Abstract 9515: ATP Synthase Subunit Alpha and Left Ventricular Hypertrophy in Ischemic Cardiomyopathy: A Mitochondrial Proteomic Approach Using Human Cardiac Tissue
Introduction: Mitochondrial dysfunction plays a critical role in the development of ischemic cardiomyopathy (ICM). In this study, the mitochondrial proteome in the cardiac tissue of ICM patients was analyzed for the first time to identify potential molecular targets for therapeutic intervention in this cardiomyopathy.
Methods: We isolated mitochondria from left ventricular (LV) samples of explanted hearts of ICM patients (n=10) and control donors (n=10) and we used a proteomic approach to investigate the variations in mitochondrial protein expression.
Results: We found that most of the altered proteins were involved in cardiac energy metabolism (82%). We focused on ATPA, which is involved in energy production, and DLDH, implicated in substrate utilization, and observed that these molecules were overexpressed and that the changes detected in the processes mediated by these proteins were closely related. Notably, we found that ATPA overexpression was associated with reduction in LV mass (r=-0.74, P<0.01). We also found a substantial increase in the expression of EFTU, a molecule implicated in protein synthesis, and PRDX3, involved in the stress response. All of these changes were validated using classical techniques and by using novel and precise selected reaction monitoring analysis (mitochondrial isolation and proteomic analysis, Western blot, fluorescence microscopy, immunocytochemistry, electron microscopy, and an RNA sequencing approach), with the total heart samples being increased to 44.
Conclusions: We report that most of the mitochondrial proteins altered in ICM hearts are involved in cardiac energy metabolism. Notably, our results are consistent and have been validated using diverse well-established techniques and by using novel and precise SRM analysis and RNA-seq approach. Interestingly, we found a significant increase in the protein levels of ATPA in the cardiac tissue of ICM patients, but the most remarkable finding was the strong correlation between ATPA levels and LV mass. As a result, new strategies based on gene therapy to clarify the mechanisms that lead to energetic derangement and, moreover, to restore ventricular function and reverse hypertrophy must be investigated.
Author Disclosures: M. Rivera: None. E. Rosello: None. M. Barderas: None. E. Tarazon: None. A. Ortega: None. L. Rodriguez Padial: None. A. Salvador: None. M. Portoles: None.
- © 2014 by American Heart Association, Inc.