Background: Pathological cardiac hypertrophy induced by stresses such as aging and neurohumoral activation is an independent risk factor for heart failure and is considered a target for the treatment of heart failure. However, the mechanisms underlying pathological cardiac hypertrophy remain largely unknown. We aimed to investigate the roles of SIRT2 in aging-related and angiotensin II (Ang II)–induced pathological cardiac hypertrophy.

Methods: Male C57BL/6J wild-type and Sirt2 knockout mice were subjected to the investigation of aging-related cardiac hypertrophy. Cardiac hypertrophy was also induced by Ang II (1.3 mg/kg/d for 4 weeks) in male C57BL/6J Sirt2 knockout mice, cardiac-specific SIRT2 transgenic (SIRT2-Tg) mice, and their respective littermates (8 to ≈12 weeks old). Metformin (200 mg/kg/d) was used to treat wild-type and Sirt2 knockout mice infused with Ang II. Cardiac hypertrophy, fibrosis, and cardiac function were examined in these mice.

Results: SIRT2 protein expression levels were downregulated in hypertrophic hearts from mice. Sirt2 knockout markedly exaggerated cardiac hypertrophy and fibrosis and decreased cardiac ejection fraction and fractional shortening in aged (24-month-old) mice and Ang II–infused mice. Conversely, cardiac-specific SIRT2 overexpression protected the hearts against Ang II–induced cardiac hypertrophy and fibrosis and rescued cardiac function. Mechanistically, SIRT2 maintained the activity of AMP-activated protein kinase (AMPK) in aged and Ang II–induced hypertrophic hearts in vivo as well as in cardiomyocytes in vitro. We identified the liver kinase B1 (LKB1), the major upstream kinase of AMPK, as the direct target of SIRT2. SIRT2 bound to LKB1 and deacetylated it at lysine 48, which promoted the phosphorylation of LKB1 and the subsequent activation of LKB1-AMPK signaling. Remarkably, the loss of SIRT2 blunted the response of AMPK to metformin treatment in mice infused with Ang II and repressed the metformin-mediated reduction of cardiac hypertrophy and protection of cardiac function.

Conclusions: SIRT2 promotes AMPK activation by deacetylating the kinase LKB1. Loss of SIRT2 reduces AMPK activation, promotes aging-related and Ang II–induced cardiac hypertrophy, and blunts metformin-mediated cardioprotective effects. These findings indicate that SIRT2 will be a potential target for therapeutic interventions in aging- and stress-induced cardiac hypertrophy.

背景：由诸如衰老和神经体液激活等压力引起的病理性心脏肥大是心力衰竭的独立危险因素，被认为是治疗心力衰竭的目标。但是，病理性心脏肥大的潜在机制仍然未知。我们旨在研究SIRT2在衰老相关和血管紧张素II（Ang II）诱导的病理性心肌肥大中的作用。

方法：对雄性C57BL / 6J野生型和Sirt2基因敲除小鼠进行衰老相关性心肌肥大的研究。Ang II（1.3 mg / kg / d持续4周）还在雄性C57BL / 6J Sirt2基因敲除小鼠，心脏特异性SIRT2转基因（SIRT2- Tg）小鼠及其同窝仔中诱导心脏肥大（8至≈12周）老的）。二甲双胍（200 mg / kg / d）用于治疗注入Ang II的野生型和Sirt2基因敲除小鼠。在这些小鼠中检查了心脏肥大，纤维化和心脏功能。

结果： SIRT2蛋白表达水平在小鼠肥厚性心脏中被下调。Sirt2基因敲除显着夸大了老年（24个月大）小鼠和注入Ang II的小鼠的心脏肥大和纤维化，并降低了心脏射血分数和分数缩短。相反，心脏特异性SIRT2过表达保护心脏免受Ang II引起的心脏肥大和纤维化，并挽救了心脏功能。从机制上讲，SIRT2在体内和体外以及在心肌细胞中都保持了AMP激活的蛋白激酶（AMPK）在衰老和Ang II诱导的肥大性心脏中的活性。我们确定肝脏激酶B1（LKB1），AMPK的主要上游激酶，是SIRT2的直接目标。SIRT2与LKB1结合并在赖氨酸48上脱乙酰化，从而促进LKB1的磷酸化并随后激活LKB1-AMPK信号传导。值得注意的是，SIRT2的丧失使注入Ang II的小鼠中AMPK对二甲双胍治疗的反应减弱，并抑制了二甲双胍介导的心肌肥大的减轻和对心脏功能的保护。

结论： SIRT2通过使激酶LKB1脱乙酰化而促进AMPK活化。SIRT2的丢失会降低AMPK的激活，促进衰老相关和Ang II引起的心肌肥大，并削弱二甲双胍介导的心脏保护作用。这些发现表明SIRT2将成为衰老和压力诱发的心肌肥大的治疗干预的潜在靶标。