Yuyu Yao

Vascular smooth muscle cells (VSMCs), which form the media layer of blood vessels, play a vital role in vascular homeostasis and remodeling. Dysfunction of VSMCs represents a key pathological basis and an important contributor to vascular diseases. Ferroptosis, an iron-dependent accumulation of lipid hydroperoxides, is a novel form of regulated cell death. VSMC ferroptosis is involved in a range of vascular diseases, such as atherosclerosis, vascular calcification, hypertension, aortic aneurysm, aortic dissection, neointimal hyperplasia, intracranial aneurysm, and pulmonary arterial hypertension. This review summarizes the current evidence, underlying potential mechanisms, and therapeutic targets of VSMC ferroptosis in vascular diseases. A deeper understanding of this process may provide therapeutic insights and help in mitigating cardiovascular risk in affected patients.

Obesity has emerged as one of the most critical global health challenges. However, current anti‐obesity pharmacotherapies are limited by suboptimal efficacy and significant side effects. White adipose tissue (WAT) browning may contribute to ameliorating obesity. In this study, a water‐soluble lipophilic second near‐infrared region (NIR‐II) photothermal agent, CPDT‐BBT‐N (BTN), which specifically targets lipid droplets (LDs) and accumulates in adipocytes, was developed. Upon NIR irradiation, BTN induced a strong photothermal effect, enabling localized mild hyperthermia that specifically triggers white adipocyte browning with high efficiency and minimal off‐target effects. WAT browning markedly accelerated the burning of the excessive fat accumulated in adipocytes. Notably, this intervention also showed systemic metabolic benefits. In high‐fat diet (HFD)‐induced obese mice, the BTN + NIR treatment attenuated weight gain by 20%, reduced subcutaneous WAT mass by 43%, and decreased visceral fat mass by 35%. Furthermore, it significantly reduced serum cholesterol (38%), triglycerides (30%), insulin (30%), and glucose levels (35%) while improving insulin sensitivity. Mechanistically, mild thermal stimulation promoted calcium influx in adipocytes, upregulating the expression of the thermogenic protein UCP1, enhancing mitochondrial oxidative respiration, and facilitating lipid catabolism. Together, these findings provide a novel and feasible strategy for effectively and safely managing obesity.

Epicardial adipose tissue (EpAT), particularly pericoronary adipose tissue (PCAT), plays a crucial role in diabetes mellitus (DM)-aggravated coronary arter

Obesity is closely associated with arterial stiffening and pathological vascular remodeling, yet its key molecular mechanisms remain incompletely understood. The endocrine function of adipocytes reveals the significance in regulating vascular diseases. This study investigated the adipocyte-derived serine protease inhibitor A3c (Serpina3c) in regulating vascular extracellular matrix (ECM) homeostasis and vascular smooth muscle cell (VSMC) phenotypic switching during obesity-related vascular injury. Serpina3c expression was significantly reduced in perivascular and epididymal adipose tissue in high-fat diet (HFD)-fed mice. Serpina3c deficiency exacerbated arterial stiffening and impaired vascular reactivity in HFD-fed mice, accompanied by ECM disorganization and VSMC switching toward a synthetic phenotype. Conversely, adipocyte-specific restoration of Serpina3c in perivascular/epididymal fat effectively reversed these abnormalities. Mechanistically, adipocyte-derived Serpina3c bound to the ADAMTS4 proteinase domain and inhibited its enzymatic activity, leading to decreased fibronectin cleavage. The reduction in fibronectin fragments suppressed integrin-mediated activation of the AKT1/NF-κB signaling pathway, ultimately maintaining ECM homeostasis and preventing the transition of VSMCs to a synthetic phenotype. Accordingly, the impaired vascular reactivity in HFD-fed Serpina3c knockout mice was rescued by an ADAMTS4 antagonist. Clinically, aneurysmal tissues from patients with a high body mass index showed decreased co‑localization of Kallistatin (the human homolog of Serpina3c) with ADAMTS4, alongside more severe aneurysmal progression and arterial structural damage. In summary, this study identifies the adipokine Serpina3c as a novel endogenous inhibitor of ADAMTS4 that limits ECM proteolysis and VSMC synthetic switching by attenuating fragmented fibronectin-mediated AKT1/NF-κB signaling. Targeting Serpina3c provides a new therapeutic approach for obesity-related arterial remodeling.

Background: Visceral white adipose tissue (vWAT) inflammation is a critical pathology of obesity-caused heart damage and is closely associated with adipocyte endoplasmic reticulum (ER) dysfunction. Serine (or cysteine) peptidase inhibitor, clade A, member 3C (Serpina3c) has been identified as an adipokine with anti-vWAT inflammatory effects. However, it remains unclear whether Serpina3c deficiency promotion of vWAT inflammation involves adipocyte ER dysfunction and whether it further contributes to heart damage in obesity.Methods: Wild type and Serpina3c knockout (Serpina3c–/–) mice were fed a high-fat diet (HFD) for 12 weeks. An adeno-associated virus (AAV) was injected locally into epididymal white adipose tissue (eWAT) of Serpina3c–/– mice to induce eWAT-adipocyte- specific overexpression of Serpina3c (AAV-Serpina3c) or knockdown of hypoxia-inducible factor 1α (AAV-shHIF1α). In vitro experiments were performed in 3T3-L1 adipocytes.Results: Serpina3c–/– mice exhibited more severe eWAT, serum and heart inflammation after HFD feeding. Consistently, these adverse phenotypes were mitigated in AAV-Serpina3c and AAV-shHIF1α mice. Mechanistically, ER oxidoreductase 1α (Ero1α) and protein disulfide isomerase (PDI) family members PDIA3 and PDIA4 were found to be target genes of HIF1α. In the obese mice, Serpina3c deficiency caused adipocyte more hypertrophy, and activated HIF1α-Ero1α/PDI mediated ER overoxidation and ER stress in eWAT. Subsequently, this led to increased adipocyte apoptosis and chemokine production and decreased adiponectin expression, which promoted macrophage infiltration and M1 polarization in eWAT, thus exacerbating eWAT inflammation and ultimately facilitating serum and distal heart inflammation.Conclusion: These findings indicate that Serpina3c is a significant regulator of adipocyte ER redox homeostasis, thus highlighting Serpina3c as a potential therapeutic target for obesity-related eWAT inflammation and heart damage.

Background: Epicardial adipose tissue (EAT) is implicated in exerting potential proarrhythmic effects. The relationship between EAT and tachyarrhythmias is well documented. However, the connection between EAT and bradyarrhythmias has not been comprehensively explored. This study aimed to investigate the association between EAT and bradyarrhythmias. Methods: We retrospectively quantified the volume and density of EAT using chest computed tomography scans from patients with bradyarrhythmias and case‐matched controls. Measurements were obtained through manual pericardial contour tracing with a standardized Hounsfield unit threshold of −200 to −50 Hounsfield units. Results: A total of 652 patients were included, comprising 326 patients with bradyarrhythmias (age 74.00 [interquartile range, 64.00–81.00] years, 46.01% female) and 326 matched controls (age 72.50 [interquartile range, 63.00–80.00] years, 46.01% female). Compared with the matched control group, the bradyarrhythmia group had a significantly greater volume (119.13 [interquartile range, 87.30–151.68] cm ³ versus 93.00 [interquartile range, 67.87–116.71] cm ³ , P P P =0.012). Conclusions: Patients with bradyarrhythmia demonstrated significantly higher EAT volumes compared with matched controls, with a progressive increase observed across advancing grades of AVB. This dose‐dependent relationship between EAT burden and conduction system impairment underscores its potential role as a modifiable influencing factor in arrhythmogenesis. Further investigations are warranted to determine whether targeted EAT reduction could mitigate conduction abnormalities. Registration: URL: https://www.chictr.org.cn ; Unique Identifier: ChiCTR2400088446.

Adipose tissue dysfunction leads to abnormal lipid metabolism and high inflammation levels. This research aims to explore the role of Serpina3c, which is highly expressed in adipocytes, in obesity-related hypertriglyceridemia and metaflammation. Serpina3c global knockout (KO) mice, adipocyte-specific Serpina3c overexpressing mice, Serpina3c knockdown (KD) mice, and hypoxia-inducible factor 1 alpha (Hif1α) KD mice were fed a high-fat diet (HFD) for 16 weeks to generate obesity-related hypertriglyceridemia mice models. In the present study, Serpina3c KO mice and adipocyte-specific Serpina3c KD mice exhibited more severe obesity-related hypertriglyceridemia and metaflammation under HFD conditions. Serpina3c KO epididymal white adipose tissue (eWAT) primary stromal vascular fraction (SVF)-derived adipocytes exhibited higher lipid (triglyceride and non-esterified fatty acid) levels and higher fatty acid synthase expression after palmitic acid (PA) stimulation. Adipocyte-specific Serpina3c overexpression in KO mice prevented the KO group phenotype. The RNA-seq and in vitro validation revealed that Hif1α and the glycolysis pathways were up-regulated in Serpina3c KD adipocytes, which were all validated by in vitro and in vivo reverse experiments. Co-immunoprecipitation (co-IP) provided evidence that Serpina3c bound nuclear factor erythroid 2-related factor 2 (Nrf2) regulates Hif1α. Nrf2 KD reduced Hif1α and Fasn expression, decreased lipid content, and reduced the extracellular acidification rate in Serpina3c KO adipocytes. Metabolomics revealed that lactic acid (LD) levels in eWAT were responsible for adipose-associated macrophage inflammation. In summary, Serpina3c inhibits the Hif1α-glycolysis pathway and reduces de novo lipogenesis (DNL) and LD secretion in adipocytes by binding to Nrf2, thereby improving HFD-induced lipid metabolism disorders and alleviating adipose tissue macrophage inflammation.

BACKGROUND: Vascular calcification (VC) is associated with diabetes, chronic kidney disease, and aging. VC is found to be a powerful and independent risk factor for cardiovascular mortality. Vascular smooth muscle cell (VSMC) ferroptosis, a form of cell death, is known to be involved in VC. However, whether VSMC ferroptosis is regulated by posttranslational modifications remains undefined. METHODS: We explored the potential role and mechanism of PARP1 (poly[ADP-ribose] polymerase 1)-mediated poly(ADP-ribosyl)ation (PARylation) in VSMC ferroptosis during VC. Mouse VSMCs were treated with β-glycerophosphate, and Parp1 ^flox/flox Tagln Cre ⁺ calcified mice were generated with AAV9-sh-POLG (DNA polymerase gamma) injected to establish in vitro and in vivo models, respectively. RNA-sequencing analysis was performed to determine the transcriptomic alterations in VSMCs overexpressing POLG and treated with β-glycerophosphate. RESULTS: Both PARP1 expression and PARylation levels were increased in β-glycerophosphate–induced VC, with PARP1 knockdown mitigating VC by improving mitochondrial function and inhibiting the subsequent VSMC ferroptosis. Mechanistically, POLG PARylation levels were increased in calcified VSMCs from PARP1 activation, triggering PARylation-dependent ubiquitination of POLG that resulted in POLG downregulation. This led to mitochondrial dysfunction and Adora2a (adenosine receptor A2A)/Rap1 (Ras-associated protein 1) signaling pathway activation to induce VSMC ferroptosis, which ultimately aggravated VC. CONCLUSIONS: Our study establishes the critical role of PARP1-mediated PARylation-dependent ubiquitination of POLG in VSMC ferroptosis-induced VC. These findings suggest that PARP1 inhibitors could potentially serve as novel therapeutic strategies for VC.