Effects of myosin heavy chain manipulation in experimental heart failure.
The myosin heavy chain (MHC) isoforms, alpha- and beta-MHC, are expressed in developmental- and chamber-specific patterns. Healthy human ventricle contains approximately 2-10% alpha-MHC and these levels are reduced even further in the failing ventricle. While down-regulation of alpha-MHC in failing myocardium is considered compensatory, we previously demonstrated that persistent transgenic (TG) alpha-MHC expression in the cardiomyocytes is cardioprotective in rabbits with tachycardia-induced cardiomyopathy (TIC). We sought to determine if this benefit extends to other types of experimental heart failure and focused on two models relevant to human heart failure: myocardial infarction (MI) and left ventricular pressure overload. TG and nontransgenic rabbits underwent either coronary artery ligation at 8 months or aortic banding at 10 days of age. The effects of alpha-MHC expression were assessed at molecular, histological and organ levels. In the MI experiments, we unexpectedly found modest functional advantages to alpha-MHC expression. In contrast, despite subtle benefits in TG rabbits subjected to aortic banding, cardiac function was minimally affected. We conclude that the benefits of persistent alpha-MHC expression depend upon the mechanism of heart failure. Importantly, in none of the scenarios studied did we find any detrimental effects associated with persistent alpha-MHC expression. Thus manipulation of MHC composition may be beneficial in certain types of heart failure and does not appear to compromise heart function in others. Future considerations of myosin isoform manipulation as a therapeutic strategy should consider the underlying etiology of cardiac dysfunction.
James
Jeanne
J
The Heart Institute, Cincinnati Children's Hospital Medical Center and the University of Cincinnati School of Medicine, 241 Albert Sabin Way MLC 7020, Cincinnati, OH 45229-3039, USA.
Hor
Kan
K
Moga
Michael-Alice
MA
Martin
Lisa Ann
LA
Robbins
Jeffrey
J
D000818:Animals; D030801:Animals, Genetically Modified; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D006333:Heart Failure / Q000378:metabolism*; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D011817:Rabbits; D013610:Tachycardia / Q000503:physiopathology; D018487:Ventricular Dysfunction, Left / Q000378:metabolism
D020033:Protein Isoforms; D018995:Myosin Heavy Chains