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

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 cardiac-selective, preventing potential adverse effects of systemic kinase inhibition.

SUBMITTER: Vagnozzi RJ

PROVIDER: S-EPMC4365498 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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

Vagnozzi Ronald J RJ Gatto Gregory J GJ Kallander Lara S LS Hoffman Nicholas E NE Mallilankaraman Karthik K Ballard Victoria L T VL Lawhorn Brian G BG Stoy Patrick P Philp Joanne J Graves Alan P AP Naito Yoshiro Y Lepore John J JJ Gao Erhe E Madesh Muniswamy M Force Thomas T

Science translational medicine 20131001 207

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/repe ...[more]

PMID: 24132636

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Project description:The molecular pathways that regulate the extent of ischemic injury and post-myocardial infarction (MI) remodeling are not well understood. We recently demonstrated that glycogen synthase kinase-3? (GSK-3?) is critical to the heart's response to pressure overload. However, the role, if any, of GSK-3? in regulating ischemic injury and its consequences is not known.MI was induced in wild-type (WT) versus GSK-3?((-/-)) (KO) littermates by left anterior descending coronary artery ligation. Pre-MI, WT, and KO hearts had comparable chamber dimensions and ventricular function, but as early as 1 week post-MI, KO mice had significantly more left ventricular dilatation and dysfunction than WT mice. KO mice also had increased mortality during the first 10 days post-MI (43% versus 22%; P=0.04), and postmortem examination confirmed cardiac rupture as the cause of most of the deaths. In the mice that survived the first 10 days, left ventricular dilatation and dysfunction remained worse in the KO mice throughout the study (8 weeks). Hypertrophy, fibrosis, and heart failure were all increased in the KO mice. Given the early deaths due to rupture and the significant reduction in left ventricular function evident as early as 1 week post-MI, we examined infarct size following a 48-hour coronary artery ligation and found it to be increased in the KO mice. This was accompanied by increased apoptosis in the border zone of the MI. This increased susceptibility to ischemic injury-induced apoptosis was also seen in cardiomyocytes isolated from the KO mice that were exposed to hypoxia. Finally, Bax translocation to the mitochondria and cytochrome C release into the cytosol were increased in the KO mice.GSK-3? confers resistance to ischemic injury, at least in part, via limiting apoptosis. Loss of GSK-3? promotes ischemic injury, increases risk of cardiac rupture, accentuates post-MI remodeling and left ventricular dysfunction, and increases the progression to heart failure. These findings are in striking contrast to multiple previous reports in which deletion or inhibition of GSK-3? is protective.

Dataset Information

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

Publications

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

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