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.