Liu Wenjuan, Deng Jianxin, Ding Wenwen, Wang Gang, Shen Yuanyuan, Zheng Junmeng, Zhang Xiaoming, Luo Yizhi, Lv Chifei, Wang Yonghui, Chen Liqing, Yan Dewen, Boudreau Ryan L, Song Long-Sheng, Liu Jie
From the Department of Pathophysiology, School of Medicine (W.L., G.W., Y.L., C.L., Y.W., L.C., J.L.); Department of Endocrinology, The First Affiliated Hospital of Shenzhen University (J.D., D.Y.), Center for Diabetes, Obesity and Metabolism (J.D., D.Y.), and Department of Biomedical Engineering, School of Medicine (Y.S.), Shenzhen University, China; Department of Pathology, School of Medicine, Jingchu University of Technology, Jingmen, China (W.D.); Zhongshan People's Hospital, China (J.Z.); and Division of Cardiovascular Medicine, Department of Internal Medicine and François M. Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa, Iowa City (X.Z., R.L.B., L.-S.S.).
Circ Heart Fail. 2017 Jun;10(6). doi: 10.1161/CIRCHEARTFAILURE.117.003960.
KCNE2 is a promiscuous auxiliary subunit of voltage-gated cation channels. A recent work demonstrated that KCNE2 regulates L-type Ca channels. Given the important roles of altered Ca signaling in structural and functional remodeling in diseased hearts, this study investigated whether KCNE2 participates in the development of pathological hypertrophy.
We found that cardiac KCNE2 expression was significantly decreased in phenylephrine-induced cardiomyocyte hypertrophy in neonatal rat ventricular myocytes and in transverse aortic constriction-induced cardiac hypertrophy in mice, as well as in dilated cardiomyopathy in human. Knockdown of KCNE2 in neonatal rat ventricular myocytes reproduced hypertrophy by increasing the expression of ANP (atrial natriuretic peptide) and β-MHC (β-myosin heavy chain), and cell surface area, whereas overexpression of KCNE2 attenuated phenylephrine-induced cardiomyocyte hypertrophy. Knockdown of KCNE2 increased intracellular Ca transient, calcineurin activity, and nuclear NFAT (nuclear factor of activated T cells) protein levels, and pretreatment with inhibitor of L-type Ca channel (nifedipine) or calcineurin (FK506) attenuated the activation of calcineurin-NFAT pathway and cardiomyocyte hypertrophy. Meanwhile, the phosphorylation levels of p38, extracellular signal-regulated kinase 1/2, and c-Jun N-terminal kinase were increased, and inhibiting the 3 cascades of mitogen-activated protein kinase reduced cardiomyocyte hypertrophy induced by KCNE2 knockdown. Overexpression of KCNE2 in heart by ultrasound-microbubble-mediated gene transfer suppressed the development of hypertrophy and activation of calcineurin-NFAT and mitogen-activated protein kinase pathways in transverse aortic constriction mice.
This study demonstrates that cardiac KCNE2 expression is decreased and contributes to the development of hypertrophy via activation of calcineurin-NFAT and mitogen-activated protein kinase pathways. Targeting KCNE2 is a potential therapeutic strategy for the treatment of hypertrophy.
KCNE2是电压门控阳离子通道的一种混杂辅助亚基。最近的一项研究表明，KCNE2可调节L型钙通道。鉴于钙信号改变在患病心脏的结构和功能重塑中发挥重要作用，本研究调查了KCNE2是否参与病理性肥大的发展。
我们发现，在苯肾上腺素诱导的新生大鼠心室肌细胞肥大、横断主动脉缩窄诱导的小鼠心脏肥大以及人类扩张型心肌病中，心脏KCNE2表达均显著降低。在新生大鼠心室肌细胞中敲低KCNE2可通过增加心房钠尿肽（ANP）和β-肌球蛋白重链（β-MHC）的表达以及细胞表面积来重现肥大，而KCNE2的过表达则可减轻苯肾上腺素诱导的心肌细胞肥大。敲低KCNE2可增加细胞内钙瞬变、钙调神经磷酸酶活性以及核活化T细胞核因子（NFAT）蛋白水平，而用L型钙通道抑制剂（硝苯地平）或钙调神经磷酸酶抑制剂（FK506）预处理可减弱钙调神经磷酸酶-NFAT途径的激活和心肌细胞肥大。同时，p38、细胞外信号调节激酶1/2和c-Jun氨基末端激酶的磷酸化水平升高，抑制丝裂原活化蛋白激酶的3条级联反应可减轻KCNE2敲低诱导的心肌细胞肥大。通过超声微泡介导的基因转移使心脏中KCNE2过表达可抑制横断主动脉缩窄小鼠的肥大发展以及钙调神经磷酸酶-NFAT和丝裂原活化蛋白激酶途径的激活。
本研究表明，心脏KCNE2表达降低，并通过激活钙调神经磷酸酶-NFAT和丝裂原活化蛋白激酶途径促进肥大的发展。靶向KCNE2是治疗肥大的一种潜在治疗策略。
