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

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

doi:10.3389/fcvm.2021.820416

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.

Highlights

Heart failure is a complex and heterogeneous syndrome resulting from impairment of ventricular filling or ejection of blood associated with symptoms of dyspnea, fatigue, as well as peripheral and/or pulmonary edema
We investigated whether calmodulin-dependent kinase II (CaMKII) kinase activity was required for CaMKII-δ9-induced cardiomyocyte death, cardiomyopathy, and heart failure
We first set up cardiomyocyte injury models with cultured Neonatal rat ventricle myocytes (NRVMs) with CaMKII-δ9 overexpression and found that pretreatment of KN-93 (5 μM) alleviates the CaMKII-δ9induced cardiomyocyte death as indexed by caspase 3/7 activity (Figure 1A)

Summary

Introduction

Heart failure is a complex and heterogeneous syndrome resulting from impairment of ventricular filling or ejection of blood associated with symptoms of dyspnea, fatigue, as well as peripheral and/or pulmonary edema. The pathophysiological mechanisms of heart failure consist of cardiac injuries at multiple levels, including the myocardium, vasculature, pericardium, heart valves, electrical system, or a combination of cardiac abnormalities, among which cardiomyocyte death and hypertrophy are two critical factors. Multiple myocardial injury insults lead to cardiomyocyte death. The loss of CaMKII-δ9, Cardiomyocyte Death, and Heart Failure mammalian cardiomyocytes cannot be replenished from living cells, resulting in compromised cardiac function and heart failure. In response to myocardial injury or chronically increased hemodynamic load, cardiac mass increases due to cardiomyocyte hypertrophy to help maintain ejection performance. Continued hemodynamic overload leads to the dilation of the heart and the thinning of the cavity walls, resulting in the change of myocardial geometry, an increase of wall stress, and cardiac dysfunction [5, 6]

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