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Degradation of Cardiac Myosin Light Chain Kinase by Matrix Metalloproteinase-2 Contributes to Myocardial Contractile Dysfunction during Ischemia/Reperfusion

Oct 28, 2014

Myocardial dysfunction or heart “stunning” resulting from ischemia/reperfusion (I/R) is a common clinical scenario in patients suffering from ischemic heart disease. Such dysfunction is associated with a prominent decrease of myofilament Ca2+ sensitivity because of covalent modifications or proteolytic injury to contractility-related proteins. Thus, identification of roles of proteolytic enzymes, their targeting proteins and contributions to postischemic contractile dysfunction in acute myocardial I/R injury is fundamental to the understanding of the pathological processes and development of therapeutic approaches for ischemic heart disease. 

A team of researchers, led by Prof. YANG Huangtian, at the Institute of Health Science (IHS), investigated the relationship between the changes of the status and regulation ventricular myosin regulatory light chain (MLC-2v) phosphorylation and decreased myofilament Ca2+ sensitivity in postischemic myocardium, and the effects of proteases on MLC-2v regulatory kinases in I/R hearts.

By using the I/R injury model in isolated rat hearts and the simulated I/R injury model in isolated rat myocytes, combined with the overexpression or knockdown of cardiac myosin light chain kinase (cMLCK) or matrix metalloproteinase-2 (MMP-2) by adenovirus infection, researchers determined the changes of contractile function, protein contents and/or phosphorylation level of MLC-2 and its regulating kinases (cMLCK and myosin light chain phosphatase (cMLCP)), myofibrillar Ca2+-stimulated ATPase activity, and the interaction between the MMP-2 and cMLCk with and without I/R insult. 

They showed that I/R decreases the cMLCK content by activation of MMP-2 through the specific cleavage of cMLCK protein, but not by other proteases, calpains, caspase-3, or proteasome. This leads to the decrease of MLC-2v phosphorylation and subsequently to the myocardial contractile dysfunction, while cMLCP was not involved in the I/R-induced decrease of MLC-2v phosphorylation.

These findings extend the current knowledge related to the cardioprotective effect of MMP-2 inhibition in I/R and provide new insight into the mechanisms of I/R-induced contractile dysfunction and potential therapeutic targets for the improvement of myofilament Ca2+ sensitivity against I/R injury.

This study was published online in Journal of Molecular and Cellular Cardiology on Oct 18, 2014, and was supported by the Major State Basic Research Development Program of China, National Natural Sciences Foundation of China, and National Science and Technology Major Project of China.

Contact:
YANG Huangtian
Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine
Shanghai 200031, China
E-mail: htyang@sibs.ac.cn 

 

Proposed working model (Image by Prof. YANG’s group)

 

 
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