心肌成纤维细胞自分泌CGRP对心室重构的抑制性调节作用及机制研究

The calcitonin gene-related peptide (CGRP) is the neurotransmitter of sensory nerve, and CGRP plays an important role in regulating cardiovascular function. We found that cardiac fibroblasts could also synthesize and secrete CGRP, but its pathophysiology and mechanisms were not clear. It has been reported that CGRP secreted by sensory nerve could inhibit the ventricular remodeling. Moreover, our preliminary experiments showed that the expression of CGRP was decreased in myocardial tissue of ventricular remodeling, these results suggested that CGRP secreted by cardiac fibroblasts may be an endogenous factor against ventricular remodeling. By using gene knock-down and over-expression technology, we are planning to explore the inhibitory effect of autocrine CGRP by cardiac fibroblasts on ventricular remodeling and its underlying mechanisms in hypoxia-induced ventricular remodeling and TGF-β1-induced cardiac fibroblasts proliferation. Based on the fact that TRPA1 (Transient Receptor Potential Ankyrin 1) regulates the synthesis and secretion of CGRP in sensory nerve, and TRPA1 is highly expressed in cardiac fibroblasts, we are planning to further verify whether the synthesis and secretion of CGRP in cardiac fibroblasts are regulated by TRPA1, on this basis, to reveal the inhibitory effect of cinnamaldehyde (TRPA1 specific agonist) on ventricular remodeling and its underlying mechanisms. This study would provide a new thought on the pathogenesis of ventricular remodeling and facilitate new drug development.

降钙素基因相关肽（CGRP）是感觉神经的神经递质，CGRP对心血管功能具有重要的调节作用。我们发现心肌成纤维细胞也能合成与分泌CGRP，但其病理生理作用及机制尚不清楚。神经来源的CGRP可抑制心室重构，且预实验发现，重构的心肌组织CGRP表达减少，提示心肌成纤维细胞来源的CGRP可能是一种内源性抗心室重构的因子。本项目拟在低氧诱导的心室重构小鼠模型和TGF-β1诱导的心肌成纤维细胞增殖模型，运用基因敲减和过表达技术，探讨心肌成纤维细胞自分泌CGRP抑制心室重构的作用及机制。基于TRPA1（瞬时受体电位通道蛋白A1）调节神经细胞CGRP的合成与分泌，而心肌成纤维细胞高表达TRPA1，本项目拟进一步探讨心肌成纤维细胞CGRP的合成与分泌是否受TRPA1调节，在此基础上，阐明TRPA1激动剂肉桂醛抑制心室重构的作用及机制。本研究将有助于揭示心室重构的新机制，并为寻找防治心室重构药物提供新思路。

降钙素基因相关肽（CGRP）是感觉神经的神经递质，CGRP对心血管功能具有重要的调节作用。多种非神经细胞表达和分泌CGRP，我们发现心脏表达的CGRP主要来源于心肌成纤维细胞，心肌成纤维细胞可合成和分泌CGRP。围绕这一新发现本项目开展了三方面的研究：（1）探讨心肌成纤维细胞合成和分泌CGRP的调控机制，发现其受TRPA1/Ca2+信号通路调控；（2）研究心肌成纤维细胞源性CGRP的作用及机制，发现心肌成纤维细胞自分泌CGRP通过抑制NF-κB信号通路减少TGF-β1诱导的心肌成纤维细胞活化；（3）基于上述两点的发现，进一步运用TRPA1激动剂肉桂醛干预野百合碱诱导的右心重构，发现肉桂醛可通过促进心肌成纤维细胞自分泌CGRP抑制心室重构。本研究揭示了心肌成纤维细胞自分泌CGRP在心室重构中的重要作用，并证实通过激活TRPA1促进心肌成纤维细胞分泌CGRP是寻找防治心室重构药物的新策略。