Zhang Nan, Liao Hai-Han, Feng Hong, Mou Shan-Qi, Li Wen-Jing, Aiyasiding Xiahenazi, Lin Zheng, Ding Wen, Zhou Zi-Ying, Yan Han, Chen Si, Tang Qi-Zhu
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.
Cardiovascular Research Institute of Wuhan University, Wuhan, China.
Front Pharmacol. 2021 Nov 17;12:716884. doi: 10.3389/fphar.2021.716884. eCollection 2021.
Sestrin2 (Sesn2) has been demonstrated to be a cysteine sulfinyl reductase and protects cells from multiple stress insults, including hypoxia, endoplasmic reticulum stress, and oxidative stress. However, the roles and mechanisms of Sesn2 in pressure overload-induced mouse cardiac hypertrophy have not been clearly clarified. This study intended to investigate whether sestrin2 (Sesn2) overexpression could prevent pressure overload-induced cardiac hypertrophy via an AMPKα2 dependent pathway through conditional knockout of AMPKα2. Sesn2 expression was significantly increased in mice hearts at 2 and 4 weeks after aortic banding (AB) surgery, but decreased to 60-70% of the baseline at 8 weeks. Sesn2 overexpression (at 3, 6, and 9 folds) showed little cardiac genetic toxicity in transgenic mice. Cardiac dysfunctions induced by pressure overload were attenuated by cardiomyocyte-specific Sesn2 overexpression when measured by echocardiography and hemodynamic analysis. Results of HE and PSR staining showed that Sesn2 overexpression significantly alleviated cardiac hypertrophy and fibrosis in mice hearts induced by pressure overload. Meanwhile, adenovirus-mediated-Sesn2 overexpression markedly suppressed angiotensin II-induced neonatal rat cardiomyocyte hypertrophy . Mechanistically, Sesn2 overexpression increased AMPKα2 phosphorylation but inhibited mTORC1 phosphorylation. The cardiac protections of Sesn2 overexpression were also regulating oxidative stress by enhancing Nrf2/HO-1 signaling, restoring SOD activity, and suppressing NADPH activity. Particularly, we first proved the vital role of AMPKα2 in the regulation of Sesn2 with AMPKα2 knockout (AMPKα2-/-) mice and Sesn2 transgenic mice crossed with AMPKα2-/-, since Sesn2 overexpression failed to improve cardiac function, inhibit cardiac hypertrophy and fibrosis, and attenuate oxidative stress after AMPKα2 knockout. This study uniquely revealed that Sesn2 overexpression showed little genetic toxicity in mice hearts and inhibited mTORC1 activation and oxidative stress to protect against pressure overload-induced cardiac hypertrophy in an AMPKα2 dependent pathway. Thus, interventions through promoting Sesn2 expression might be a potential strategy for treating pathological cardiac hypertrophy and heart failure.
Sestrin2（Sesn2）已被证明是一种半胱氨酸亚磺酰还原酶，可保护细胞免受多种应激损伤，包括缺氧、内质网应激和氧化应激。然而，Sesn2在压力超负荷诱导的小鼠心脏肥大中的作用和机制尚未明确阐明。本研究旨在通过条件性敲除AMPKα2来研究Sesn2过表达是否能通过AMPKα2依赖性途径预防压力超负荷诱导的心脏肥大。在主动脉缩窄（AB）手术后2周和4周，小鼠心脏中Sesn2表达显著增加，但在8周时降至基线的60 - 70%。Sesn2过表达（3倍、6倍和9倍）在转基因小鼠中显示出几乎没有心脏遗传毒性。通过超声心动图和血流动力学分析测量，心肌细胞特异性Sesn2过表达减轻了压力超负荷诱导的心脏功能障碍。HE和PSR染色结果显示，Sesn2过表达显著减轻了压力超负荷诱导的小鼠心脏肥大和纤维化。同时，腺病毒介导的Sesn2过表达显著抑制了血管紧张素II诱导的新生大鼠心肌细胞肥大。机制上，Sesn2过表达增加了AMPKα2磷酸化，但抑制了mTORC1磷酸化。Sesn2过表达的心脏保护作用还通过增强Nrf2/HO-1信号、恢复SOD活性和抑制NADPH活性来调节氧化应激。特别地，我们首先通过AMPKα2敲除（AMPKα2-/-）小鼠以及与AMPKα2-/-杂交的Sesn2转基因小鼠证明了AMPKα2在Sesn2调节中的重要作用，因为在AMPKα2敲除后，Sesn2过表达未能改善心脏功能、抑制心脏肥大和纤维化以及减轻氧化应激。本研究独特地揭示，Sesn2过表达在小鼠心脏中显示出几乎没有遗传毒性，并通过AMPKα2依赖性途径抑制mTORC1激活和氧化应激以预防压力超负荷诱导的心脏肥大。因此，通过促进Sesn2表达进行干预可能是治疗病理性心脏肥大和心力衰竭的潜在策略。
