Altered myofilament stoichiometry in response to heart failure in a cardioprotective α-myosin heavy chain transgenic rabbit model

Brian A. Stanley, David R. Graham, Jeanne James, Megan Mitsak, Patrick M. Tarwater, Jeff Robbins, Jennifer E. Van Eyk

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: Decreases in α myosin heavy chain (α-MHC) is a common feature of human heart failure (HF), whereas α-MHC overexpression in transgenic (TG) rabbits is cardioprotective against tachycardia-induced cardiomyopathy (TIC). Hypothesizing that MHC isoform content alterations would impact sarcomere and mitochondrial energetics protein complement, we investigated the impact of α-MHC overexpression on global cardiac protein expression. Experimental design: Protein expression was assessed by two-dimensional gel electrophoresis and MS on the extracts from TG and nontransgenic (NTG) rabbits under TIC or sham-operated conditions. Results: We observed significant changes in the levels of actin, myosin light chain 2, and desmin between the left ventricular (LV) tissue of TG and NTG animals. The proteome was broadly impacted, with significant changes in mitochondrial energetics and chaperone protein families. No changes were observed in total cellular MHC or in myofibril-associated MHC. In myofibrils isolated from TGsham animals, only actin levels were altered in TGsham compared with NTGsham animals, suggesting careful myofibril assembly regulation. Conclusions and clinical Relevance: These data suggest that myofibril protein composition may protect against TIC, emphasizing protein interconnectivity and demonstrating the need for broad-based proteomic studies in understanding targeted genetic manipulations. This study identifies the targets for future development of cardioprotective agents and elucidates tachycardia-induced heart failure pathways.

Original languageEnglish (US)
Pages (from-to)147-158
Number of pages12
JournalProteomics - Clinical Applications
Volume5
Issue number3-4
DOIs
StatePublished - Apr 2011

Keywords

  • MS
  • Myofilament
  • Two-dimensional gel
  • α Myosin heavy chain

ASJC Scopus subject areas

  • Clinical Biochemistry

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