Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada; Faculty of Pharmacy, Minia University, Minia, Egypt.
Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
Int J Cardiol. 2019 Apr 15;281:90-98. doi: 10.1016/j.ijcard.2019.01.075. Epub 2019 Jan 24.
Diabetes is associated with an increased risk of heart failure, cardiac arrhythmias and sudden cardiac death. We previously showed that ROCK2 expression is elevated in diabetic rat hearts, and that ROCK inhibition acutely improves their contractile function. In the present study we investigated whether inhibition of ROCK or partial deletion of ROCK2 improves impaired Ca handling in the diabetic heart.
Contractile properties and Ca transients were measured before and after treatment with the ROCK inhibitor Y-27632 (1 μM) in fluo-4-loaded cardiomyocytes isolated from streptozotocin (STZ)-diabetic or non-diabetic rats. Cardiac function was determined in vivo, and contractile properties and Ca transients also measured in cardiomyocytes from non-diabetic and STZ-diabetic wild-type (WT) and ROCK2+/- mice.
ROCK inhibition improved some parameters of contractile function and Ca handling in cardiomyocytes from diabetic rat hearts. In addition, ROCK inhibition attenuated the diabetes-induced delayed aftercontractions (DACs) and associated irregular Ca transients induced by increased [Ca]o. Although no overt cardiac dysfunction was detected in diabetic WT mice, cardiomyocytes from these mice also developed arrhythmic Ca transients in response to increased [Ca]. These were attenuated in cardiomyocytes from diabetic ROCK2+/- mice, in association with decreased diastolic Ca leak and with reduction of the diabetes-induced increased phosphorylation of both CaMKII and the ryanodine receptor (RyR).
These data suggest that ROCK2 contributes to diabetes-induced impaired cardiac Ca homeostasis, at least in part by promoting CaMKII-mediated phosphorylation of RyR. This may have important clinical implications for the treatment of the increased incidence of dysrhythmias in diabetes.
糖尿病与心力衰竭、心律失常和心脏性猝死的风险增加有关。我们之前的研究表明，ROCK2 在糖尿病大鼠心脏中的表达升高，ROCK 抑制可急性改善其收缩功能。在本研究中，我们研究了 ROCK 抑制或 ROCK2 部分缺失是否能改善糖尿病心脏中受损的 Ca 处理。
在使用 ROCK 抑制剂 Y-27632（1μM）处理前后，测量负载 fluo-4 的来自链脲佐菌素（STZ）-糖尿病或非糖尿病大鼠的心肌细胞的收缩性能和 Ca 瞬变。在体内测定心脏功能，并测量非糖尿病和 STZ 糖尿病野生型（WT）和 ROCK2+/- 小鼠的心肌细胞的收缩性能和 Ca 瞬变。
ROCK 抑制改善了糖尿病大鼠心脏心肌细胞的一些收缩功能和 Ca 处理参数。此外，ROCK 抑制减弱了糖尿病引起的延迟后收缩（DAC）和增加[Ca]o 引起的不规则 Ca 瞬变。尽管在糖尿病 WT 小鼠中未检测到明显的心脏功能障碍，但这些小鼠的心肌细胞也对增加的[Ca]产生心律失常性 Ca 瞬变。这些在糖尿病 ROCK2+/- 小鼠的心肌细胞中减弱，与舒张期 Ca 渗漏减少以及糖尿病诱导的 CaMKII 和肌浆网 Ca 释放通道（RyR）磷酸化增加减少有关。
这些数据表明，ROCK2 至少部分通过促进 CaMKII 介导的 RyR 磷酸化，导致糖尿病引起的心脏 Ca 稳态受损。这对于治疗糖尿病中心律失常发生率的增加可能具有重要的临床意义。
