Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK.
Department of Medicine, Institute of Molecular Cardiology, University of Louisville, Louisville, KY, USA.
Sci Rep. 2021 Jan 15;11(1):1518. doi: 10.1038/s41598-021-81170-2.
Ischaemic heart disease is the world's leading cause of mortality. Survival rates from acute myocardial infarction (MI) have improved in recent years; however, this has led to an increase in the prevalence of heart failure (HF) due to chronic remodelling of the infarcted myocardium, for which treatment options remain poor. We have previously shown that inhibition of isoform 4 of the plasma membrane calcium ATPase (PMCA4) prevents chronic remodelling and HF development during pressure overload, through fibroblast mediated Wnt signalling modulation. Given that Wnt signalling also plays a prominent role during remodelling of the infarcted heart, this study investigated the effect of genetic and functional loss of PMCA4 on cardiac outcomes following MI. Neither genetic deletion nor pharmacological inhibition of PMCA4 affected chronic remodelling of the post-MI myocardium. This was the case when PMCA4 was deleted globally, or specifically from cardiomyocytes or fibroblasts. PMCA4-ablated hearts were however less prone to acute arrhythmic events, which may offer a slight survival benefit. Overall, this study demonstrates that PMCA4 inhibition does not affect chronic outcomes following MI.
缺血性心脏病是世界上主要的死亡原因。近年来，急性心肌梗死（MI）的存活率有所提高；然而，这导致心力衰竭（HF）的患病率增加，原因是梗死心肌的慢性重塑，而治疗选择仍然很差。我们之前已经表明，通过成纤维细胞介导的 Wnt 信号调节抑制质膜钙 ATP 酶（PMCA4）同工型 4 的抑制可防止在压力超负荷期间发生慢性重塑和 HF 发展。鉴于 Wnt 信号在梗死心脏的重塑中也起着突出的作用，本研究调查了 MI 后遗传和功能丧失 PMCA4 对心脏结局的影响。PMCA4 的遗传缺失或药理学抑制均不影响 MI 后心肌的慢性重塑。当 PMCA4 全局缺失或仅从心肌细胞或成纤维细胞中缺失时，就是这种情况。然而，PMCA4 缺失的心脏更不容易发生急性心律失常事件，这可能会带来轻微的生存获益。总体而言，这项研究表明，PMCA4 抑制不会影响 MI 后的慢性结局。
