Differential effects of the formin inhibitor SMIFH2 on contractility and Ca2+ handling in frog and mouse cardiomyocytes

• Published in: Genes to cells : devoted to molecular & cellular mechanisms 2021-08, Vol.26 (8), p.583-595
• Main Authors: Sakata, Koji, Matsuyama, Sho, Kurebayashi, Nagomi, Hayamizu, Kengo, Murayama, Takashi, Nakamura, Kunihide, Kitamura, Kazuo, Morimoto, Sachio, Takeya, Ryu
• Format: Article
• Language: English
• Subjects: Actin; Calcium; cardiac function; Cardiomyocytes; Cardiomyopathy; Contraction; Fhod3; formin; Heart; Muscle contraction; Myocardium; Ryanodine receptors; SMIFH2
• ISSN: 1356-9597; 1365-2443
• DOI: 10.1111/gtc.12873

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. The formin inhibitor SMIFH2 significantly enhanced the cardiac contractility of isolated frog hearts, thereby augmenting cardiac performance.