Department of Cardiac Surgery, Guangdong Cardiovascular Institute, Guangdong Province People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 519041, China.
Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China; State Key Laboratory of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
Life Sci. 2024 Nov 1;356:123021. doi: 10.1016/j.lfs.2024.123021. Epub 2024 Aug 28.
Chronic caloric restriction triggers unfavorable alterations in cardiac function albeit responsible scenarios remain unclear. This work evaluated the possible involvement of Akt2 in caloric restriction-evoked cardiac geometric and functional changes and responsible processes focusing on autophagy and mitophagy. Akt2 knockout and WT mice were subjected to caloric restriction for 30 weeks prior to assessment of myocardial homeostasis. Caloric restriction compromised echocardiographic parameters (decreased LV wall thickness, LVEDD, stroke volume, cardiac output, ejection fraction, fractional shortening, and LV mass), cardiomyocyte contractile and intracellular Ca capacity, myocardial atrophy, interstitial fibrosis and mitochondrial injury associated with elevated blood glucocorticoids, autophagy (LC3B, p62, Atg7, Beclin-1), and mitophagy (Pink1, Parkin, TOM20), dampened cardiac ATP levels, mitochondrial protein PGC1α and UCP2, anti-apoptotic protein Bcl2, intracellular Ca governing components Na-Ca exchanger, phosphorylation of SERCA2a, mTOR (Ser) and ULK1 (Ser), and upregulated Bax, phospholamban, phosphorylation of Akt2, AMPK, and ULK1 (Ser), the responses except autophagy markers (Beclin-1, Atg7), phosphorylation of AMPK, mTOR and ULK1 were negated by Akt2 ablation. Levels of CDK1 and DRP1 phosphorylation were overtly upregulated with caloric restriction, the response was reversed by Akt2 knockout. Caloric restriction-evoked changes in cardiac remodeling and cardiomyocyte function were alleviated by glucocorticoid receptor antagonism, Parkin ablation and Mdivi-1. In vitro experiment indicated that serum deprivation or glucocorticoids evoked GFP-LC3B accumulation and cardiomyocyte dysfunction, which was negated by inhibition of Akt2, CDK1 or DRP1, whereas mitophagy induction reversed Akt2 ablation-evoked cardioprotection. These observations favor a protective role of Akt2 ablation in sustained caloric restriction-evoked cardiac pathological changes via correction of glucocorticoid-induced mitophagy defect in a CDK1-DRP1-dependent manner.
慢性热量限制会引发心脏功能的不利变化，尽管其负责的情况尚不清楚。本研究评估了 Akt2 在热量限制引起的心脏几何和功能变化以及自噬和线粒体自噬过程中的可能作用。在评估心肌稳态之前，Akt2 敲除和 WT 小鼠接受 30 周的热量限制。热量限制损害了超声心动图参数（左室壁厚度、LVEDD、每搏输出量、心输出量、射血分数、缩短分数和左室质量降低）、心肌细胞收缩和细胞内 Ca 能力、心肌萎缩、间质纤维化和线粒体损伤与升高的血液糖皮质激素、自噬（LC3B、p62、Atg7、Beclin-1）和线粒体自噬（Pink1、Parkin、TOM20）有关，抑制心脏 ATP 水平、线粒体蛋白 PGC1α 和 UCP2、抗凋亡蛋白 Bcl2、细胞内 Ca 调节成分 Na-Ca 交换体、SERCA2a 磷酸化、mTOR（Ser）和 ULK1（Ser），上调 Bax、磷蛋白、Akt2、AMPK 和 ULK1（Ser）磷酸化，除自噬标志物（Beclin-1、Atg7）、AMPK、mTOR 和 ULK1 磷酸化外，这些反应均被 Akt2 缺失所否定。热量限制明显上调了 CDK1 和 DRP1 的磷酸化水平，该反应被 Akt2 敲除所逆转。通过糖皮质激素受体拮抗、Parkin 消融和 Mdivi-1，减轻了热量限制引起的心脏重塑和心肌细胞功能变化。体外实验表明，血清剥夺或糖皮质激素可引起 GFP-LC3B 积累和心肌细胞功能障碍，而 Akt2、CDK1 或 DRP1 的抑制可消除这一作用，而线粒体自噬的诱导则逆转了 Akt2 缺失引起的心脏保护作用。这些观察结果表明，Akt2 缺失通过纠正糖皮质激素诱导的以 CDK1-DRP1 依赖的方式的线粒体自噬缺陷，在持续热量限制引起的心脏病理变化中发挥保护作用。
