Caveolin-3 KO disrupts t-tubule structure and decreases t-tubular ICa density in mouse ventricular myocytes
Caveolin-3 KO disrupts t-tubule structure and decreases t-tubular ICa density in mouse ventricular myocytes
复制标题
DOI：
10.1152/ajpheart.00209.2018
复制
发表时间：
2018-11-01
影响因子：
4.8
通讯作者：
Orchard, Clive H.
中科院分区：
文献类型：
--
作者：
Bryant, Simon M.;Kong, Cherrie H. T.;Orchard, Clive H.
小窝蛋白-3(Cav-3)是一种与心肌细胞T小管形成和功能有关的蛋白质。在心肌肥厚和衰竭时，Cav-3表达减少，t-微管结构破坏，兴奋-收缩偶联受损。然而，Cav-3表达减少在多大程度上是这些变化的基础尚不清楚。因此，我们研究了从Cav-3基因敲除(KO)小鼠心脏分离的心肌细胞的结构和功能。与野生型对照小鼠相比，这些小鼠在体内表现出心脏扩张和射血分数降低。分离的KO心肌细胞肥大，T管结构改变，L型钙通道电流(ICa)密度降低。这种密度的下降主要发生在T管，而总钙没有变化，因此是膜面积增加的结果。CaV-3KO对KO细胞L钙通道的表达无影响，模拟CaV-3支架结构域的C3SD多肽对KO细胞的I-Ca无影响。然而，H-89抑制PKA可降低KO和野生型心肌细胞表面和T管膜上的钙离子浓度。CaV-3KO对Na+/Ca~(2+)交换电流和Ca~(2+)释放无明显影响。这些数据表明，Cav-3KO导致细胞肥大，从而降低T管的密度。新发现和值得注意的Caveolin-3(Cav-3)是一种抑制肥大途径的蛋白质，与心脏T管的形成和功能有关，并在心力衰竭中表达减少。本研究表明，Cav-3基因敲除小鼠在活体内表现为心功能不全，而分离的心肌细胞则表现为细胞肥大、T管结构改变、T管L型钙电流密度降低，提示Cav-3表达降低是导致心肌肥厚和衰竭的原因之一。
Caveolin-3 (Cav-3) is a protein that has been implicated in t-tubule formation and function in cardiac ventricular myocytes. In cardiac hypertrophy and failure, Cav-3 expression decreases, t-tubule structure is disrupted, and excitation-contraction coupling is impaired. However, the extent to which the decrease in Cav-3 expression underlies these changes is unclear. We therefore investigated the structure and function of myocytes isolated from the hearts of Cav-3 knockout (KO) mice. These mice showed cardiac dilatation and decreased ejection fraction in vivo compared with wild-type control mice. Isolated KO myocytes showed cellular hypertrophy, altered t-tubule structure, and decreased L-type Ca2+ channel current (I-Ca) density. This decrease in density occurred predominantly in the t-tubules, with no change in total I-Ca, and was therefore a consequence of the increase in membrane area. Cav-3 KO had no effect on L-type Ca2+ channel expression, and C3SD peptide, which mimics the scaffolding domain of Cav-3, had no effect on I-Ca in KO myocytes. However, inhibition of PKA using H-89 decreased I-Ca at the surface and t-tubule membranes in both KO and wild-type myocytes. Cav-3 KO had no significant effect on Na+/Ca2+ exchanger current or Ca2+ release. These data suggest that Cav-3 KO causes cellular hypertrophy, thereby decreasing t-tubular I-ca density.NEW & NOTEWORTHY Caveolin-3 (Cav-3) is a protein that inhibits hypertrophic pathways, has been implicated in the formation and function of cardiac t-tubules, and shows decreased expression in heart failure. This study demonstrates that Cav-3 knockout mice show cardiac dysfunction in vivo, while isolated ventricular myocytes show cellular hypertrophy, changes in t-tubule structure, and decreased t-tubular L-type Ca2+ current density, suggesting that decreased Cav-3 expression contributes to these changes in cardiac hypertrophy and failure.