Loss of cardiac phosphoinositide 3-kinase p110 alpha results in contractile dysfunction.
Loss of cardiac phosphoinositide 3-kinase p110 alpha results in contractile dysfunction.
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DOI：
10.1161/circulationaha.109.873380
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发表时间：
2009-07-28
期刊：
影响因子：
37.8
通讯作者：
Lin RZ
中科院分区：
文献类型：
--
作者：
Lu Z;Jiang YP;Wang W;Xu XH;Mathias RT;Entcheva E;Ballou LM;Cohen IS;Lin RZ
磷脂酰肌醇3-激酶（PI 3 K）p110α在胰岛素作用和肿瘤发生中起关键作用。心肌细胞收缩由通过电压依赖性L型钙通道（LTCC）的内向钙电流（伊卡，L）启动。本研究的目的是评估p110α是否也通过调节LTCC来控制心肌收缩力。在成年小鼠心肌细胞中，基因切除p110α（也称为Pik 3ca），而不是p110β（也称为Pik 3cb），降低了伊卡，L并阻断了心脏中的胰岛素信号传导。p110α缺失的心肌细胞细胞表面LTCC数量减少，收缩缺陷降低体内心脏功能。同样，药物抑制p110α可降低犬心肌细胞的伊卡、L和收缩性。抑制p110β并不降低伊卡，L。PI 3 K p110α而非p110β调节心肌细胞的LTCC。p110α信号的减少减少了细胞表面LTCC的数量，从而减弱了伊卡，L和收缩性。
Phosphoinositide 3-kinase (PI3K) p110α plays a key role in insulin action and tumorigenesis. Myocyte contraction is initiated by an inward Ca2+ current (ICa,L) through the voltage-dependent L-type Ca2+ channel (LTCC). The aim of this study was to evaluate if p110α also controls cardiac contractility by regulating the LTCC. Genetic ablation of p110α (also known as Pik3ca), but not p110β (also known as Pik3cb), in cardiac myocytes of adult mice reduced ICa,L and blocked insulin signaling in the heart. p110α-null myocytes had a reduced number of LTCCs on the cell surface and a contractile defect that decreased cardiac function in vivo. Similarly, pharmacological inhibition of p110α decreased ICa,L and contractility in canine myocytes. Inhibition of p110β did not reduce ICa,L. PI3K p110α but not p110β regulates the LTCC in cardiac myocytes. Decreased signaling to p110α reduces the number of LTCCs on the cell surface and thus attenuates ICa,L and contractility.