Chatterjee Arunachal, Barnard John, Moravec Christine, Desnoyer Russell, Tirupula Kalyan, Karnik Sadashiva S
Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America.
Department of Zoology, Acharya Jagadish Chandra Bose College, Kolkata, West Bengal, India.
PLoS One. 2017 Dec 29;12(12):e0190217. doi: 10.1371/journal.pone.0190217. eCollection 2017.
Perspectives on whether the functions of MAS, a G protein-coupled receptor, are beneficial or deleterious in the heart remain controversial. MAS gene knockout reduces coronary vasodilatation leading to ischemic injury. G protein signaling activated by MAS has been implicated in progression of adaptive cardiac hypertrophy to heart failure and fibrosis. In the present study, we observed increased expression of MAS, connective tissue growth factor (CTGF) and collagen genes in failing (HF) human heart samples when compared to non-failing (NF). Expression levels of MAS are correlated with CTGF in HF and NF leading to our hypothesis that MAS controls CTGF production and the ensuing expression of collagen genes. In support of this hypothesis we show that the non-peptide MAS agonist AR234960 increases both mRNA and protein levels of CTGF via ERK1/2 signaling in HEK293-MAS cells and adult human cardiac fibroblasts. MAS-mediated CTGF expression can be specifically blocked by MAS inverse agonist AR244555 and also by MEK1 inhibition. Expression of CTGF gene was essential for MAS-mediated up-regulation of different collagen subtype genes in HEK293-MAS cells and human cardiac fibroblasts. Knockdown of CTGF by RNAi disrupted collagen gene regulation by the MAS-agonist. Our data indicate that CTGF mediates the profibrotic effects of MAS in cardiac fibroblasts. Blocking MAS-CTGF-collagen pathway should be considered for pharmacological intervention for HF.
关于G蛋白偶联受体MAS在心脏中的功能是有益还是有害，目前仍存在争议。MAS基因敲除会减少冠状动脉舒张，导致缺血性损伤。MAS激活的G蛋白信号传导与适应性心脏肥大向心力衰竭和纤维化的进展有关。在本研究中，我们观察到与非衰竭（NF）的人类心脏样本相比，衰竭（HF）的人类心脏样本中MAS、结缔组织生长因子（CTGF）和胶原蛋白基因的表达增加。在HF和NF中，MAS的表达水平与CTGF相关，这使我们提出假设，即MAS控制CTGF的产生以及随后胶原蛋白基因的表达。为支持这一假设，我们表明非肽类MAS激动剂AR234960通过ERK1/2信号传导增加了HEK293-MAS细胞和成人心脏成纤维细胞中CTGF的mRNA和蛋白质水平。MAS介导的CTGF表达可被MAS反向激动剂AR244555以及MEK1抑制特异性阻断。CTGF基因的表达对于MAS介导的HEK293-MAS细胞和人类心脏成纤维细胞中不同胶原蛋白亚型基因的上调至关重要。通过RNAi敲低CTGF会破坏MAS激动剂对胶原蛋白基因的调控。我们的数据表明，CTGF介导了MAS在心脏成纤维细胞中的促纤维化作用。对于HF的药物干预，应考虑阻断MAS-CTGF-胶原蛋白途径。
