Centre of Experimental Medicine, Slovak Academy of Sciences, Institute for Heart Research, 841 04 Bratislava, Slovakia.
Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, 140 21 Prague, Czech Republic.
Int J Mol Sci. 2023 Feb 9;24(4):3490. doi: 10.3390/ijms24043490.
The extracellular matrix (ECM) is a highly dynamic structure controlling the proper functioning of heart muscle. ECM remodeling with enhanced collagen deposition due to hemodynamic overload impairs cardiomyocyte adhesion and electrical coupling that contributes to cardiac mechanical dysfunction and arrhythmias. We aimed to explore ECM and connexin-43 (Cx43) signaling pathways in hemodynamically overloaded rat heart as well as the possible implication of angiotensin (1-7) (Ang (1-7)) to prevent/attenuate adverse myocardial remodeling. Male 8-week-old, normotensive Hannover Spraque-Dawley rats (HSD), hypertensive (mRen-2)27 transgenic rats (TGR) and Ang (1-7) transgenic rats (TGR(A1-7)3292) underwent aortocaval fistula (ACF) to produce volume overload. Five weeks later, biometric and heart tissue analyses were performed. Cardiac hypertrophy in response to volume overload was significantly less pronounced in TGR(A1-7)3292 compared to HSD rats. Moreover, a marker of fibrosis hydroxyproline was increased in both ventricles of volume-overloaded TGR while it was reduced in the Ang (1-7) right heart ventricle. The protein level and activity of MMP-2 were reduced in both ventricles of volume-overloaded TGR/TGR(A1-7)3292 compared to HSD. SMAD2/3 protein levels were decreased in the right ventricle of TGR(A1-7)3292 compared to HSD/TGR in response to volume overload. In parallel, Cx43 and pCx43 implicated in electrical coupling were increased in TGR(A1-7)3292 versus HSD/TGR. It can be concluded that Ang (1-7) exhibits cardio-protective and anti-fibrotic potential in conditions of cardiac volume overload.
细胞外基质（ECM）是一种高度动态的结构，控制着心肌的正常功能。由于血液动力学过载导致 ECM 重塑和胶原沉积增加，会损害心肌细胞的黏附和电偶联，导致心脏机械功能障碍和心律失常。我们旨在探索血液动力学过载大鼠心脏中的 ECM 和连接蛋白 43（Cx43）信号通路，以及血管紧张素（1-7）（Ang（1-7））可能对预防/减轻心肌不良重塑的作用。雄性 8 周龄、正常血压的 Hannover Spraque-Dawley 大鼠（HSD）、高血压（mRen-2）27 转基因大鼠（TGR）和 Ang（1-7）转基因大鼠（TGR（A1-7）3292）接受腔静脉吻合术（ACF）以产生容量过载。5 周后，进行生物计量和心脏组织分析。与 HSD 大鼠相比，TGR（A1-7）3292 对容量过载的心脏肥大反应明显不明显。此外，在容量过载的 TGR 两个心室中，羟脯氨酸的纤维化标志物增加，而在 Ang（1-7）右心室中则减少。与 HSD 相比，在容量过载的 TGR/TGR（A1-7）3292 两个心室中，MMP-2 的蛋白水平和活性均降低。SMAD2/3 蛋白水平在 TGR（A1-7）3292 的右心室中降低，而在 HSD/TGR 中则增加。与 HSD/TGR 相比，在 TGR（A1-7）3292 中，与电偶联有关的 Cx43 和 pCx43 增加。可以得出结论，Ang（1-7）在心脏容量过载的情况下具有心脏保护和抗纤维化的潜力。
