Resolution of established cardiac hypertrophy and fibrosis and prevention of systolic dysfunction in a transgenic rabbit model of human cardiomyopathy through thiol-sensitive mechanisms.
BACKGROUND
Cardiac hypertrophy, the clinical hallmark of hypertrophic cardiomyopathy (HCM), is a major determinant of morbidity and mortality not only in HCM but also in a number of cardiovascular diseases. There is no effective therapy for HCM and generally for cardiac hypertrophy. Myocardial oxidative stress and thiol-sensitive signaling molecules are implicated in pathogenesis of hypertrophy and fibrosis. We posit that treatment with N-acetylcysteine, a precursor of glutathione, the largest intracellular thiol pool against oxidative stress, could reverse cardiac hypertrophy and fibrosis in HCM.


RESULTS
We treated 2-year-old beta-myosin heavy-chain Q403 transgenic rabbits with established cardiac hypertrophy and preserved systolic function with N-acetylcysteine or a placebo for 12 months (n=10 per group). Transgenic rabbits in the placebo group had cardiac hypertrophy, fibrosis, systolic dysfunction, increased oxidized to total glutathione ratio, higher levels of activated thiol-sensitive active protein kinase G, dephosphorylated nuclear factor of activated T cells (NFATc1) and phospho-p38, and reduced levels of glutathiolated cardiac alpha-actin. Treatment with N-acetylcysteine restored oxidized to total glutathione ratio, normalized levels of glutathiolated cardiac alpha-actin, reversed cardiac and myocyte hypertrophy and interstitial fibrosis, reduced the propensity for ventricular arrhythmias, prevented cardiac dysfunction, restored myocardial levels of active protein kinase G, and dephosphorylated NFATc1 and phospho-p38.


CONCLUSIONS
Treatment with N-acetylcysteine, a safe prodrug against oxidation, reversed established cardiac phenotype in a transgenic rabbit model of human HCM. Because there is no effective pharmacological therapy for HCM and given that hypertrophy, fibrosis, and cardiac dysfunction are common and major predictors of clinical outcomes, the findings could have implications in various cardiovascular disorders.
Lombardi
Raffaella
R
Center for Cardiovascular Genetics, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, and Texas Heart Institute, Houston, TX, USA.
Rodriguez
Gabriela
G
Chen
Suet Nee
SN
Ripplinger
Crystal M
CM
Li
Wenwen
W
Chen
Junjie
J
Willerson
James T
JT
Betocchi
Sandro
S
Wickline
Samuel A
SA
Efimov
Igor R
IR
Marian
Ali J
AJ
D000111:Acetylcysteine / Q000627:therapeutic use*; D000199:Actins / Q000032:analysis; D000818:Animals; D030801:Animals, Genetically Modified; D000975:Antioxidants / Q000627:therapeutic use*; D002312:Cardiomyopathy, Hypertrophic / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D048429:Cell Size; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D005978:Glutathione / Q000378:metabolism; D054143:Heart Failure, Systolic / Q000209:etiology / Q000517:prevention & control*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D018995:Myosin Heavy Chains / Q000172:deficiency / Q000235:genetics; D050778:NFATC Transcription Factors / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011817:Rabbits; D013438:Sulfhydryl Compounds / Q000378:metabolism*; D014693:Ventricular Fibrillation / Q000209:etiology / Q000517:prevention & control; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000199:Actins; D000975:Antioxidants; D050778:NFATC Transcription Factors; D013438:Sulfhydryl Compounds; D048051:p38 Mitogen-Activated Protein Kinases; D018995:Myosin Heavy Chains; D005978:Glutathione; D000111:Acetylcysteine