Jing-Song Ou

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.

BACKGROUND: Recent studies have revealed heterogeneity among ribosomes. Pathological cardiac hypertrophy is characterized by profound alterations in translation. However, how ribosome heterogeneity contributes to this process remains largely unclear. METHODS: We used translating ribosome affinity purification coupled with mass spectrometry to profile ribosome-interacting proteins. Cardiomyocyte-specific gene manipulation was achieved through either genetic knockout or adeno-associated virus–mediated overexpression. Pathological cardiac hypertrophy was induced by transverse aortic constriction surgery in vivo and by phenylephrine stimulation in vitro. RESULTS: The cardiomyocyte-specific ribosome proteomics indicated dynamic alterations in ribosome-interacting proteins during pathological hypertrophy. Notably, multiple proteins associated with ribosome stalling were detected in the ribosome-interactome of hypertrophic hearts. Among these, we verified that CDK5RAP3 (CDK5 regulatory subunit-associated protein 3) exhibited the most specific ribosome binding in hypertrophic hearts. CDK5RAP3 was upregulated and recruited to ribosomes during pathological hypertrophy. It promoted RPL26 (ribosomal protein L26) UFMylation and ribosome-associated quality control on the mitochondrial surface. In vitro, CDK5RAP3 knockdown exacerbated cardiomyocyte hypertrophy induced by phenylephrine, whereas its overexpression attenuated it. In vivo, cardiomyocyte-specific CDK5RAP3 knockout promoted, while adeno-associated virus–mediated overexpression suppressed pathological cardiac hypertrophy induced by transverse aortic constriction. Mechanistically, ribosome stalling on the mitochondrial surface was exacerbated in hypertrophic hearts of both humans and mice, which was associated with impaired mitochondrial protein import. CDK5RAP3 enhanced ribosome-associated quality control, alleviated ribosome stalling, and restored mitochondrial protein import, thereby improving mitochondrial function. Notably, mitochondrial import of PDP1 (pyruvate dehydrogenase phosphatase catalytic subunit 1) was maintained by CDK5RAP3-mediated ribosome-associated quality control. Knockdown of PDK (pyruvate dehydrogenase kinase) 1/2, functional antagonists of PDP1, reversed cardiomyocyte hypertrophy caused by CDK5RAP3 deficiency. CONCLUSIONS: This study identifies CDK5RAP3-mediated ribosome-associated quality control on the mitochondrial surface as a critical protective mechanism that preserves protein import and mitochondrial function during pathological cardiac hypertrophy.

Dyslipidemia is an important risk factor for coronary artery disease (CAD). However, the relationship between high-density lipoprotein (HDL) antioxidant function and plasma lipid profile has not been fully investigated. Lipid-lowering therapy is recommended in patients with CAD. The relationship between HDL antioxidant function and lipid-lowering therapy remains unclear. This study aimed to analyze the association between HDL antioxidant function, lipid profiles, and lipid-lowering therapy in patients with CAD. To investigate this, we recruited 1,000 patients with CAD and 200 healthy subjects. HDL lipid peroxide content was measured and normalized by HDL cholesterol (HDL-C) levels to represent HDL antioxidant function (nHDLox). nHDLox levels were compared across different CAD severities. The association between nHDLox and lipid profiles was also analyzed. The difference in nHDLox between patients who received lipid-lowering therapy and those who did not was analyzed. A correlation analysis was performed to investigate the association between nHDLox and fasting blood glucose and inflammatory markers. Results demonstrated that nHDLox levels were elevated in patients with CAD compared to healthy subjects, and were also higher in patients with acute coronary syndrome and CAD combined with three-vessel disease. Receiver operating characteristic curve analysis showed that nHDLox was better than triglyceride-glucose index and HDL-C levels in predicting CAD. nHDLox positively correlated with total cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglyceride levels. Further analysis showed an approximately "L"-shaped relationship between nHDLox and HDL-C levels. Moreover, among CAD patients with LDL-C < 3.0 mmol/L, nHDLox was significantly reduced in the lipid-lowering therapy group compared to that in the group without lipid-lowering therapy. Furthermore, nHDLox positively correlated with fasting blood glucose levels and inflammatory markers. In conclusion, HDL antioxidant function is associated with lipid profiles. Lipid-lowering therapy improves HDL antioxidant function in patients with CAD, and nHDLox may serve as an indicator for the efficacy of such treatment.

Cardiovascular disease (CVD), the leading global cause of death, highlights the critical need for effective blood pressure management. Non-invasive blood pressure (NIBP) monitoring, compared with invasive methods, enables home-based and long-term use, supporting early detection and continuous care. Despite significant progress, challenges remain, including accuracy issues, insufficient validation in real-world settings, limited application-specific sensor designs, and inadequate calibration standards and validation platforms. These gaps call for a systematic review to clarify the unmet needs and future research directions. This article reviews current advances in four key areas: (1) novel NIBP estimation principles designed to minimize user intervention; (2) flexible and wearable electronics that improve accuracy and comfort; (3) integration with theranostic applications and broader healthcare scenarios enabled by NIBP technologies; (4) calibration and validation strategies that enhance reliability and accuracy. With the rapid growth of home healthcare and AI-enabled wearable systems, addressing these challenges is essential to advance personalized, precise and stable cardiovascular medicine.

BACKGROUND: Doxorubicin (DOX) cardiotoxicity increases cardiovascular risk in cancer patients, mainly through mitochondrial damage. However, the underlying mechanisms remain unclear, and whether mitochondrial short open reading frame-encoded peptides can mitigate DOX-induced cardiotoxicity is unknown. METHODS: Five adeno-associated viruses expressing mitochondrial short open reading frame-encoded peptides under the cardiac troponin T promoter, including MODICA (mito-SEP protector against DOX-induced cardiac injury), were screened in a DOX-induced cardiotoxicity mouse model (n=3–5 per group). Male and female mice were randomized to adeno-associated virus-CTRL or adeno-associated virus-MODICA, respectively, combined with saline or DOX treatment. Sample sizes were: males—saline-CTRL (n=4), saline-MODICA (n=4), DOX-CTRL (n=11), DOX-MODICA (n=10); females—saline-CTRL (n=8), saline-MODICA (n=10), DOX-CTRL (n=10), DOX-MODICA (n=13). MODICA-heterozygous mice generated by CRISPR/Cas9 were also included: saline-WT (n=7), saline-heterozygous (n=4), DOX-WT (n=11), DOX-heterozygous (n=8). Echocardiography was performed at baseline and after 2 weeks of DOX treatment; myocardial tissue and serum samples were collected for molecular and histological analyses. RESULTS: The mitochondrial short open reading frame-encoded peptide MODICA was identified through biochemical analysis and functional screening in a DOX-induced cardiac injury model. MODICA localizes to the outer mitochondrial membrane and is significantly downregulated by DOX (1.00±0.08 versus 0.42±0.09; P P P P P =0.009). Proteomic analyses revealed that MODICA interacts with apoptosis-related voltage-dependent anion channel proteins, inhibiting their DOX-induced oligomerization ( P <0.001) on the outer mitochondrial membrane, thereby reducing mitochondrial permeability, decreasing cardiomyocyte apoptosis and improving calcium handling. CONCLUSIONS: Our study shows that the mitochondrial short open reading frame-encoded peptide MODICA alleviates DOX-induced cardiac dysfunction and may represent a therapeutic target against DOX cardiotoxicity.

Background: Cardiogenic shock requiring mechanical circulatory support is a life-threatening complication of cardiac surgery with cardiopulmonary bypass (CPB). This study aimed to determine the role of myoglobin in predicting the occurrence of postoperative cardiogenic shock requiring mechanical circulatory support within 14 days. Methods: A total of 4,610 patients undergoing cardiac surgery with CPB were included and analyzed. Mechanical circulatory support included the form of intra-aortic balloon pump and extracorporeal membrane oxygenation. Cox regression with a natural cubic spline was used to assess the relationship between postoperative myoglobin levels and the 14-day risk of mechanical circulatory support for cardiogenic shock. Results: Of 4,610 patients, 279 (6.1%) required mechanical circulatory support within 14 days after surgery. The 14-day risk of using mechanical circulatory support increased with the postoperative peak myoglobin levels. Among the patients who underwent aortic surgery, the threshold myoglobin level measured within 1 day after surgery, associated with an adjusted hazard ratio greater than 1.00 for using mechanical circulatory support within 14 days, was 1,568 ng/mL (95% confidence interval [CI], 195–6,040). Among the patients who underwent non-aortic surgery, the corresponding threshold myoglobin level was 419 ng/mL (95% CI, 180–452). Conclusions: Postoperative myoglobin levels are closely related to the 14-day risk of using mechanical circulatory support after cardiac surgery. When postoperative myoglobin exceeds certain thresholds, the 14-day risk of using mechanical circulatory support after surgery starts to increase with the myoglobin level. Myoglobin has potential value in predicting postoperative cardiogenic shock requiring mechanical circulatory support within 14 days after cardiac surgery.

Cardiac surgery with cardiopulmonary bypass (CPB) may lead to many postoperative complications. However, many complications cannot be predicted in time using the current clinical methods, or the prediction is not sufficiently accurate, resulting in a delay in treatment. Extracellular vesicles (EVs) are a group of membrane vesicles generated from various sources, including endothelial cells and platelets, upon activation or apoptosis. Here, we summarize the role of circulating EVs in predicting complications after cardiac surgery with cardiopulmonary bypass. We found that EV levels can predict acute heart failure. EV subtypes can predict acute heart failure, acute kidney injury, acute lung injury, blood transfusion, and neurological complications. The components of EVs can predict acute heart failure, acute kidney injury, acute lung injury, and neurological complications. The size distribution of EVs can predict acute lung injury. Therefore, circulating EVs can be used to predict complications after cardiac surgery with cardiopulmonary bypass. Graphical Abstract

Size distribution is an important biophysical property of extracellular vesicles (EVs). EVs include small EVs (s-EVs) and large EVs (l-EVs) by size. Differential ultracentrifugation (dUC) is widely used to separate EVs from biofluids, but it can precipitate large impurity particles. Dynamic light scattering (DLS) is a simple and fast method for analyzing the size distribution of EVs. However, this approach is nonideal for heterogeneous and polydisperse samples since a small quantity of large impurity particles can markedly disturb the DLS results. Here, we developed a simple method to improve the reliability of DLS measurements. Plasma was obtained from 13 volunteers. The plasma was first processed by dUC to obtain crude l-EVs. The crude l-EVs were filtered with syringe filters (pore size of 1 μm and membrane material of hydrophilic polyvinylidene fluoride (PVDF)) to remove large impurity particles from l-EVs. The size distributions of the crude l-EVs and filtered l-EVs were measured via DLS. After the samples were filtered, the coefficients of variation of the hydrodynamic radius and Peak 1 intensity of the filtered l-EVs decreased from 20.39% (12.76-28.96%) and 20.44% (14.58-28.32%) to 3.05% (1.79-4.72%) and 3.43% (1.76-5.88%), respectively, compared with those of the crude l-EVs. These findings suggest that filtration can effectively separate circulating l-EVs in plasma to remove large impurity particles and make samples suitable for characterization by DLS. Our findings provide a simple method to improve precision via DLS to measure the size distribution of EVs.

Inflammation is a critical pathological process in myocardial infarction. Although immunosuppressive therapies can mitigate inflammatory responses and improve outcomes in myocardial infarction, they also increase the risk of infections. Identifying novel regulators of local cardiac inflammation could provide safer therapeutic targets for myocardial ischemia/reperfusion injury. In this study, we identified a previously uncharacterized micropeptide, which we named Inflammation Associated MicroPeptide (IAMP). IAMP is predominantly expressed in cardiac fibroblasts, and its expression is closely associated with cardiac inflammation. Downregulation of IAMP promotes, whereas its overexpression prevents, the transformation of cardiac fibroblasts into a more inflammatory phenotype under stressed/stimulated conditions, as evidenced by changes in the expression and secretion of proinflammatory cytokines. Consequently, loss of IAMP function leads to uncontrolled inflammation and worsens cardiac injury following ischemia/reperfusion surgery. Mechanistically, IAMP promotes the degradation of HIF-1α by interacting with its stabilizing partner HSP90 and, thus, suppresses the transcription of proinflammatory genes downstream of HIF-1α. This study underscores the significance of fibroblast-mediated inflammation in cardiac ischemia/reperfusion injury and highlights the therapeutic potential of targeting micropeptides for myocardial infarction.

Vascular calcification is an important risk factor related to all‐cause mortality of cardiovascular events in patients with chronic kidney disease (CKD). Vascular extracellular matrix (ECM) proteins have been demonstrated to regulate vascular calcification. ECM protein thrombospondin 1 (THBS1/TSP‐1) plays a critical role in the regulation of vascular diseases. However, whether THBS1 is involved in vascular calcification in CKD patients remains unclear. In this study, RNA sequencing datasets from the Gene Expression Omnibus (GEO) database GSE146638 showed that THBS1 was upregulated in the aortas of CKD rats. Enzyme‐linked immunosorbent assay (elisa) revealed that serum THBS1 levels were increased in CKD patients with thoracic calcification. Western blotting and immunofluorescence analysis showed that THBS1 expression was increased in calcified vascular smooth muscle cells (VSMCs) and arteries. THBS1 knockdown exacerbated rat VSMC calcification induced by high phosphorus and calcium, as shown by Alizarin red staining and calcium content assays. Conversely, THBS1 overexpression attenuated VSMC calcification and abdominal aortic calcification in rats with CKD. Moreover, addition of recombinant THBS1 protein inhibited calcification of VSMC_S and human arterial rings. Smooth muscle cell‐specific knockout of THBS1 mice treated with vitamin D3 displayed aggravated aortic calcification. Mechanistically, the protein–protein interaction database STRING (http://string-db.org/) analysis and coimmunoprecipitation assays revealed THBS1 bound to integrin β3. Reduction of integrin β3 levels abrogated the protective effect of THBS1 on vascular calcification. RNA‐seq analysis revealed that THBS1 overexpression modulated the nuclear factor‐kappa B (NF‐κB) signaling pathway. Of note, the inhibitory effect of THBS1 overexpression on the NF‐κB signal was abolished by knockdown of integrin β3. In conclusion, THBS1 interacts with integrin β3 to inhibit vascular calcification through suppression of NF‐κB signal, suggesting a promising therapeutic target for vascular calcification in CKD. © 2025 The Pathological Society of Great Britain and Ireland.