GHRH受体调节巨噬细胞在动脉粥样硬化中的作用

巨噬细胞在动脉粥样硬化中起关键作用。该细胞传统地被分为促炎的M1型和抑炎的M2型，其极化状态受AMPK活性调控。生长激素释放激素（GHRH）通过结合其受体（GHRH-R）而发挥生物学效应。我们发现作为G偶联蛋白受体一员的GHRH-R在M1型巨噬细胞高表达，在M2型低表达。GHRH-R能否影响巨噬细胞M1/M2亚型转换尚不明了。我们假设： GHRH-R激活抑制AMPK活性导致巨噬细胞炎性反应增多；应用GHRH拮抗剂抑制GHRH-R激活，提高AMPK活性，促进巨噬细胞向M2型极化，从而防止斑块形成。我们将通过LDLr-/-小鼠和髓系特异GHRH-R敲除小鼠杂交获得双敲小鼠构建动脉硬化模型，应用荧光探针技术明确巨噬细胞中GHRH-R对巨噬细胞极化和斑块形成的影响及作用机制。应用GHRH拮抗剂抑制GHRH-R，阐明GHRH-R调节巨噬细胞炎性能力的机理，明确GHRH拮抗剂对动脉粥样硬化的治疗作用。

Macrophages play a key role in atherosclerosis. According to its function, Macrophage is broadly categorized as “classically activated” pro-inflammatory M1 macrophages and “alternatively activated” anti-inflammatory M2 macrophages. Energy metabolism which is regulated by AMP-activated protein kinase (AMPK) is an important factor in regulating the phenotypic transformation of macrophages. Growth hormone releasing hormone (GHRH) exerts its biological effects by binding to its receptor (GHRH-R). We found that there is more GHRH-R expressed in M1 macrophages than that in M2 macrophages. However, whether GHRH-R can affect macrophage M1/M2 isoform conversion is unknown. We hypothesize that activation of GHRH-R enhances the production of cAMP, which inhibits AMPK activity and results in higher production of inflammatory factors and severer atherosclerosis; GHRH antagonist can inhibit the activation of GHRHR, therefore increase the activity of AMPK which enhances the lipid metabolic activity and promotes M2 polarization of macrophages, resulting in less plaque formation. We will hybridized LDLr-/- mice and myeloid specific GHRHR-/- knockout mice to create a double-knockout mouse, which will be used to establish an atherosclerotic model of mice. Then we will clarify the effect of GHRHR on polarization of macrophages and plaque formation. By such, GHRH antagonist will be applied to inhibit GHRH receptor to elucidate the role and mechanism of GHRH-R in regulating the inflammatory ability of macrophages and their lipid metabolic activity. The effects of GHRH-R on polarization of macrophage and development of atherosclerosis will be determined.