Cardiomyocyte-GSK-3α promotes mPTP opening and heart failure in mice with chronic pressure overload
Cardiomyocyte-GSK-3α promotes mPTP opening and heart failure in mice with chronic pressure overload
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DOI：
10.1016/j.yjmcc.2019.03.020
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发表时间：
2019-05-01
影响因子：
5
通讯作者：
Force, Thomas
中科院分区：
文献类型：
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作者：
Ahmad, Firdos;Singh, Anand P.;Force, Thomas
慢性压力超负荷(PO)所致的心肌病是导致左室重构和心力衰竭的主要原因之一。糖原合成酶-3的α亚型(GSK-3α)在PO诱导的心脏重构中的作用尚不清楚，其下游分子靶点也很大程度上是未知的。为了研究GSK-3α的潜在作用，心肌细胞特异性GSK-3α条件性基因敲除(CKO)小鼠和对照组小鼠接受了经主动脉缩窄(TAC)或假手术。在TAC治疗2周时，CKO组和产仔对照组的心功能均有下降。在4周时，CKO组保持向心性左室重构，收缩和舒张期收缩功能的下降明显低于对照组，直到研究结束(6wk)。组织学分析证实，CKO保存了LV腔，并对TAC诱导的细胞肥大具有保护作用。与心肌肥厚程度减轻相一致的是，在CKO中观察到心肌细胞凋亡水平显著降低。从机制上讲，GSK-3α可以调节线粒体通透性转换孔(MPTP)的开放，而GSK-3α缺陷的线粒体在钙超载时表现出延迟的MPTP开放。一直以来，GSK-3α在心肌细胞中过表达导致Bax表达增加，细胞凋亡率增加，最大呼吸量和细胞存活率降低。基因消融心肌细胞GSK-3α可预防慢性PO引起的心肌病和不良的左室重构，并保留收缩功能。使用异构体特异性抑制剂选择性抑制GSK-3α可能是限制PO诱导的心力衰竭的一种可行的治疗策略。
Chronic pressure-overload (PO)-induced cardiomyopathy is one of the leading causes of left ventricular (LV) remodeling and heart failure. The role of the a isoform of glycogen synthase kinase-3 (GSK-3 alpha) in PO-induced cardiac remodeling is unclear and its downstream molecular targets are largely unknown. To investigate the potential roles of GSK-3 alpha, cardiomyocyte-specific GSK-3 alpha conditional knockout (cKO) and control mice underwent trans-aortic constriction (TAC) or sham surgeries. Cardiac function in the cKOs and littermate controls declined equally up to 2 weeks of TAC. At 4 week, cKO animals retained concentric LV remodeling and showed significantly less decline in contractile function both at systole and diastole, vs. controls which remained same until the end of the study (6 wk). Histological analysis confirmed preservation of LV chamber and protection against TAC-induced cellular hypertrophy in the cKO. Consistent with attenuated hypertrophy, significantly lower level of cardiomyocyte apoptosis was observed in the cKO. Mechanistically, GSK-3 alpha was found to regulate mitochondrial permeability transition pore (mPTP) opening and GSK-3 alpha-deficient mitochondria showed delayed mPTP opening in response to Ca2+ overload. Consistently, overexpression of GSK-3 alpha in cardiomyocytes resulted in elevated Bax expression, increased apoptosis, as well as a reduction of maximum respiration capacity and cell viability.Taken together, we show for the first time that GSK-3 alpha regulates mPTP opening under pathological conditions, likely through Bax overexpression. Genetic ablation of cardiomyocyte GSK-3 alpha protects against chronic PO induced cardiomyopathy and adverse LV remodeling, and preserves contractile function. Selective inhibition of GSK-3 alpha using isoform-specific inhibitors could be a viable therapeutic strategy to limit PO-induced heart failure.