Differential effects of the formin inhibitor SMIFH2 on contractility and Ca 2+ handling in frog and mouse cardiomyocytes
Differential effects of the formin inhibitor SMIFH2 on contractility and Ca 2+ handling in frog and mouse cardiomyocytes
复制标题
福尔马林抑制剂 SMIFH2 对青蛙和小鼠心肌细胞收缩性和 Ca 2 处理的不同影响
DOI：
10.1111/gtc.12873
复制
发表时间：
2021
期刊：
影响因子：
2.1
通讯作者：
Takeya Ryu
中科院分区：
文献类型：
--
作者：
Sakata Koji;Matsuyama Sho;Kurebayashi Nagomi;Hayamizu Kengo;Murayama Takashi;Nakamura Kunihide;Kitamura Kazuo;Morimoto Sachio;Takeya Ryu
肌动蛋白调节因子的基因突变已经成为心肌病的一个原因，尽管肌动蛋白动力学和心脏收缩之间的功能联系在很大程度上仍然未知。为了深入了解这个问题，我们研究了formins（一种主要的肌动蛋白组装蛋白）的药理抑制作用。双胍抑制剂SMIFH2显著增强离体青蛙心脏的收缩力，从而提高心脏性能。SMIFH2处理对蛙肌纤维Ca2+敏感性无显著影响。相反，它出乎意料地增加了分离的青蛙心肌细胞的Ca2+浓度，表明肌力效应是由于增强的Ca2+瞬态。与青蛙心脏相反，小鼠心肌细胞的收缩力被SMIFH2处理减弱，Ca2+瞬态减少。因此，SMIFH2对青蛙和小鼠心肌细胞之间的Ca2+瞬态和收缩性具有相反的作用。我们进一步发现SMIFH2通过2型ryanodine受体抑制Ca2+‐释放；这种抑制作用可以解释物种差异，因为RyR2在小鼠心肌中对Ca2+瞬态至关重要，但在青蛙心肌中不存在。虽然青蛙心肌细胞中Ca2+瞬态增强的机制尚不清楚，但SMIFH2通过不同地调节它们的Ca2+处理来影响两栖动物和哺乳动物的心脏收缩。
Genetic mutations in actin regulators have been emerging as a cause of cardiomyopathy, although the functional link between actin dynamics and cardiac contraction remains largely unknown. To obtain insight into this issue, we examined the effects of pharmacological inhibition of formins, a major class of actin‐assembling proteins. The formin inhibitor SMIFH2 significantly enhanced the cardiac contractility of isolated frog hearts, thereby augmenting cardiac performance. SMIFH2 treatment had no significant effects on the Ca2+sensitivity of frog muscle fibers. Instead, it unexpectedly increased Ca2+concentrations of isolated frog cardiomyocytes, suggesting that the inotropic effect is due to enhanced Ca2+transients. In contrast to frog hearts, the contractility of mouse cardiomyocytes was attenuated by SMIFH2 treatment with decreasing Ca2+transients. Thus, SMIFH2 has opposing effects on the Ca2+transient and contractility between frog and mouse cardiomyocytes. We further found that SMIFH2 suppressed Ca2+‐release via type 2 ryanodine receptor (RyR2); this inhibitory effect may explain the species differences, since RyR2 is critical for Ca2+transients in mouse myocardium but absent in frog myocardium. Although the mechanisms underlying the enhancement of Ca2+transients in frog cardiomyocytes remain unclear, SMIFH2 differentially affects the cardiac contraction of amphibian and mammalian by differentially modulating their Ca2+handling.