Meyer-Jens Moritz, Wenzel Kristin, Grube Karina, Rüdebusch Julia, Krämer Elisabeth, Bahls Martin, Müller Kilian, Voß Hannah, Schlüter Hartmut, Felix Stephan B, Carrier Lucie, Könemann Stephanie, Schlossarek Saskia
Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.
German Centre for Cardiovascular Research (DZHK), partner site Hamburg/Kiel/Lübeck, Germany.
J Mol Cell Cardiol Plus. 2024 Jan 7;7:100059. doi: 10.1016/j.jmccpl.2023.100059. eCollection 2024 Mar.
Sacubitril/valsartan (Sac/Val) belongs to the group of angiotensin receptor-neprilysin inhibitors and has been used for the treatment of heart failure (HF) for several years. The mechanisms that mediate the beneficial effects of Sac/Val are not yet fully understood. In this study we investigated whether Sac/Val influences the two proteolytic systems, the ubiquitin-proteasome system (UPS) and the autophagy-lysosomal pathway (ALP), in a mouse model of pressure overload induced by transverse aortic constriction (TAC) and in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) treated with endothelin-1 (ET1) serving as a human cellular model of hypertrophy. TAC mice showed a continuous decline in cardiac function starting from day 14 after surgery. Administration of Sac/Val for 6 weeks counteracted the deterioration of cardiac function and attenuated hypertrophy and fibrosis in TAC mice. The expression of ALP key markers did not differ between the groups. Proteasome activity was higher in TAC mice and normalized by Sac/Val. In hiPSC-CMs, all treatments (Sac, Val or Sac/Val) normalized mean cell area. However, Sac alone or in combination with Val, but not Val alone prevented ET1-induced hypertrophic gene program and proteomic changes. In conclusion, Sac/Val normalized proteasome activity, improved cardiac function and reduced fibrosis and hypertrophy in TAC mice. Molecular analysis in hiPSC-CMs suggests that a major part of the beneficial effects of Sac/Val is derived from the Sac action rather than from Val.
沙库巴曲缬沙坦（Sac/Val）属于血管紧张素受体脑啡肽酶抑制剂类药物，已用于治疗心力衰竭（HF）数年。介导Sac/Val有益作用的机制尚未完全明确。在本研究中，我们研究了Sac/Val是否会影响两种蛋白水解系统，即泛素-蛋白酶体系统（UPS）和自噬-溶酶体途径（ALP），研究对象为经主动脉缩窄（TAC）诱导的压力超负荷小鼠模型，以及用内皮素-1（ET1）处理的人诱导多能干细胞衍生心肌细胞（hiPSC-CMs），后者作为肥大的人类细胞模型。TAC小鼠术后第14天开始心脏功能持续下降。给予Sac/Val 6周可对抗TAC小鼠心脏功能的恶化，并减轻肥大和纤维化。各组间ALP关键标志物的表达无差异。TAC小鼠的蛋白酶体活性较高，Sac/Val可使其恢复正常。在hiPSC-CMs中，所有处理（Sac、Val或Sac/Val）均可使平均细胞面积恢复正常。然而，单独使用Sac或与Val联合使用可预防ET1诱导的肥大基因程序和蛋白质组学变化，而单独使用Val则无此作用。总之，Sac/Val可使TAC小鼠的蛋白酶体活性恢复正常，改善心脏功能，减轻纤维化和肥大。对hiPSC-CMs的分子分析表明，Sac/Val的有益作用主要源于Sac的作用而非Val。
