Pyruvate Kinase M2 Protects Heart from Pressure Overload-Induced Heart Failure by Phosphorylating RAC1.
Pyruvate Kinase M2 Protects Heart from Pressure Overload-Induced Heart Failure by Phosphorylating RAC1.
复制标题
丙酮酸激酶 M2 通过磷酸化 RAC1 来保护心脏免受压力过载引起的心力衰竭。
DOI：
10.1161/jaha.121.024854
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发表时间：
2022-06-07
影响因子：
5.4
通讯作者：
Shi, Dan
中科院分区：
文献类型：
--
作者：
Ni, Le;Lin, Bowen;Hu, Lingjie;Zhang, Ruoyu;Fu, Fengmei;Shen, Meiting;Yang, Jian;Shi, Dan
由持续压力超负荷引起的心力衰竭仍然是一个主要的公共卫生问题。PKM（丙酮酸激酶M）是糖酵解的限速酶。PKM 2（pyruvate kinase M2）是PKM的一种选择性剪接产物，在多种生物学过程和疾病中起着复杂的作用。然而，PKM 2在心力衰竭发展中的作用仍然未知。通过将floxed Pkm 2小鼠与α-MHC（myosin heavy chain）-Cre转基因小鼠杂交产生心肌细胞特异性Pkm 2敲除小鼠，并通过注射腺相关病毒血清9型系统建立心脏特异性Pkm 2过表达小鼠。结果表明，心肌细胞特异性Pkm 2缺失导致压力超负荷下心脏功能显著恶化，而Pkm 2过表达减轻了横向主动脉缩窄诱导的心脏肥大并改善了心脏功能。从机制上讲，我们证明PKM 2作为蛋白激酶而不是丙酮酸激酶，在心力衰竭的进展中通过磷酸化RAC 1抑制RAC 1（rho家族，小GTP结合蛋白）-MAPK（丝裂原活化蛋白激酶）信号通路的激活。此外，通过NSC 23766（一种特异性RAC 1抑制剂）阻断RAC 1，可减弱Pkm 2缺陷小鼠的病理性心脏重塑，这些小鼠经受横主动脉缩窄。这项研究表明，PKM 2减弱了超负荷诱导的病理性心脏肥大和心力衰竭，这为预防和治疗心肌病提供了一个有吸引力的靶点。
Heart failure, caused by sustained pressure overload, remains a major public health problem. PKM (pyruvate kinase M) acts as a rate‐limiting enzyme of glycolysis. PKM2 (pyruvate kinase M2), an alternative splicing product of PKM, plays complex roles in various biological processes and diseases. However, the role of PKM2 in the development of heart failure remains unknown. Cardiomyocyte‐specific Pkm2 knockout mice were generated by crossing the floxed Pkm2 mice with α‐MHC (myosin heavy chain)‐Cre transgenic mice, and cardiac specific Pkm2 overexpression mice were established by injecting adeno‐associated virus serotype 9 system. The results showed that cardiomyocyte‐specific Pkm2 deletion resulted in significant deterioration of cardiac functions under pressure overload, whereas Pkm2 overexpression mitigated transverse aortic constriction‐induced cardiac hypertrophy and improved heart functions. Mechanistically, we demonstrated that PKM2 acted as a protein kinase rather than a pyruvate kinase, which inhibited the activation of RAC1 (rho family, small GTP binding protein)‐MAPK (mitogen‐activated protein kinase) signaling pathway by phosphorylating RAC1 in the progress of heart failure. In addition, blockade of RAC1 through NSC23766, a specific RAC1 inhibitor, attenuated pathological cardiac remodeling in Pkm2 deficiency mice subjected to transverse aortic constriction. This study revealed that PKM2 attenuated overload‐induced pathological cardiac hypertrophy and heart failure, which provides an attractive target for the prevention and treatment of cardiomyopathies.