Advance-CTR

Advance-CTR Pilot Projects Program (2017)

"A Novel Therapy to Reduce Cardiac Injury and Dysfunction after Myocardial Infarction"

Co-PI: Frank Sellke, MD

Coronary heart disease is the principal cause of myocardial infarction (MI) and is a major cause of morbidity and mortality worldwide. While great strides have been made with initial therapy directed toward restoration of perfusion pharmacologically or mechanically to salvage as much of the jeopardized myocardium as possible, patients are often left with residual heart damage, which frequently causes contractile dysfunction and heart failure (HF). Therefore, new therapeutic approaches are urgently needed for effectively reducing or stopping the progression of HF after MI in addition to the restoration of coronary perfusion. During myocardial ischemia, overproduction of reactive oxygen species (ROS) production determines the infarction size and severity of heart dysfunction after MI. My preliminary data demonstrates that protein kinase D (PKD), an oxidative stress-sensitive kinase, can translocate to the outer mitochondrial membrane (OMM), where it induces mitochondrial fragmentation, leading to enhanced mitochondrial ROS (mROS) generation and mitochondrial permeability transition pore (mPTP) opening, followed by activation of apoptotic signaling and cardiomyocyte (CM) death. I also found that these effects are mediated via PKD-dependent phosphorylation of a mitochondrial fission protein, Dynamin-Like Protein 1 (DLP1), and that a novel small-molecule PKD inhibitory compound, CRT, can block these detrimental pathways in CMs. Therefore, I hypothesize that PKD inhibition will reduce mROS and subsequently inhibit oxidative stress-induced CM death, which will prevent the progression of HF after MI in vivo. In Aim 1, I will inhibit PKD in vivo using PKD inhibitor CRT in a rat MI model and test whether PKD inhibition can rescue cardiac dysfunction after MI. In Aim 2, we will biochemically determine the levels of PKD-DLP1 signaling activity in atrial myocardium samples obtained from post-MI patients undergoing cardiac surgery to correlate these parameters to the severity of cardiac dysfunction before surgery. We will also obtain white blood cells (WBCs) from each patient to test whether the levels of PKD-DLP1 signaling activity in WBC can be the reflection of those in the atrial myocardium, which enable us to establish the feasibility of a blood test to assess the severity of cardiac dysfunction and to assess the efficiency of HF treatment in the clinic. These studies will delineate a novel signaling pathways leading to the increased cardiac injury in MI patients and will provide data on the efficacy of PKD-DLP1 inhibition on cardiac function in HF. The results from these experiments will lead us in designing a pilot translational study evaluating the efficacy and safety of the use of PKD inhibitor in patients with cardiac dysfunction in settings of MI.

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