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.

Inhibition of the Cardiomyocyte-Specific Troponin I–Interacting Kinase Limits Oxidative Stress, Injury, and Adverse Remodeling due to Ischemic Heart Disease

“…Importantly, transgenic TNNI3K overexpression also resulted in marked worsening of mortality, cardiac function, and left ventricular remodeling. 9 The current work presented by Vagnozzi et al 3 supports the hypothesis that TNNI3K has a deleterious effect on the mammalian cardiac response to injury and that the inhibition of this kinase has a protective role.…”

“…However, in the current article, the genetic deletion of TNNI3K did not result in a significant change in hypertrophy in the basal state or after ischemic injury. 3 Although recent work has suggested that TNNI3K has a limited role in the regulation of sarcomeric proteins, recent work by both our group and other laboratories has suggested that this is not the case. Phosphorylation of cardiac troponin I is known to affect myofilament sensitivity and cardiac inotropy.…”

“…The article published by Vagnozzi et al 3 suggests that TNNI3K may play a critical role in the development of ischemia-reperfusion injury and provides proof-of-principle that TNNI3K blockers may have a clinical application. However, the clinical application of TNNI3K may present some challenges.…”

“…Oxidative stress, in particular reactive oxygenation species production, is thought to induce calcium handling abnormalities, protein oxidation, lipid peroxidation, and cell death. 2 The mitigation of cellular death from oxidative stress from ischemia-reperfusion injury is the focus of a recent article by Vagnozzi et al 3 Their work investigates the novel role of the cardiac-specific protein, troponin I-interacting kinase (TNNI3K), in the development of this injury and provides an approach for treating ischemia-perfusion injury in a clinical setting. In mice, genetic overexpression of TNNI3K increased infarct size and cellular death after ischemic injury in comparison with wild-type animals or animals overexpressing kinase inactive versions of TNNI3K.…”

Inhibition of NADPH oxidase 2 (NOX2) prevents sepsis-induced cardiomyopathy by improving calcium handling and mitochondrial function

“…NADPH autofluorescence was acquired using a 2-photon laser at 720 nm excitation and emission at 380-550 nm. Images were acquired using a Zeiss 710 Microscope equipped with 10× objective and a Coherent Chameleon 2-photon laser (48).…”