Inhibition of the cardiomyocyte-specific kinase TNNI3K limits oxidative stress, injury, and adverse remodeling in the ischemic heart

Ronald J. Vagnozzi, Gregory J. Gatto, Lara S. Kallander, Nicholas E. Hoffman, Karthik Mallilankaraman, Victoria L.T. Ballard, Brian G. Lawhorn, Patrick Stoy, Joanne Philp, Alan P. Graves, Yoshiro Naito, John J. Lepore, Erhe Gao, Muniswamy Madesh, Thomas Force

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

Percutaneous coronary intervention is first-line therapy for acute coronary syndromes (ACS) but can promote cardiomyocyte death and cardiac dysfunction via reperfusion injury, a phenomenon driven in large part by oxidative stress. Therapies to limit this progression have proven elusive, with no major classes of new agents since the development of anti-platelets/anti-thrombotics. We report that cardiac troponin I-interacting kinase (TNNI3K), a cardiomyocyte-specific kinase, promotes ischemia/reperfusion injury, oxidative stress, and myocyte death. TNNI3K-mediated injury occurs through increased mitochondrial superoxide production and impaired mitochondrial function and is largely dependent on p38 mitogen-activated protein kinase (MAPK) activation. We developed a series of small-molecule TNNI3K inhibitors that reduce mitochondrial-derived superoxide generation, p38 activation, and infarct size when delivered at reperfusion to mimic clinical intervention. TNNI3K inhibition also preserves cardiac function and limits chronic adverse remodeling. Our findings demonstrate that TNNI3K modulates reperfusion injury in the ischemic heart and is a tractable therapeutic target for ACS. Pharmacologic TNNI3K inhibition would be cardiacselective, preventing potential adverse effects of systemic kinase inhibition.

Original languageEnglish (US)
Article number207ra141
JournalScience translational medicine
Volume5
Issue number207
DOIs
StatePublished - Oct 16 2013
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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