Troponin I-interacting protein kinase: a novel cardiac-specific kinase, emerging as a molecular target for the treatment of cardiac disease

Abstract

Coronary artery disease is the leading cause of death and disability worldwide. In patients with acute coronary syndromes, timely and effective myocardial reperfusion by percutaneous coronary intervention is the primary treatment of choice to minimize the ischemic injury and limit the size of the myocardial infarction (MI). However, reperfusion can itself promote cardiomyocyte death, which leads to cardiac dysfunction via reperfusion injury. The molecular mechanisms of ischemia-reperfusion (IR) injury are not completely understood and new drug targets are needed. Recently, we reported that cardiac troponin I-interacting protein kinase (TNNI3K), a cardiomyocyte-specific kinase, promotes IR injury via profound oxidative stress, thereby promoting cardiomyocyte death. By using novel genetic animal models and newly developed small-molecule TNNI3K inhibitors, we demonstrated that TNNI3K-mediated IR injury occurs through impaired mitochondrial function and is in part dependent on p38 MAPK. Here we discuss the emerging role of TNNI3K as a promising new drug target to limit IR-induced myocardial injury. We will also examine the underlying mechanisms that drive the profoundly reduced infarct size in mice in whichTNNI3Kis specifically deleted in cardiomyocytes. Because TNNI3K is a cardiac-specific kinase, it could be an ideal molecular target, as inhibiting it would have little or no effect on other organ systems, a serious problem associated with the use of kinase inhibitors targeting kinases that are more widely expressed.

Fig. 1. Schematic of TNNI3K structure

Three distinct domains are shown. The N-terminal ankyrin repeat, a central kinase domain and the Serine-rich domain at C-terminal. It shares a domain structure similar to that of ILK. ANK, Ankyrin; Ser-rich, Serine-rich; ILK, integrin-linked kinase.

Fig. 2

TNNI3K has been implicated in regulation of several essential myocardial pathophysiological conditions.

Fig. 3. Molecular signaling mechanism of TNNI3K in response to cardiac injury

After cardiac injury, TNNI3K induces p38 phosphorylation by an unknown mechanism. Activation of p38 results in increased mitochondrial reactive oxygen species generation, resulting in cell death which leads to increased infarct size and adverse ventricular remodeling. The role of TNNI3K-dependent mitochondrial dysfunction or oxidative stress in development of cardiac hypertrophy is not known. Overexpression studies have suggested that TNNI3K also increases the velocity of diastolic depolarization of phase 4 of spontaneous action potential through suppressing phosphorylation of cTnI, resulting in increased contractile force. TNNI3K may increase the contractile force by modulating the ryanodine receptor-mediated intracellular Ca2+ concentration. MI, Myocardial infarction; I/R, Ischemia-reperfusion injury; TAC, Transverse aortic constriction; SR, Sarcoplasmic reticulum, RyR, Ryanodine receptor; cTnI, Cardiac troponin I.