Marston Steven, Pinto Jose Renato
National Heart and Lung Institute, Imperial College London, London, United Kingdom.
Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL, United States.
Front Cardiovasc Med. 2023 Jan 9;9:1080965. doi: 10.3389/fcvm.2022.1080965. eCollection 2022.
In cardiac muscle the action of adrenaline on β1 receptors of heart muscle cells is essential to adjust cardiac output to the body's needs. Adrenergic activation leads to enhanced contractility (inotropy), faster heart rate (chronotropy) and faster relaxation (lusitropy), mainly through activation of protein kinase A (PKA). Efficient enhancement of heart output under stress requires all of these responses to work together. Lusitropy is essential for shortening the heartbeat when heart rate increases. It therefore follows that, if the lusitropic response is not present, heart function under stress will be compromised. Current literature suggests that lusitropy is primarily achieved due to PKA phosphorylation of troponin I (TnI) and phospholamban (PLB). It has been well documented that PKA-induced phosphorylation of TnI releases Ca from troponin C faster and increases the rate of cardiac muscle relaxation, while phosphorylation of PLB increases SERCA activity, speeding up Ca removal from the cytoplasm. In this review we consider the current scientific evidences for the connection between suppression of lusitropy and cardiac dysfunction in the context of mutations in phospholamban and thin filament proteins that are associated with cardiomyopathies. We will discuss what advances have been made into understanding the physiological mechanism of lusitropy due to TnI and PLB phosphorylation and its suppression by mutations and we will evaluate the evidence whether lack of lusitropy is sufficient to cause cardiomyopathy, and under what circumstances, and consider the range of pathologies associated with loss of lusitropy. Finally, we will discuss whether suppressed lusitropy due to mutations in thin filament proteins can be therapeutically restored.
在心肌中，肾上腺素作用于心肌细胞的β1受体对于根据身体需求调节心输出量至关重要。肾上腺素能激活主要通过蛋白激酶A（PKA）的激活，导致心肌收缩力增强（变力性）、心率加快（变时性）和舒张加快（变松弛性）。在应激状态下有效增强心输出量需要所有这些反应协同作用。变松弛性对于心率增加时缩短心跳时间至关重要。因此，如果不存在变松弛反应，应激状态下的心脏功能将受到损害。当前文献表明，变松弛性主要是由于PKA使肌钙蛋白I（TnI）和受磷蛋白（PLB）磷酸化所致。有充分的文献记载，PKA诱导的TnI磷酸化能更快地从肌钙蛋白C释放钙，并增加心肌舒张速率，而PLB磷酸化则增加肌浆网钙ATP酶（SERCA）活性，加速从细胞质中清除钙。在这篇综述中，我们在与心肌病相关的受磷蛋白和细肌丝蛋白突变的背景下，考虑变松弛性抑制与心脏功能障碍之间联系的当前科学证据。我们将讨论在理解由于TnI和PLB磷酸化及其被突变抑制而产生的变松弛性生理机制方面取得了哪些进展，我们将评估缺乏变松弛性是否足以导致心肌病以及在何种情况下会导致心肌病的证据，并考虑与变松弛性丧失相关的一系列病理情况。最后，我们将讨论由于细肌丝蛋白突变导致的变松弛性抑制是否可以通过治疗恢复。
