生物活性肽Intermedin在衰老血管钙化中的作用和机制

Intermedin(IMD) is a cardiovascular regulatory peptides which has multifunction. Our previous work found that IMD can inhibit vascular calcification(VC)。 Recent work showed that IMD can inhibit aging related marker and upregulate anti-aging molecule Klotho and Sirt1. However, the role and mechanism of IMD in aging VC. We infer that IMD might be an important regulatory peptide inhibiting aging vascular calcification which mechanism involved in upregulating Klotho and Sirt1. In this project, we aim to study roles and changes of IMD on the model of aging rat, IMD-/- and IMD tg mice vascular calcification in in vivo and in in vitro; Clarify the mechanism of IMD inhibiting aging VSMC phenotype transition into osteoblast-like cells and therfore inhibiting aging vascular calcification by upregulating Klotho and Sirt1; And further demonstrate cecullar signal transduction pathway and molecular mechanism of IMD upregulating Klotho and Sirt1. This project will provide new theoretical base and strategies for preventing and treating aging related cardiovascular diseases, diabetes and senile arteriosclerosis.

Intermedin(IMD)是有多种生物学效应的心血管调节肽。前期工作发现IMD抑制血管钙化，最近发现IMD抑制血管衰老相关分子及上调抗衰老抑制钙化的Klotho和Sirt1。我们推测IMD是抑制衰老血管钙化的重要内源性防御调节肽，其机制可能与上调Klotho和Sirt1有关。本项目拟用衰老大鼠以及衰老IMD基因敲除和过表达小鼠建立衰老血管钙化模型和衰老VSMC钙化模型，通过皮下埋置渗透泵给IMD、受体信号通路药物或基因手段干预IMD及其受体/受体后信号通路，研究IMD及其受体在衰老血管钙化中的改变和作用；用Klotho和Sirt1敲除鼠研究IMD上调Klotho和Sirt1抑制衰老VSMC向成骨细胞样表型转变抑制衰老血管钙化；阐明IMD上调Klotho和Sirt1抑制衰老VSMC向成骨细胞样表型转变的细胞信号传导和分子机制，为防治衰老血管钙化及衰老相关的心血管疾病、糖尿病提供理论依据。

Intermedin(IMD)是有多种生物学效应的心血管调节肽。前期工作发现IMD抑制血管钙化，抑制导致血管衰老的氧化应激、炎症反应以及上调抗衰老相关蛋白，我们提出IMD可能是抑制衰老血管钙化的重要内源性调节肽的假说。本项目在老年大鼠血管钙化模型以及VSMC特异性敲除IMD小鼠衰老钙化的VSMC上发现IMD显著抑制衰老大鼠血管钙化以及衰老VSMC的钙化，其机制与IMD激活PI3K / Akt、AMPK和cAMP / PKA信号通路上调Sirt1表达、增加Sirt1乙酰化活性有关。IMD还可通过抑制内质网应激和炎症反应抑制动脉粥样硬化性血管钙化以及上调Sirt3 抑制线粒体氧化应激和功能障碍减轻慢性肾病血管钙化。提出IMD是抑制衰老相关血管钙化和动脉粥样硬化性血管钙化的内源性生物活性小分子调节肽。 项目按计划完成，阐明了IMD抑制衰老血管钙化的分子机制，为有效预防和治疗衰老相关的心血管疾病、糖尿病及老年血管硬化提供理论依据和新策略。