Abstract 16900: Global Proteomics and Pathway Analysis of Pressure-Overload Induced Heart Failure And Its Attenuation by Mitochondrial Targeted Peptides
Background: Mitochondrial dysfunction has been implicated in pressure-overload induced heart failure.
Methods and Results: We applied an improved label-free shotgun proteomics approach to evaluate the global proteomics changes in transverse aortic constriction (TAC) induced heart failure. We investigated the modifying effect of mitochondrial-targeted peptides, SS31, SS20 and SS48 on the protection of cardiac function and proteomic remodeling and signaling pathways, the latter studied using Ingenuity Pathway Analysis (IPA). We found 538 proteins significantly changed after TAC, which mapped to 93 signaling pathways. The top pathways included mitochondrial oxidative phosphorylation, citrate cycle, branched chain amino acid degradation, actin cytoskeleton/Rho /integrin signaling, coenzyme A and fatty acid metabolism. Concomitant treatment with SS31 ameliorated the congestive heart failure phenotypes and mitochondrial damage induced by TAC, in parallel with global attenuation of mitochondrial proteome changes, with an average of 84% protection of mitochondrial and 69% of non-mitochondrial protein changes. This included significant amelioration of 55 signaling pathways. There was little evidence of SS31 induced proteomic changes other than attenuation of TAC. SS48 peptide had little protective effect and SS20 had intermediate effects on heart failure and this tracked closely with the magnitude of attenuation of global proteomics changes.
Conclusion: This study elucidates the signaling pathways significantly changed in pressure-overload induced heart failure. The global attenuation of TAC-induced proteomic alterations by the mitochondrial targeted peptide suggests that perturbed mitochondrial function is an upstream signal to many of pathway alterations in TAC and supports the potential clinical application of mitochondrial-targeted peptide drugs for the treatment heart failure.
- © 2012 by American Heart Association, Inc.