic and lipidomic composition of HDL particles associated with cardiovascular disease, highlighting molecular alterations that may drive HDL particle dysfunction.
To investigate whether empagliflozin (EMPA) delays the progression of atherosclerosis (AS) by promoting mitophagy in endothelial cells. In vivo and in vitro AS models were established using ApoE−/− mice fed a high-fat diet (HFD) and HUVECs treated with oxLDL, respectively. Models received EMPA intervention alone or combined with the autophagy inhibitor 3-MA. To specifically confirm the pivotal role of Pink1, siRNA-mediated knockdown was performed in HUVECs. Aortic plaque area was evaluated by Oil Red O staining. Serum lipids, mitochondrial function, and endothelial markers were assessed. Mitophagy-related proteins were detected by Western blot, and the co-localization of TOM20 with LC3 and CD31 with LC3 was observed via immunofluorescence. EMPA significantly reduced aortic plaque area and ameliorated lipid metabolism in mice, independent of hypoglycemic effects. In vitro, EMPA restored mitochondrial membrane potential and ATP levels while reducing ROS production. Furthermore, EMPA upregulated Pink1/Parkin expression and the LC3-II/LC3-I ratio, and promoted TOM20-LC3 co-localization. Critically, both 3-MA treatment and Pink1 knockdown reversed EMPA-induced improvements in endothelial viability and migration, abolished its inhibition of inflammatory cytokine release, and negated its regulatory effects on endothelial function, demonstrating that mitophagy is essential for EMPA’s action. EMPA inhibits the progression of AS by activating Pink1/Parkin-mediated mitophagy, thereby improving mitochondrial function and alleviating endothelial injury. This finding provides a novel basis for the cardiovascular protective mechanisms of EMPA.
Noonan syndrome-associated hypertrophic cardiomyopathy (NS-HCM) occurs frequently in patients with RAF1 mutations, but the signaling mechanisms underlying the hypertrophic cardiomyocyte phenotype remain incompletely understood, and effective therapeutic targets remain to be defined. This study aimed to characterize MAPK signaling dysregulation in RAF1-mutant induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and to determine whether berberine (BBR) attenuates the hypertrophic phenotype through modulation of ERK5-Cyclin D1 signaling. An in vitro NS-HCM cardiomyocyte model was established using induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from a patient harboring the RAF1 p.Ser257Leu mutation. Wild-type iPSC-CMs were generated from healthy donors. Immunofluorescence was used to assess cardiomyocyte surface area, sarcomeric organization, and Ki-67/EdU-based cell-cycle activity. Transcriptomic analyses of public NS-HCM datasets were performed to identify differentially expressed genes and enriched pathways. Western blotting was performed to evaluate the activation of MEK1/2-ERK1/2 and ERK5 signaling pathways, downstream Cyclin D1 expression, and hypertrophic markers including ANP and BNP. RAF1S257L/+ iPSC-CMs were treated with BBR, a MEK1/2 inhibitor (U0126), or a MEK5 inhibitor (BIX02189) to evaluate pathway modulation and hypertrophic phenotype. RAF1S257L/+ iPSC-CMs exhibited hallmark features of NS-HCM, including increased cell surface area, disrupted sarcomeric organization, and elevated expression of hypertrophic markers ANP and BNP. Transcriptomic analysis revealed significant enrichment of the MAPK pathway. Both MEK1/2-ERK1/2 and ERK5-Cyclin D1 pathways were markedly activated in RAF1S257L/+ iPSC-CMs, and treatment with U0126 or BIX02189 attenuated this activation and reduced cardiomyocyte hypertrophy. BBR treatment suppressed ERK5 phosphorylation and Cyclin D1 expression, decreased Ki-67 positivity, and similarly attenuated the hypertrophic phenotype. RAF1-mutant iPSC-CMs exhibited concurrent activation of the MEK1/2-ERK1/2 and ERK5-Cyclin D1 signaling pathways. BBR attenuated the hypertrophic phenotype while reducing ERK5 phosphorylation and Cyclin D1 expression without significantly altering MEK1/2-ERK1/2 signaling. These findings suggest that ERK5-Cyclin D1 signaling contributes to the hypertrophic phenotype of RAF1-mutant cardiomyocytes and support further investigation of BBR as a potential therapeutic candidate for RAF1-associated NS-HCM.
Cardiovascular (CV) disease represents the leading cause of morbidity and mortality in patients with chronic kidney disease (CKD), particularly in those with advanced stages and dialysis dependence. Dyslipidemia is highly prevalent in this population and displays distinct features, substantially affected by multiple factors such inflammation and dialysis modality. Although statins remain the cornerstone of lipid-lowering therapy in earlier CKD stages, their benefit becomes less certain in advanced disease and predominantly end-stage kidney disease. This phenomenon, termed the dialysis paradox, is further confounded by reverse epidemiology, wherein lower cholesterol paradoxically associates with worse outcomes due to malnutrition and inflammation. Injectable lipid-lowering therapies, including proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies (evolocumab, alirocumab), small interfering RNA (inclisiran), and emerging agents targeting ANGPTL3, apolipoprotein C-III, and lipoprotein(a), offer novel mechanisms of action with pharmacokinetic profiles largely preserved across CKD stages. Available evidence demonstrates substantial low-density lipoprotein (LDL) reduction without renal toxicity, though patients with advanced CKD and dialysis dependence remain critically underrepresented in clinical trials. Current guidelines diverge significantly for dialysis populations, reflecting this persistent evidence gap. This review synthesizes the biological rationale, pharmacologic properties, and available clinical evidence for injectable lipid-lowering therapies in advanced CKD. Moreover, it highlights why their integration into the care of this high-risk population merits serious consideration - not only for their potent and durable lipid-lowering effects, but also for their ability to target other paths that contribute to the excess CV risk not captured by LDL alone. However, key unresolved questions require dedicated investigation.
Atherosclerosis (AS) is a chronic inflammatory vascular disease characterized by lipid accumulation, immune activation, and plaque formation. This study investigated the anti-atherosclerotic effects of Lentinan (LNT) and explored its potential macrophage-associated mechanisms. In high-fat diet-fed ApoE⁻/⁻ mice, LNT markedly attenuated aortic plaque formation, lipid deposition, serum pro-inflammatory cytokine levels, and dyslipidemia, indicating a protective effect against AS progression. Integrated target screening and transcriptomic analyses identified HCK and GUSB as key candidate targets associated with the response to LNT. Both genes were upregulated in atherosclerotic tissues and were further assessed in an independent human dataset. Experimental validation in ApoE⁻/⁻ mouse aortic tissues showed that LNT reduced HCK and GUSB expression, while single-cell transcriptomic analysis indicated that both genes were predominantly enriched in macrophage populations within atherosclerotic lesions. In ox-LDL-induced RAW264.7 foam cells, LNT decreased intracellular lipid accumulation and downregulated HCK and GUSB expression, further supporting a macrophage-related protective mechanism. In addition, targeted metabolomic analysis suggested that LNT reshaped amino acid metabolism, which may contribute to improvement of the inflammatory and immunometabolic microenvironment in AS. Molecular docking and molecular dynamics simulations further indicated potential interactions between LNT and HCK/GUSB. Overall, these findings suggest that LNT attenuates experimental atherosclerosis by regulating macrophage-associated HCK/GUSB expression, suppressing foam cell formation, and modulating amino acid metabolic remodeling.
Stroke-heart syndrome (SHS) represents a serious complication after stroke that significantly elevates mortality risk, especially in the short term. The primary initiating pathological event in SHS is acute ischemic stroke, which subsequently triggers secondary cardiac dysfunction through a complex and continuous interplay among the brain, the immune system, and systemic metabolism. In the acute phase, an acute surge of stress hormones such as norepinephrine induces calcium overload and subsequent myocardial damage. Meanwhile, a progressive cardiac remodeling process begins, which continues to evolve over subsequent weeks. Subacutely, systemic immune activation drives splenic leukocyte mobilization and the formation of neutrophil extracellular traps (NETs), thereby exacerbating inflammation and plaque instability. Over time, gut microbiota derived metabolites, particularly phenylacetylglutamine (PAGln), may further aggravate thrombotic risk and cardiac metabolic vulnerability. To address this multifactorial complexity, this review proposes a hypothesis-generating conceptual framework that categorizes SHS into three endophenotypes, including neurogenic arrhythmic (Type I), inflammatory thrombotic (Type II), and metabolic remodeling (Type III). Potential phenotype-specific interventions include beta blockers for neural stabilization, NETs degradation for immunomodulation, and metabolic pathway antagonists. Although interventions like remote ischemic conditioning (RIC) demonstrate promising biological activity and safety in preclinical evaluations, translating these exploratory findings into consistent clinical outcomes remains a significant translational challenge. Furthermore, sex specific mechanisms, notably the altered estrogen signaling in women, highlight the potential need for tailored therapeutic strategies. Transitioning toward this etiology-based paradigm provides an essential foundation for future precision therapeutics, aiming to mitigate targeted pathophysiological drivers rather than relying solely on generalized cardioprotection.
Endothelial-to-mesenchymal transition (EndMT) is implicated in cardiac remodeling under pathological stress, although its full in vivo occurrence may be context-dependent. Emerging evidence suggests that protein methylation is an important post-translational modification involved in regulating endothelial phenotypic transition (EndMT-like process). However, the role of protein arginine methyltransferase 2 (PRMT2), a key protein arginine methyltransferase, in modulating endothelial phenotypic transition—particularly in the context of cardiac remodeling—remains poorly understood. A transverse aortic constriction (TAC) mouse model was used to induce cardiac remodeling, and adeno-associated virus serotype 9 (AAV9) was administered to specifically silence PRMT2 in endothelial cells. We found that PRMT2 expression was significantly upregulated in cardiac endothelial cells following pressure overload. Endothelial-specific silencing of PRMT2 markedly attenuated cardiac hypertrophy, fibrosis, and endothelial phenotypic transition in TAC mice. In vitro, PRMT2 knockdown in isolated murine cardiac microvascular endothelial cells alleviated TGF-β1–induced endothelial phenotypic transition, while PRMT2 overexpression exacerbated these phenotypic changes. Mechanistically, PRMT2 enhanced endothelial phenotypic transition by promoting monomethylation of Snail1 and activation of the Snail signaling pathway. Importantly, endothelial-specific knockdown of Snail1 reversed the phenotypic transition induced by PRMT2 overexpression. These findings identify PRMT2 as a key epigenetic regulator of endothelial phenotypic transition in cardiac remodeling, suggesting it may serve as a potential therapeutic target for heart failure.
Ferroptosis plays a critical role in myocardial ischemia-reperfusion injury (MIRI). Here, we discovered that MSMO1, a key enzyme in the cholesterol biosynthesis pathway, regulates ferroptosis in MIRI, and identified miR-26a-5p as an upstream regulator of MSMO1. During MIRI, downregulation of miR-26a-5p led to suppression of MSMO1, reduction of 7-DHC accumulation, and promotion of lipid peroxidation and ferroptosis. To translate this mechanism, we developed engineered exosomes delivering miR-26a-5p. In cellular and mouse MIRI models, this intervention significantly attenuated serum levels of cardiac injury biomarkers (cTnI and CK-MB), restored systemic antioxidant capacity, and attenuated early myocardial fibrosis. This work provides a novel therapeutic strategy for MIRI and provides preclinical evidence supporting the potential of engineered exosomes as a cell-free therapeutic platform.
Despite increased cardiovascular morbidity among patients with mental disorders, real-world data on lipid-lowering therapy (LLT) use and low-density lipoprotein cholesterol (LDL-C) target attainment after acute coronary syndrome (ACS) remain limited. We evaluated disparities in LLT utilization and LDL-C target attainment among patients with and without mental disorders following ACS in a real-world setting. Data of consecutive ACS hospitalizations in a large healthcare system (2013–2023) were analyzed. Patients were stratified by mental illness and compared with controls. LDL-C target attainment and LLT use were assessed at baseline and during early (1–4 months) and late (6–12 months) post-discharge periods. Multivariable logistic regression evaluated independent associations. Among 9,192 patients surviving ≥ 1 year after ACS, 32.1
