The prokineticin receptor-1 (GPR73) promotes cardiomyocyte survival and angiogenesis
The prokineticin receptor-1 (GPR73) promotes cardiomyocyte survival and angiogenesis
复制标题
DOI：
10.1096/fj.07-8116com
复制
发表时间：
2007-09-01
期刊：
影响因子：
4.8
通讯作者：
Nebigil, Canan G.
中科院分区：
文献类型：
--
作者：
Urayama, Kyoji;Guilini, Celia;Nebigil, Canan G.
原激动素是一种强大的血管生成因子，可与两个G蛋白偶联受体结合，启动其生物学效应。我们推测原激动素受体-1(PKR1/GPR73)信号可能有助于心肌梗死后心肌细胞的存活或修复。由于我们发现原运动素-2和PKR1在成年小鼠心脏和心肌细胞中都有表达，我们研究了原运动素-2对毛细血管内皮细胞和心肌细胞功能的影响。在培养的心肌内皮细胞中，原激动素-2或过表达PKR1可诱导血管样形成，而不增加血管内皮细胞生长因子水平。在心肌细胞和H9c2细胞中，原激动素-2或过表达的PKR1激活Akt以保护心肌细胞免受氧化应激的伤害。SiRNA-PKR1可完全逆转原激动素-2对心肌细胞的存活和促进血管生成的作用，提示PKR1参与了心肌细胞的存活和血管生成。因此，我们进一步研究了心肌内转移编码PKR1的DNA是否可以挽救小鼠心肌梗死后的心肌。冠状动脉结扎后瞬时的PKR1基因转移可在不改变血管内皮生长因子水平的情况下，通过促进新生血管和保护心肌细胞来降低死亡率和保护左心功能。在人类终末期衰竭的心脏样本中，PKR1和Prokineticin-2转录本和蛋白水平的降低意味着Prokineticin 2/PKR1信号在心脏中扮演着更重要的角色。我们的结果表明，PKR1可能是限制缺血事件后心肌损伤的一个新的治疗靶点。Urayama，K.，Guilini，C.，Messaddeq，N.，Hu，K.，Steenman，M.，Kurose，H.，ERT，G.，Nebigil，C.G.原激动素受体-1(GPR73)促进心肌细胞存活和血管生成。
Prokineticins are potent angiogenic factors that bind to two G protein-coupled receptors to initiate their biological effects. We hypothesize that prokineticin receptor-1 (PKR1/GPR73) signaling may contribute to cardiomyocyte survival or repair in myocardial infarction. Since we showed that prokineticin-2 and PKR1 are expressed in adult mouse heart and cardiac cells, we investigated the role of prokineticin-2 on capillary endothelial cell and cardiomyocyte function. In cultured cardiac endothelial cells, prokineticin-2 or overexpression of PKR1 induces vessel-like formation without increasing VEGF levels. In cardiomyocytes and H9c2 cells, prokineticin-2 or overexpressing PKR1 activates Akt to protect cardiomyocytes against oxidative stress. The survival and angiogenesis promoting effects of prokineticin-2 in cardiac cells were completely reversed by siRNA-PKR1, indicating PKR1 involvement. We thus, further investigated whether intramyocardial gene transfer of DNA encoding PKR1 may rescue the myocardium against myocardial infarction in mouse model. Transient PKR1 gene transfer after coronary ligation reduces mortality and preserves left ventricular function by promoting neovascularization and protecting cardiomyocytes without altering VEGF levels. In human end-stage failing heart samples, reduced PKR1 and prokineticin-2 transcripts and protein levels implicate a more important role for prokineticin2/PKR1 signaling in heart. Our results suggest that PKR1 may represent a novel therapeutic target to limit myocardial injury following ischemic events. Urayama, K., Guilini, C., Messaddeq, N., Hu, K., Steenman, M., Kurose, H., Ert, G., Nebigil, C. G. The prokineticin receptor-1(GPR73) promotes cardiomyocyte survival and angiogenesis.