TRPM8调控EPC介导的血管新生在心梗后心肌重构中的作用及机制研究

The cardiac remodeling is the major pathological process of heart failure after myocardial infarction (MI). Endothelial progenitor cell (EPC) mediated angiogenesis has the potential to salvage ischemic myocardium and inhibit cardiac remodeling. In our previous work, we found that transient receptor potential melastatin 8 (TRPM8) agonist could significantly attenuate myocardial dysfunction and improve survival after myocardial infarction. In addition, TRPM8 was expressed in EPC and TRPM8 agonist could enhance EPC proliferation and migration. What’s more, TRPM8 agonist induced TRPM8–eNOS complex formation. Therefore, we speculate that TRPM8 might increase proliferation and migration of EPC and promote EPC-mediated angiogenesis via Ca2+/eNOS/NO signaling pathway, subsequently reduce myocardial infarct size and attenuate cardiac remodeling. In this project, we are going to reveal the role of TRPM8 in post-MI cardiac remodeling by using TRPM8 knockout mice, myocardial infarction model and EPC transplantation model. Moreover, we will explore the molecular mechanisms via focusing on Ca2+/eNOS/NO signal, protein kinases (PKA, Akt, AMPK and CaMKII), EPC function (proliferation and migration) and angiogenesis. The aim of the project is to clarify the role of TRPM8 in post-MI cardiac remodeling and its underlying mechanisms, and to provide a novel target for the prevention and treatment of heart failure.

心肌重构是心肌梗死（心梗）后心力衰竭的关键病理环节，内皮祖细胞（EPC）介导的血管新生可挽救缺血心肌和抑制心肌重构。我们前期发现：瞬时受体电位通道M8（TRPM8）激动剂可显著改善小鼠心梗后的心脏功能，并提高生存率。细胞实验证实：TRPM8表达于EPC，TRPM8激动剂促进EPC增殖、迁移，并促使TRPM8-eNOS复合体形成。据此，我们推测：TRPM8通过Ca2+/eNOS/NO信号途径增强EPC的增殖、迁移能力，促进血管新生，从而减少梗死面积和抑制心肌重构。本项目以TRPM8基因敲除小鼠为工具，建立心肌梗死模型和EPC移植模型，探讨TRPM8在心梗后心肌重构中的作用；以Ca2+/eNOS/NO信号、蛋白激酶（PKA、Akt、AMPK、CaMKII）、EPC功能（增殖、迁移）和血管新生为切入点，研究其潜在机制。以阐明TRPM8在心梗后心肌重构中的作用和机制，为心力衰竭的防治提供新靶点。

心肌重构是心肌梗死（心梗）后心力衰竭的关键病理环节，过度的炎症反应导致心肌梗死面积增加，加重心肌重构，内皮祖细胞（EPC）介导的血管新生可挽救缺血心肌和抑制心肌重构。本项目以基因敲除小鼠为工具，建立心肌梗死模型，我们发现：（1）瞬时受体电位通道M8（TRPM8）在心梗后心肌中表达增加；（2）TRPM8通过上调CGRP表达抑制心肌中炎性细胞过度浸润和降低炎症因子水平，从而抑制心肌重构，改善心脏功能；（3）TRPM8表达于EPC，TRPM8激活后可通过蛋白激酶Akt促进TRPM8-eNOS复合体形成和激活eNOS/NO信号，增强EPC的增殖、迁移和血管生成能力，促进心梗后心肌中的血管新生，从而减少梗死面积和抑制心肌重构，改善心脏功能。