Global proteomics and pathway analysis of pressure-overload-induced heart failure and its attenuation by mitochondrial-targeted peptides

We investigated the protective effects of mitochondrial-targeted antioxidant and protective peptides, Szeto-Schiller (SS) 31 and SS20, on cardiac function, proteomic remodeling, and signaling pathways. We applied an improved label-free shotgun proteomics approach to evaluate the global proteomics ch...

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Bibliographic Details
Published in:	Circulation. Heart failure Vol. 6; no. 5; pp. 1067 - 1076
Main Authors:	Dai, Dao-Fu, Hsieh, Edward J, Chen, Tony, Menendez, Lorena G, Basisty, Nathan B, Tsai, Lauren, Beyer, Richard P, Crispin, David A, Shulman, Nicholas J, Szeto, Hazel H, Tian, Rong, MacCoss, Michael J, Rabinovitch, Peter S
Format:	Journal Article
Language:	English
Published:	United States 01-09-2013
Subjects:	Animals Antioxidants - pharmacology Aorta - physiopathology Aorta - surgery Arterial Pressure Disease Models, Animal Heart Failure - etiology Heart Failure - metabolism Heart Failure - pathology Heart Failure - physiopathology Heart Failure - prevention & control Ligation Male Mice Mice, Inbred C57BL Mitochondria, Heart - drug effects Mitochondria, Heart - metabolism Mitochondria, Heart - pathology Myocardium - metabolism Myocardium - pathology Oligopeptides - pharmacology Proteomics - methods Signal Transduction - drug effects Ventricular Remodeling - drug effects heart failure proteomics signal transduction mitochondria
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Summary:	We investigated the protective effects of mitochondrial-targeted antioxidant and protective peptides, Szeto-Schiller (SS) 31 and SS20, on cardiac function, proteomic remodeling, and signaling pathways. We applied an improved label-free shotgun proteomics approach to evaluate the global proteomics changes in transverse aortic constriction (TAC)-induced heart failure and the associated signaling pathway changes using ingenuity pathway analysis. We found that 538 proteins significantly changed after TAC, which mapped to 53 pathways. The top pathways were in the categories of actin cytoskeleton, mitochondrial function, intermediate metabolism, glycolysis/gluconeogenesis, and citrate cycle. 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 nonmitochondrial protein changes. This included significant amelioration of all the ingenuity pathway analysis noted above. SS20 had only modest effects on heart failure and this tracked with only partial attenuation of global proteomics changes; furthermore, actin cytoskeleton pathways were significantly protected in SS20, whereas mitochondrial and metabolic pathways essentially were not. 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 SS31 suggests that perturbed mitochondrial function may be an upstream signal to many of the pathway alterations in TAC and supports the potential clinical application of mitochondrial-targeted peptide drugs for the treatment heart failure.
ISSN:	1941-3289 1941-3297
DOI:	10.1161/circheartfailure.113.000406