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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acute Coronary Syndrome / complications
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Acute Coronary Syndrome / enzymology
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Acute Coronary Syndrome / pathology
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Acute Coronary Syndrome / physiopathology
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Animals
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Cell Death / drug effects
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Disease Models, Animal
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Energy Metabolism / drug effects
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Enzyme Activation / drug effects
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Gene Deletion
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Heart Failure / complications
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Heart Failure / enzymology
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Heart Failure / physiopathology
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Humans
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MAP Kinase Kinase Kinases / antagonists & inhibitors*
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MAP Kinase Kinase Kinases / metabolism
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Mice
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Mice, Inbred C57BL
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Mitochondria / metabolism
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Myocardial Ischemia / complications
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Myocardial Ischemia / enzymology*
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Myocardial Ischemia / pathology
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Myocardial Ischemia / physiopathology*
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Myocardial Reperfusion Injury / pathology
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Myocytes, Cardiac / enzymology
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Myocytes, Cardiac / pathology
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Oxidative Stress* / drug effects
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology
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Protein Kinases / metabolism*
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Protein Serine-Threonine Kinases
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Small Molecule Libraries / chemistry
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Small Molecule Libraries / pharmacology
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Superoxides / metabolism
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Up-Regulation / drug effects
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Ventricular Dysfunction, Left / complications
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Ventricular Dysfunction, Left / enzymology
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Ventricular Dysfunction, Left / pathology
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Ventricular Dysfunction, Left / physiopathology
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Ventricular Remodeling* / drug effects
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Protein Kinase Inhibitors
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Small Molecule Libraries
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Superoxides
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Protein Kinases
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Tnni3k protein, mouse
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Protein Serine-Threonine Kinases
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TNNI3K protein, human
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p38 Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinases