ASIC1/RIP1 accelerates atherosclerosis via disrupting lipophagy.

INTRODUCTION: Atherosclerosis, a major contributor to cardiovascular disease, remains a significant health concern worldwide. While previous research has shown that acid-sensing ion channel 1 (ASIC1) impedes macrophage cholesterol efflux, its precise role in atherogenesis and the underlying mechanisms have remained elusive. OBJECTIVES: This study aimed to investigate the role of ASIC1 in atherosclerosis and its underlying mechanisms. METHODS: First, data from a single-cell RNA sequencing (scRNA-seq) database were used to explore the relationships between ASIC1 differential expression and lipophagy in human atherosclerotic lesions. Finally, we validated the role of ASIC1/RIP1 signaling in lipophagy in vivo (human and mice) and in vitro (RAW264.7 and HTP-1 cells). RESULT: Our results demonstrated a significant increase in ASIC1 protein levels within CD68+ macrophages in both human aortic lesions and AopE-/- mouse lesion areas compared to nonlesion regions. Concurrently, there was a notable decrease in lipophagy, a crucial process for lipid metabolism. In vitro assays further elucidated that ASIC1 interaction with RIP1 (receptor-interacting protein 1) promoted the phosphorylation of RIP1 at serine 166 and transcription factor EB (TFEB) at serine 142, leading to disrupted lipophagy and increased lipid accumulation. Intriguingly, all these events were reversed upon ASIC1 deficiency and RIP1 inhibition. Furthermore, in ApoE-/- mouse models of atherosclerosis, silencing ASIC1 expression or inhibiting RIP1 activation not only significantly attenuated atherogenesis but also restored TFEB-mediated lipophagy in aortic tissues. This was evidenced by reduced TFEB Ser-142 phosphorylation, decreased LC3II and LAMP1 protein expression, increased numbers of lipophagosomes, and a decrease in lipid droplets. CONCLUSION: Our findings unveil the critical role of macrophage ASIC1 in interacting with RIP1 to inhibit lipophagy, thereby promoting atherogenesis. Targeting ASIC1 represents a promising therapeutic avenue for the treatment of atherosclerosis.

Myocardin suppression increases lipid retention and atherosclerosis via downregulation of ABCA1 in vascular smooth muscle cells.

Myocardin (MYOCD) plays an important role in cardiovascular disease. However, its underlying impact on atherosclerosis remains to be elucidated. ATP binding cassette transporter A1 (ABCA1), a key membrane-associated lipid transporter which maintains intracellular lipid homeostasis, has a protective function in atherosclerosis progress. The purpose of this study was to investigate whether and how the effect of MYOCD on atherosclerosis is associated with ABCA1 in vascular smooth muscle cells (VSMCs). We found both MYOCD and ABCA1 expression were dramatically decreased in atherosclerotic patient aortas compared to control. MYOCD knockdown inhibited ABCA1 expression in human aortic vascular smooth muscle cells (HAVSMCs), leading to reduced cholesterol efflux and increased intracellular cholesterol contents. MYOCD overexpression exerted the opposite effect. Mechanistically, MYOCD regulates ABCA1 expression in an SRF-dependent manner. Consistently, apolipoprotein E-deficient mice treated with MYOCD shRNA developed more plaques in the aortic sinus, which is associated with reduced ABCA1 expression, increased cholesterol retention in the aorta, and decreased high-density lipoprotein cholesterol levels in the plasma. Our data suggest that MYOCD deficiency exacerbates atherosclerosis by downregulating ABCA1 dependent cholesterol efflux from VSMCs, thereby providing a novel strategy for the therapeutic treatment of atherosclerotic cardiovascular disease.

[Bovine jugular venous conduit treated with the polyepoxy compound].

OBJECTIVE: To determine the feasibility whether the bovine jugular venous conduit (BJVC) can be fixed with polyepoxy compound (PC). METHODS: Twenty-four BJVCs were divided into 3 groups and fixed with polyepoxy compound (PC group, n = 8), glutaraldehyde (GA group, n = 8), and unfixed group (Control group, n = 8), respectively. The morphologic and mechanical properties of BJVCs in the 3 groups, including thickness, diameter, moisture content, denaturation temperature, tensile strength, elongation at break, and fixation index were measured. The rat subcutaneous model for the assessment of tissue calcification was used. The calcium content in bovine jugular vein patches and valves was determined by flame atomic absorption spectrophotometer. RESULTS: There was no difference in the wall thickness, diameter, and tissue water content between PC and the control group, but significant difference was found between GA and PC groups. The mechanical properties of PC group and GA group were not significantly different, but they were better than those of the control group. GA-fixed BJVC samples showed clear calcification, while PC fixed BJVC were calcified significantly less. CONCLUSION: PC is an effective and suitable choice for the treatment of BJVC since it can effectively preserve the structure and the anti-reflow function of valves in bovine jugular vein and it has better anti-calcification properties.

[Immunogenicity of bovine jugular vein conduits treated with different cross-linking methods].

OBJECTIVE: To evaluate the immunogenicity of bovine jugular vein conduits (BJVCs) treated with different cross-linking methods. METHODS: The BJVCs were treated with glutaradehyde (GA), dye-mediated photooxidation (DMP) and polyepoxy compound (PC) (n = 10). The tissue homogenates obtained from BJVCs treated with PC, GA, DMP, and fresh BJVCs, were mixed with the complete Freand adjavant to form the emulsive antigen, which were used to immunize rabbits correspondently. The antibody concentrations to BJVCs in those rabbits' serum were measured by counter double immuno diffusion. The immunologic responses to the BJVCs in different groups were measured with Western blotting. RESULTS: The positive bands appeared when the sera of rabbits were immunized by fresh BJVCs reacted with antigens of fresh BJVCs, but no bands appeared when the sera of rabbits were immunized by fresh BJVCs reacted with those antigens of the BJVCs treated with GA, DMP, and PC in Western blotting. CONCLUSION: The immunogenicity of BJVCs treated with PC, DMP, and GA can be reduced significantly and meet the clinical standard.

[Myocardial protective effects of pretreatment with captopril on ischemia-reperfusion myocardium in rabbits].

OBJECTIVE: To investigate the effect of pretreatment with captopril on myocardium ischemia-reperfusion injury in atherosclerotic rabbits. METHODS: Thirty-two New Zealand white rabbits were assigned randomly to the normally feed group, cholesterol-feed (CF) group, and cholesterol food plus captopril group (cap-feed group), which were fed for 10 weeks. We examined the changes in the size of the infarct and changes in the myocardium ultrastructure resulting from coronary ischemia/reperfusion. Levels of endothelin (ET) and nitic oxide (NO) were measured in the different experiment stages. RESULTS: The ET levels significantly increased and the content of NO significantly decreased in the CF group compared with those of the cap-feed group. The ultrastructure of myocardium cell was slightly destroyed and the infarct size was significantly smaller in the cap-feed group than the normally feed rabbits and CF rabbits. CONCLUSION: The long-term captopril treatment can lighten the severity of myocardial injury produced by coronary ischemia/reperfusion.

[Morphologic and physiochemical properties of bovine jugular conduit stabilized by dye-mediated poto-oxidation].

OBJECTIVE: To determine the morphologic and physiochemical properties of bovine jugular conduit with valves stabilized by dye-mediated photo-oxidation. METHODS: Twenty-four bovine jugular conduits with valves were divided into 3 groups and treated with dye-mediated photo-oxidation (Group I), glutaraldehyde (Group II) and untreated group (Group II), respectively. Morphologic and physiochemical properties of the 3 groups, including wall thickness, diameter, tissue water content, heat shrinking temperature, breaching strength, and tissue protein extraction assay were studied. RESULTS: There was no difference in wall thickness, diameter, tissue water content, and heat shrinking temperature between Group I and II ,but there was significant difference between Group I and II. The breaching strength of Group I was higher than that of Group IU (P < 0.05), but lower than that of Group II (P < 0. 05). A decrease in extractable tissue protein was found in Group I and II. CONCLUSION: The dye-mediated photooxidation can effectively preserve the structure and the anti-regurgitation function of valves and improve the tissue stability and enhance the tension of bovine jugular conduit with valves.