Abstract P3195: Mitochondrial CaMKII Drives Cardiometabolic Dysfunction In Heart Failure

Abstract

Background: Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) is an established negative regulator of cardiac injury. Both the expression and activity levels of CaMKII delta, the primary cardiac isoform of this kinase, are elevated in models of heart failure (HF) such as ischemia-reperfusion (I/R) injury and following myocardial infarction (MI). This upregulation is due in part to CaMKII’s role in the regulation of excitation-contraction coupling, apoptosis, activation of hypertrophic programming, arrhythmias and pro-inflammatory signaling. Recently, a pool of mitochondrial CaMKII (mtCaMKII) has been identified; we have demonstrated that there is an observed increase in mitochondrial CaMKII activation with left ventricular dilation acutely following injury in a mouse model of MI. This deleterious post-MI phenotype is rescued with genetic mitochondrial CaMKII inhibition; conversely, mice with myocardial mitochondrial CaMKII overexpression present with a severe dilated cardiomyopathy phenotype, alterations in electron transport chain (ETC) activity, and decreased ATP production. Objective: To date, the molecular mechanisms by which CaMKII regulates mitochondrial energetics are unknown and present a novel therapeutic target for HF which we are currently studying. Methods: As we have identified changes in the activity of enzymes, particularly complexes I and II, in the mitochondrial ETC as well as TCA cycle in response to increased CaMKII levels or activity, we are in the process of assessing changes in the mitochondrial CaMKII interactome between uninjured and failing hearts. Utilizing liquid chromatography-mass spectrometry (LCMS) and proteomics analysis of both scaffolding interactions alongside a novel ATP analogue labeling technique, we have mapped novel mitochondrial proteins which interact with mtCaMKII. Significance: The identification of previously unknown mitochondrial pathways involving CaMKII may uncover promising pharmacological targets for cardiovascular therapeutics, as this kinase is a critical player in the progression of HF.