PKM2 deficiency exacerbates gram-negative sepsis-induced cardiomyopathy via disrupting cardiac calcium homeostasis

Le Ni; Bowen Lin; Meiting Shen; Can Li; Lingjie Hu; Fengmei Fu; Lei Chen; Jian Yang; Dan Shi

doi:10.1038/s41420-022-01287-9

PKM2 deficiency exacerbates gram-negative sepsis-induced cardiomyopathy via disrupting cardiac calcium homeostasis

Cell Death Discov. 2022 Dec 23;8(1):496. doi: 10.1038/s41420-022-01287-9.

Authors

Le Ni^#^{1

2}, Bowen Lin^#^{1

2}, Meiting Shen^#^{1

2}, Can Li^#^{2

3}, Lingjie Hu^{1

2}, Fengmei Fu^{2

3}, Lei Chen^{1

2}, Jian Yang^{1

2

4}, Dan Shi^{5

6}

Affiliations

¹ Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.
² Key Laboratory of Arrhythmias of the Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.
³ Jinzhou Medical University, Liaoning, 121000, China.
⁴ Shanghai Frontiers Science Center of Nanocatalytic Medicine, Shanghai, 200092, China.
⁵ Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China. [email protected].
⁶ Key Laboratory of Arrhythmias of the Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China. [email protected].

^# Contributed equally.

Abstract

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.