Inhibition of the Cardiomyocyte-Specific Kinase TNNI3K Limits Oxidative Stress, Injury, and Adverse Remodeling in the Ischemic Heart

Blocking the activity of a cardiomyocyte-specific protein kinase with a small-molecule inhibitor reduces oxidative stress, myocyte death, and adverse remodeling in the ischemic heart. Blocking Cardiac Kinase Prevents Heart Damage Restoring blood flow after a heart attack is essential; yet, rapid reperfusion of blood can cause adverse effects on heart cells (cardiomyocytes) via oxidative damage, calcium overload, and inflammation. To limit these effects, Vagnozzi and colleagues developed an inhibitor that targets a cardiomyocyte-specific kinase called TNNI3K, which may be intimately involved in signaling events after ischemia (blockage of blood flow) and reperfusion. The authors first confirmed that TNNI3K is up-regulated in tissues from patients with heart failure who were undergoing transplant. Mice that overexpressed active TNNI3K had larger infarcts than those with an inactive form of the kinase, as well as worse ischemic injury and cardiomyocyte death. Conversely, deletion of Tnni3k reduced infarct size and prevented cardiomyocyte death in mice. From the human tissues, the kinase appeared to be limited to cardiomyocytes, which lends itself to targeted therapy. Vagnozzi et al. administered two different small-molecule inhibitors during reperfusion to mice with ischemic injury and observed a reduction in left ventricle dysfunction, progressive remodeling, and fibrosis (a hardening of the heart tissue). The authors believe that these functional benefits stem from a concomitant reduction in superoxide production, p38 activation, and infarct size. This inhibition strategy will need to be tested in a large-animal model before translation. If successful, it could find immediate application to patients with chronic ischemic cardiomyopathy, where recurrent ischemia is followed by reperfusion. 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.