Ischemic heart disease impacts millions worldwide and can progress to heart failure. Percutaneous coronary intervention (PCI) is first-line therapy for patients presenting with an acute ischemic event or acute coronary syndrome (ACS). However, PCI can also worsen cardiomyocyte death, cardiac dysfunction and adverse remodeling via reperfusion injury, largely an oxidative stress-mediated insult. Novel alternative therapies for ACS have proven elusive, with no new classes of agents in years. We investigated cardiac troponin I-interacting kinase (TNNI3K), a cardiomyocyte-specific kinase, as a potential modulator of ischemia/reperfusion (I/R) injury and chronic left ventricular (LV remodeling). We found TNNI3K enhances production of mitochondrial reactive oxygen species (mROS) and induces mitochondrial dysfunction, thus increasing cardiomyocyte death and I/R injury. Moreover, TNNI3K-mediated injury is largely dependent on p38 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 ACS intervention. Moreover, although TNNI3K inhibition does not modulate the adverse remodeling that occurs after a non-reperfused myocardial infarction (MI), TNNI3K inhibition preserves cardiac function and limits chronic adverse remodeling in a model of MI with reperfusion. Taken together, TNNI3K plays an adverse role in the cardiomyocyte response to I/R, in part by driving mROS production and augmenting p38-mediated cell death specifically via reperfusion injury. Our findings reveal a previously unexplored role for TNNI3K in regulating the oxidative stress response in the heart, and support the potential for TNNI3K as a novel therapeutic target for ACS.
|Advisor:||Force, Thomas L.|
|Commitee:||Houser, Steven R., Koch, Walter J., Radice, Glenn, Wedegaertner, Philip|
|School:||Thomas Jefferson University|
|Department:||Cell and Developmental Biology|
|School Location:||United States -- Pennsylvania|
|Source:||DAI-B 75/08(E), Dissertation Abstracts International|
|Subjects:||Molecular biology, Cellular biology, Pathology|
|Keywords:||Cardiomyocyte, Cell death, Heart failure, Ischemia/reperfusion, Mitochondria, Protein kinases|
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