动脉粥样硬化性疾病威胁人类健康。如何防治动脉粥样硬化是心血管领域的关键科学问题。平滑肌细胞转分化成泡沫样细胞是动脉斑块进展的关键因素，但其机制及干预措施有待研究。研究表明线粒体介导的氧化应激在平滑肌细胞转分化中起重要作用。我们前期研究发现，促生长激素释放激素激动剂（MR409）抑制小鼠动脉粥样硬化进展，并抑制平滑肌细胞向泡沫样细胞转分化。同时，MR409促进主动脉组织线粒体融合蛋白OPA1的表达，激活cAMP/PKA，而既往研究提示cAMP/PKA可促进OPA1表达。因此，我们推测MR409可通过cAMP/PKA激活OPA1促进线粒体融合，减轻氧化应激，抑制平滑肌细胞转分化，进而抑制动脉粥样硬化。本项目在前期工作基础上，采用多种分子生物学和转基因动物模型，研究MR409调控动脉粥样斑块的作用，深入探讨MR409抑制平滑肌细胞转分化的机制，可望为临床防治动脉粥样硬化性疾病提供新靶点和思路。

Atherosclerotic diseases threaten human health. How to effectively prevent the progression of atherosclerosis is a key scientific issue in the cardiovascular field. Transdifferentiation of smooth muscle cells into foam-like cells is a key factor in the progression of arterial plaques, but its mechanisms and interventions need further study. Previous studies have shown that mitochondria-mediated oxidative stress plays an important role in smooth muscle cell transdifferentiation. Our previous study found that the agonist of growth hormone-releasing hormone (MR409) inhibits the progression of atherosclerosis in high-fat-fed low-density lipoprotein receptor knockout mice and inhibits smooth muscle cell transdifferentiation into foam-like cells. At the same time, MR409 promotes the expression of mitochondrial fusion protein OPA1 in aortic tissue and activates cAMP/PKA, whereas previous studies suggest that cAMP/PKA promote OPA1 expression. Therefore, we hypothesized that MR409 can promote mitochondrial fusion through cAMP/PKA activation of OPA1, reduce oxidative stress, inhibit smooth muscle cell transdifferentiation, and then inhibit atherosclerosis. Based on the preliminary work, this project uses a variety of molecular biology and transgenic animal models to study the role of MR409 in regulating atherosclerotic plaque, and to explore the mechanism of MR409 in inhibiting smooth muscle cell transdifferentiation. It is expected to provide new thoughts and targets to prevent and treat atherosclerosis.