寒邪通过冷受体TRPM8介导UCP1依赖性脂解并促进动脉粥样硬化斑块增生和不稳定

Clinical epidemiological studies show that cardiovascular events are significantly increased in winter, but the mechanisms underlying cold-induced CVD are poorly unknown. Based on the existing articles and research, we proposed the following hypothesize: " Cold evil activates the cold-sensing TRPM8 triggers UCP1-dependent lipolysis and promotes atherosclerotic plaque growth and instability ". In order to verify the hypothesis, we will use the classic AS mouse model ApoE-/- mice, to study if the Cold evil can stimulate the cold-sensing TRPM8 expression of adipocytes, trigger UCP1-dependent lipolysis, then activate the BAT, convert the WAT into BAT-like tissue (BRITE), further change blood lipid profiles , therefore promote atherosclerotic plaque growth and instability. We will use the PKA inhibitor, to see if the TRPM8-mediated UCP1 production is associated with PKA phosphorylation. This study can develop new ideas of TCM treatments on AS- associated diseases, lay a scientific foundation for TCM intervention on cold-induced CVD. Cold evil is one of the six evils of TCM exogenous pathogenic factors, it's of great significance to enrich the scientific connotation of TCM etiology through explaining the pathogenic mechanism of cold evil by modern scientific research methods.

临床流行病学研究发现，冬季心血管事件显著高发，但其原因未明。我们根据已有文献和研究，提出"寒邪通过冷受体TRPM8引发UCP1依赖性脂解并促进动脉粥样硬化斑块增生和不稳定"的假说。为了验证以上假说，我们利用动脉粥样硬化经典动物模型ApoE-/-小鼠，研究寒邪是否可以刺激脂肪细胞冷受体TRPM8表达，继而引发UCP1依赖性脂解，棕色脂肪组织活化，白色脂肪组织向棕色样脂肪组织转化，从而导致血脂升高，动脉粥样硬化斑块增生和不稳定。利用PKA抑制剂，研究寒邪通过冷受体TRPM8介导UCP1增量表达是否与PKA磷酸化相关。本课题可开拓中医药防治动脉粥样硬化相关疾病的新思路，为中医干预减少冬季心血管事件高发奠定科学基础。寒邪为中医六淫致病因素之一，用现代科研方法阐释寒邪的致病机理，对于丰富中医病因学说的科学内涵，具有重要意义。

本课题中，我们利用动脉粥样硬化经典动物模型ApoE-/-小鼠，研究寒邪是否可以刺激脂肪细胞冷受体TRPM8表达，继而引发UCP1依赖性脂解，棕色脂肪组织活化，白色脂肪组织向棕色样脂肪组织转化，从而导致血脂升高，动脉粥样硬化斑块增生和不稳定。利用PKA抑制剂，研究寒邪通过冷受体TRPM8介导UCP1增量表达是否与PKA磷酸化相关。按照课题计划，我们完成了实验动物饲养、取材，以及大部分相关指标的检测，并在原有方案的基础上，进一步对实验方案进行了细化与完善。研究结果表明，持续冷暴露后HE染色观察可见冷刺激组白色脂肪组织明显棕色化，并可以激活UCP1依赖性脂解以及显著降低血清胆固醇水平。此外，我们团队研究发现，寒气暴露可以使LDL-C平均下降63%，但背后机制仍待进一步研究。