PKM2 deficiency exacerbates gram-negative sepsis-induced cardiomyopathy via disrupting cardiac calcium homeostasis.
PKM2 deficiency exacerbates gram-negative sepsis-induced cardiomyopathy via disrupting cardiac calcium homeostasis.
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PKM2 缺乏通过破坏心脏钙稳态而加剧革兰氏阴性败血症诱发的心肌病。
DOI：
10.1038/s41420-022-01287-9
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发表时间：
2022-12-23
影响因子：
7
通讯作者：
Shi, Dan
中科院分区：
文献类型：
--
作者：
Ni, Le;Lin, Bowen;Shen, Meiting;Li, Can;Hu, Lingjie;Fu, Fengmei;Chen, Lei;Yang, Jian;Shi, Dan
败血症是一种威胁生命的综合征，在重症监护医学中具有多器官功能障碍（PKM2）在多种生物学过程中的功能和糖酵解以外的其他疾病，并且已被记录为多种心脏病的心脏保护因素。在体外和体内用LPS治疗的心肌细胞加剧了LPS诱导的对新生大鼠心肌细胞的心脏损害（NRCMS）激活缓解了SIC。总而言之，这些发现强调了PKM2在革兰氏阴性败血症诱导的心肌病中起着至关重要的作用，这为预防和治疗化粪池心肌病提供了有吸引力的靶标。
Sepsis is a life-threatening syndrome with multi-organ dysfunction in critical care medicine. With the occurrence of sepsis-induced cardiomyopathy (SIC), characterized by reduced ventricular contractility, the mortality of sepsis is boosted to 70–90%. Pyruvate kinase M2 (PKM2) functions in a variety of biological processes and diseases other than glycolysis, and has been documented as a cardioprotective factor in several heart diseases. It is currently unknown whether PKM2 influences the development of SIC. Here, we found that PKM2 was upregulated in cardiomyocytes treated with LPS both in vitro and in vivo. Pkm2 inhibition exacerbated the LPS-induced cardiac damage to neonatal rat cardiomyocytes (NRCMs). Furthermore, cardiomyocytes lacking PKM2 aggravated LPS-induced cardiomyopathy, including myocardial damage and impaired contractility, whereas PKM2 overexpression and activation mitigated SIC. Mechanism investigation revealed that PKM2 interacted with sarcoplasmic/endoplasmic reticulum calcium ATPase 2a (SERCA2a), a key regulator of the excitation-contraction coupling, to maintain calcium homeostasis, and PKM2 deficiency exacerbated LPS-induced cardiac systolic dysfunction by impairing SERCA2a expression. In conclusion, these findings highlight that PKM2 plays an essential role in gram-negative sepsis-induced cardiomyopathy, which provides an attractive target for the prevention and treatment of septic cardiomyopathy.
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