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Highly selective Src kinase inhibition protects myocardial injury after ischemia/reperfusion

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Martyn D. Lewis, John P. McKew¹, Kathleen E. Neuzi, Takashi Akasaka*

       
 

 Abstract

Timely intervention at reperfusion is the current standard of care for the treatment of an acute myocardial infarction (AMI). However, the consequences of reperfusion injury still represent a major limitation to treatment. Therefore, developing novel approaches to minimize such injury is needed to further improve outcomes following an AMI.However, the underlying mechanism of Src has not been fully elucidated. The purpose of this study was to determine whether the Src inhibition is associated with cardiac protection and decreased myocardial inflammatory response. An adult male wild type C57BL/6 mice model of myocardial ischemia/reperfusion (I/R) injury was established using the Langendorff isolated heart perfusion apparatus. At the beginning of reperfusion, vehicle alone or PP1, a highly selective Src inhibitor, was used as a postconditioning treatment. The cardiac function indicators, myocardial infarct size, lactic dehydrogenase (LDH) release, mitochondrial ultrastructure, mitochondrial reactive oxygen species (ROS) generation mice, ATP content, protein expression of proinflammatory cytokines, chemokines, Cardiac troponin, Bcl-2 and Bax were measured. I/R injury to the heart resulted in increased Src phosphorylation at tyrosine. Administration of PP1, a highly selective Src inhibitor, blocked Src phosphorylation, improved cardiac function and decreased myocardial injury markers and pathological damage. PP1 treatment also suppressed myocardial infiltration of macrophages, suppression of inflammatory response and reduced apoptosis. Moreover, Src inhibition prevented downregulation of several adherens and tight junction proteins, including in the myocardium after I/R injury. Finally, PP1 inhibited I/R-induced nuclear factor-κB. These data indicate that Src is a pivotal mediator of cardiac injury and that its inhibition may have a therapeutic potential to treat myocardial I/R.
Keywords: Acute myocardial infarction; Src; Ischemia/reperfusion (I/R)

Copyright © 2017 by The American Society for BioMedicine and BM-Publisher, Inc.

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Research Article
DOI: http://dx.doi.org/10.18081/2333-5106/017-3/146-158
American Journal of BioMedicine Volume 5, Issue 3, pages 146-158
Received December 23, 2016; accepted February 26, 2017; published March 24, 2017

How to cite this article
Lewis MD, McKew JP, Neuzi KE, Akasaka T. Highly selective Src kinase inhibition protects myocardial injury after ischemia/reperfusion. American Journal of BioMedicine 2017;5(3):146-158.

Article outline
1. Abstract
2. Keywords
3. Introduction
4. Methods
5. Results
6. Discussion
7. References

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