CaMKII-δ9 Induces Cardiomyocyte Death to Promote Cardiomyopathy and Heart Failure

Mao Zhang; Junxia Zhang; Wenjia Zhang; Qingmei Hu; Li Jin; Peng Xie; Wen Zheng; Haibao Shang; Yan Zhang

doi:10.3389/fcvm.2021.820416

CaMKII-δ9 Induces Cardiomyocyte Death to Promote Cardiomyopathy and Heart Failure

Front Cardiovasc Med. 2022 Jan 20:8:820416. doi: 10.3389/fcvm.2021.820416. eCollection 2021.

Authors

Mao Zhang^{1

2}, Junxia Zhang¹, Wenjia Zhang³, Qingmei Hu¹, Li Jin¹, Peng Xie¹, Wen Zheng¹, Haibao Shang¹, Yan Zhang^{1

3

4}

Affiliations

¹ State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, China.
² Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, United States.
³ Key Laboratory of Molecular Cardiovascular Sciences, School of Basic Medical Sciences, Institute of Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center, Beijing, China.
⁴ Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China.

Abstract

Heart failure is a syndrome in which the heart cannot pump enough blood to meet the body's needs, resulting from impaired ventricular filling or ejection of blood. Heart failure is still a global public health problem and remains a substantial unmet medical need. Therefore, it is crucial to identify new therapeutic targets for heart failure. Ca²⁺/calmodulin-dependent kinase II (CaMKII) is a serine/threonine protein kinase that modulates various cardiac diseases. CaMKII-δ9 is the most abundant CaMKII-δ splice variant in the human heart and acts as a central mediator of DNA damage and cell death in cardiomyocytes. Here, we proved that CaMKII-δ9 mediated cardiomyocyte death promotes cardiomyopathy and heart failure. However, CaMKII-δ9 did not directly regulate cardiac hypertrophy. Furthermore, we also showed that CaMKII-δ9 induced cell death in adult cardiomyocytes through impairing the UBE2T/DNA repair signaling. Finally, we demonstrated no gender difference in the expression of CaMKII-δ9 in the hearts, together with its related cardiac pathology. These findings deepen our understanding of the role of CaMKII-δ9 in cardiac pathology and provide new insights into the mechanisms and therapy of heart failure.

Keywords: CaMKII; CaMKII-δ9; cardiomyocyte death; cardiomyopathy; heart failure; hypertrophy.