Zhongqun Wang

Vascular calcification (VC), a key predictor of cardiovascular morbidity and mortality, is an active cell-mediated pathological process deeply coupled with cellular senescence. This review systematically dissects the mechanisms by which senescent vascular smooth muscle cells, endothelial cells and macrophages drive VC progression via phenotypic switching, intercellular crosstalk, and endothelial–mesenchymal transition and clarifies the extensive signaling crosstalk and heterogeneous regulation between cellular senescence and VC. Nevertheless, these two biological processes do not inevitably occur in parallel, and experimental evidence indicates that they may diverge in some settings. We further summarize representative senotherapeutic agents that concurrently suppress cellular senescence and VC, including fisetin, dasatinib plus quercetin, metformin, sodium-glucose cotransporter 2 inhibitors, and liraglutide, and elaborate their core regulatory targets such as AMP-activated protein kinase, silent information regulator 1/6, nuclear factor kappa B and nuclear factor erythroid 2-related factor 2. Of note, direct experimental evidence demonstrating whether these pharmacological interventions attenuate VC via modulating SASP remains limited. Finally, we address key challenges in this field and provide novel perspectives for senescence-associated VC therapeutic strategies.

Absrtact: Atherosclerosis (AS) constitutes the primary underlying etiology of cardiovascular diseases (CVDs), and diabetes mellitus exacerbates the risk of mortality and disability in patients with AS-related CVDs. Given the pivotal role of endothelial cell dysfunction in the progression of diabetic AS plaques, our series of studies has identified that endothelial IDH2 lactylation exerts a cardiovascular protective effect. Lysine residue 272 serves as the specific lactylation site, and the level of this modification is significantly elevated in diabetic plaques. Furthermore, adenovirus was used to infect mouse aortic endothelial cells (MAECs) to abrogate the lactylation activity at the K272 site of IDH2. Experimental results demonstrated that IDH2-K272 lactylation contributes to the maintenance of IDH2 enzymatic activity, thereby ensuring sufficient biosynthesis of α-ketoglutarate (α-KG) and attenuating mitochondrial damage and endothelial dysfunction under hyperglycemic and hyperlipidemic conditions. Additionally, utilizing adeno-associated viruses encoding the K272 site (AAV ^ENT -IDH2-K272R) to abrogate endothelial IDH2 lactylation activity of ApoE ^–/– male mice, we induced diabetic plaques with streptozotocin (STZ). Concurrently, in endothelial cell-specific IDH2-K272R knock-in (IDH2 ^EC-K272R ) male mice, plaques were induced using AAV-PCSK9 and STZ. Both animal models consistently demonstrated that loss of K272 lactylation exacerbates mitochondrial dysfunction and endothelial injury, thereby promoting plaque formation and instability. Furthermore, we validated that exogenous supplementation of α-KG effectively mitigates the progression of diabetic plaques. In summary, our study is the first to reveal that endothelial IDH2-K272 lactylation counteracts diabetic atherosclerosis via α-KG, thereby offering a valuable therapeutic strategy.

Atherosclerosis is a chronic inflammatory disease driven by metabolic disorders, and macrophages play a central role in their occurrence and development. Macrophages are not static; their functional polarization and fate decisions are highly regulated by metabolic signals from the microenvironment, a process known as metabolic reprogramming. This review systematically reviews the latest progress in the metabolic reprogramming of glucose, lipids, and mitochondria in atherosclerosis, focusing on how key metabolites such as glycolysis, pentose phosphate pathway, cholesterol/sphingolipid metabolism, gut microbiota derivatives, and oxaloacetate dynamically regulate the inflammatory phenotype, foam cell formation, and immune response of macrophages. This review also delves into new concepts such as trained immunity and analyzes the therapeutic potential of targeting these metabolic pathways, aiming to comprehensively reveal the core role of metabolic‐immune cross‐talk in atherosclerosis and provide a theoretical basis for developing new strategies for diagnosing and treating atherosclerosis based on macrophage metabolic reprogramming.

Purpose of Review We aim to elucidate the formation mechanisms of microcalcification in atherosclerotic plaques, systematically clarify its heterogeneous effects on plaque vulnerability, and summarize the latest advances in microcalcification detection technologies and targeted therapeutic strategies. Recent Findings Microcalcification plays a pivotal role in atherosclerotic plaque vulnerability. Key features of microcalcification (size: 5–65 μm, irregular/prolate spheroidal morphology, h/D <0.4 spacing, and fibrous cap localization aligned with tensile axes) amplify local stress and increase plaque rupture risk. Recent studies have developed novel models to simulate the presence of microcalcifications in plaques and focused on investigating the effects of microcalcifications on collagen fibers and plaque constituent cells. Current detection technologies, such as ¹⁸F-NaF PET/CT, are capable of detecting vascular microcalcifications while performing risk stratification for atherosclerotic plaques. Hydroxyapatite mineralization and nucleation represent the initial process of microcalcification formation. Drugs targeting this process, namely SNF472 and bisphosphonates, have demonstrated excellent efficacy and safety in recent clinical trials. Summary The impact of microcalcification on atherosclerotic plaque vulnerability is determined by its size, morphology, spacing, and location. Micro-CT, optical coherence tomography, and ¹⁸F-NaF PET/CT each have their own advantages in the detection of microcalcifications. Among them, ¹⁸F-NaF PET/CT has been used as a biomarker for microcalcification activity and is capable of identifying high-risk plaques. Drugs targeting hydroxyapatite nucleation, such as SNF472 and bisphosphonates, have made considerable progress in the treatment of vascular calcification, yet further clinical translational trials are still needed to verify their efficacy. Graphical Abstract The alternative text for this image may have been generated using AI. Microcalcifications originate from multiple sources, including osteogenic differentiation, apoptosis, and extracellular vesicles (EVs), among which EV-derived microcalcifications have garnered increasing attention in recent years. The characteristics of microcalcifications, such as size, morphology, spacing, and location, exert heterogeneous effects on atherosclerotic plaque vulnerability. Detection techniques such as micro-computed tomography (micro-CT), optical coherence tomography (OCT), and ¹⁸F-sodium fluoride positron emission tomography/computed tomography (¹⁸F-NaF PET/CT) play indispensable roles in microcalcification detection owing to their respective unique advantages. Pharmacological agents including SNF472 and bisphosphonates exert distinct therapeutic effects by inhibiting hydroxyapatite nucleation, the key step in microcalcification formation.

Vascular calcification (VC) is a complex pathological process, which is closely related to chronic kidney disease, atherosclerosis, diabetes and aging. This phenomenon is mainly driven by the convergence of cellular and molecular molecular mechanisms, including osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs), persistent oxidative stress, extracellular vesicle‐mediated calcification, and activation of multiple cross‐signaling signaling pathways. The multifaceted evidence emphasizes the key role of VSMCs cytoskeleton remodeling in the progression of VC, and establishes a significant link between cytoskeleton dynamics and calcification initiation, which has potential predictive value under specific conditions. This article reviews the factors affecting the remodeling and stability of VSMCs cytoskeleton, focusing on their effects on VSMCs transdifferentiation and calcification. Finally, we highlighted the role of cytoskeleton in the process of cardiovascular calcification, explored strategies for mediating calcification, and proposed potential directions for future research.

Vascular calcification (VC), a pathological hallmark of advanced atherosclerosis, exerts a profound impact on arterial stiffness and the incidence of cardiovascular disease. Its development involves not only actively regulated biological processes but also passive mineral deposition and is particularly prevalent in patients with diabetes, chronic kidney disease, and endocrine disorders. Although conventional therapies-such as phosphate binders, calcium channel blockers, bisphosphonates, and endovascular interventions-form the current clinical foundation, they remain inadequate for preventing early VC or reversing established lesions. This review systematically summarizes advances in both standard strategies and emerging therapies. Recent studies have highlighted several breakthrough approaches: nanotechnology-based delivery systems, optimized agents such as SNF472 and GLP-1 receptor agonists, and bioactive constituents from traditional Chinese medicine (e.g., ginsenosides, chelerythrine), all of which target distinct calcification pathways. In addition, dietary interventions and lifestyle modification show preventive value. Progress in multi-omics technologies continues to uncover new molecular mechanisms and therapeutic targets, guiding precision medicine. By integrating mechanistic insights with novel therapeutic paradigms, this review aims to facilitate the development of personalized management strategies and ultimately improve cardiovascular outcomes in high-risk populations.

Background: Vascular calcification is a major cause of adverse outcomes of acute cardiovascular events in diabetic patients. However, the effective therapeutic target for diabetic atherosclerotic calcification remains unclear. Branched-chain amino acid transaminase 2 (BCAT2), a key rate-limiting enzyme of branched-chain amino acid (BCAA) catabolism, may play a potential role in the development of diabetic complications. This study aimed to elucidate the role of BCAT2 in diabetic atherosclerotic calcification. Methods: Airflow-assisted desorption electrospray ionization mass spectrometry imaging (AFADESI-MSI) was employed to investigate the spatial distribution of metabolites in frozen arterial sections obtained from diabetic foot amputations. Single-cell RNA sequencing datasets from arteries of diabetic foot amputations were used to identify the expression of metabolic enzymes in the BCAA catabolism. ApoE knockout mice with specific deletion of BCAT2 in vascular smooth muscle cells (VSMCs) were generated, and a diabetic atherosclerotic calcification model was established to evaluate the impact of BCAT2 in diabetic atherosclerotic calcification. Further, the gene regulatory mechanisms of BCAT2 in diabetic atherosclerotic calcification were investigated. Results: BCAA catabolism was enhanced in the calcified anterior tibial arteries from diabetic foot amputation revealed by spatial metabolomics. Furthermore, BCAT2 was found to be up-regulated in VSMCs of calcified anterior tibial arteries from diabetic foot amputation by single-cell transcriptomics. Notably, VSMC-specific BCAT2 deficiency attenuated diabetic atherosclerotic calcification without sex bias. Further experiments revealed that branched-chain α-ketoacids (BCKA) supplement, especially α-keto-β-methylvaleric acid (KMV) and α-ketoisovaleric acid (KIV), promoted osteogenic differentiation of VSMCs and diabetic atherosclerotic calcification. Mechanistically, VSMC-specific BCAT2 deficiency suppressed the generation of BCKA-derived propionyl-CoA, mitigating histone propionylation at the promoter of RUNX2, and thereby osteogenic differentiation of VSMCs and diabetic atherosclerotic calcification. Conclusions: Our study demonstrates a previously unrecognized role of BCAA catabolism in diabetic atherosclerotic calcification and further delineates that the BCAT2–BCKA axis contributes to the osteoblastic differentiation of VSMCs by epigenetically modulating RUNX2 expression via histone propionylation.