Cardiovascular Institute, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
Circulation. 2012 Oct 30;126(18):2208-19. doi: 10.1161/CIRCULATIONAHA.112.115592. Epub 2012 Sep 26.
Heart failure is a growing cause of morbidity and mortality. Cardiac phosphatidylinositol 3-kinase signaling promotes cardiomyocyte survival and function, but it is paradoxically activated in heart failure, suggesting that chronic activation of this pathway may become maladaptive. Here, we investigated the downstream phosphatidylinositol 3-kinase effector, serum- and glucocorticoid-regulated kinase-1 (SGK1), in heart failure and its complications.
We found that cardiac SGK1 is activated in human and murine heart failure. We investigated the role of SGK1 in the heart by using cardiac-specific expression of constitutively active or dominant-negative SGK1. Cardiac-specific activation of SGK1 in mice increased mortality, cardiac dysfunction, and ventricular arrhythmias. The proarrhythmic effects of SGK1 were linked to biochemical and functional changes in the cardiac sodium channel and could be reversed by treatment with ranolazine, a blocker of the late sodium current. Conversely, cardiac-specific inhibition of SGK1 protected mice after hemodynamic stress from fibrosis, heart failure, and sodium channel alterations.
SGK1 appears both necessary and sufficient for key features of adverse ventricular remodeling and may provide a novel therapeutic target in cardiac disease.
心力衰竭是发病率和死亡率不断上升的一个原因。心脏磷脂酰肌醇 3-激酶信号传导可促进心肌细胞存活和功能，但在心力衰竭中却反常地被激活，这表明该途径的慢性激活可能变得适应不良。在这里，我们研究了心力衰竭及其并发症中磷脂酰肌醇 3-激酶下游效应物血清和糖皮质激素调节激酶 1（SGK1）。
我们发现人类和鼠类心力衰竭中心脏 SGK1 被激活。我们通过心脏特异性表达组成型激活或显性失活的 SGK1 来研究 SGK1 在心脏中的作用。在小鼠中，心脏特异性激活 SGK1 增加了死亡率、心功能障碍和室性心律失常。SGK1 的致心律失常作用与心脏钠通道的生化和功能变化有关，用雷诺嗪（晚期钠电流的阻滞剂）治疗可以逆转。相反，心脏特异性抑制 SGK1 可防止在血流动力学应激后，心脏纤维化、心力衰竭和钠通道改变。
SGK1 似乎是不良心室重构的关键特征所必需的，并且可能为心脏疾病提供一个新的治疗靶点。
