School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia.
J Cardiovasc Pharmacol. 2011 Nov;58(5):479-86. doi: 10.1097/FJC.0b013e31822a7a09.
The anaphylatoxin C5a generated by activation of the innate immunity complement system is a potent inflammatory peptide mediator through the G-protein-coupled receptor C5aR (CD88) present in immune-inflammatory cells, including monocytes, macrophages, neutrophils, T cells, and mast cells. Inflammatory cells infiltrate and initiate the development of fibrosis in the chronically hypertensive heart. In this study, we have investigated whether treatment with a selective C5aR antagonist prevents cardiovascular remodeling in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Control and DOCA-salt rats were treated with PMX53 (AcF-[OPdChaWR], 1 mg·kg·d oral gavage) for 32 days; structural and functional changes in cardiovascular system were determined. DOCA-salt hypertension increased leukocyte extravasation into ventricular tissue, increasing collagen deposition and ventricular stiffness; PMX53 treatment attenuated these changes, thereby improving cardiac function. Further, treatment with PMX53 suppressed an increased expression of C5aR in the left ventricle from DOCA-salt rats, consistent with the reduced infiltration of inflammatory cells. Vascular endothelial dysfunction in thoracic aortic rings was attenuated by PMX53 treatment, but systolic blood pressure was unchanged in DOCA-salt rats. In the heart, PMX53 treatment attenuated inflammatory cell infiltration, fibrosis, and ventricular stiffness, indicating that C5aR is critically involved in ventricular remodeling by regulating inflammatory responses in the hypertensive heart.
补体系统固有免疫激活产生的过敏毒素 C5a 通过存在于免疫炎性细胞（包括单核细胞、巨噬细胞、中性粒细胞、T 细胞和肥大细胞）中的 G 蛋白偶联受体 C5aR（CD88），作为一种有效的炎症肽介质。炎性细胞浸润并启动慢性高血压心脏中的纤维化发展。在这项研究中，我们研究了选择性 C5aR 拮抗剂治疗是否可预防去氧皮质酮醋酸盐（DOCA）-盐高血压大鼠的心血管重塑。对照和 DOCA-盐大鼠接受 PMX53（AcF-[OPdChaWR]，口服灌胃 1mg·kg·d）治疗 32 天；确定了心血管系统的结构和功能变化。DOCA-盐高血压增加白细胞渗出到心室组织，增加胶原蛋白沉积和心室僵硬度；PMX53 治疗减轻了这些变化，从而改善了心脏功能。此外，PMX53 治疗抑制了 DOCA-盐大鼠左心室 C5aR 的表达增加，与炎性细胞浸润减少一致。PMX53 治疗减轻了胸主动脉环的血管内皮功能障碍，但 DOCA-盐大鼠的收缩压没有变化。在心脏中，PMX53 治疗减轻了炎性细胞浸润、纤维化和心室僵硬度，表明 C5aR 通过调节高血压心脏中的炎症反应，在心室重塑中起关键作用。
