ArticleJournal of the American College of Cardiology2004
Induction and reversal of cardiac phenotype of human hypertrophic cardiomyopathy mutation cardiac troponin T-Q92 in switch on-switch off bigenic mice.
Article in Journal of the American College of Cardiology, 2004. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 28 citations in OpenAlex.
- Hypertrophy Regression With N-Acetylcysteine in Hypertrophic Cardiomyopathy (HALT-HCM): A Randomized, Placebo-Controlled, Double-Blind Pilot Study.Circulation research · 2018Trial
- Effects of losartan on left ventricular hypertrophy and fibrosis in patients with nonobstructive hypertrophic cardiomyopathy.JACC. Heart failure · 2013Trial
- BET bromodomain inhibition attenuates cardiac phenotype in myocyte-specific lamin A/C-deficient mice.The Journal of clinical investigation · 2020Article
- Pre-clinical model of severe glutathione peroxidase-3 deficiency and chronic kidney disease results in coronary artery thrombosis and depressed left ventricular function.Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association · 2018Article
- Contribution of Post-translational Phosphorylation to Sarcomere-Linked Cardiomyopathy Phenotypes.Frontiers in physiology · 2016Article
- Experimental therapies in hypertrophic cardiomyopathy.Journal of cardiovascular translational research · 2009Review
- Differential interactions of thin filament proteins in two cardiac troponin T mouse models of hypertrophic and dilated cardiomyopathies.Cardiovascular research · 2008Article
- Suppression of canonical Wnt/beta-catenin signaling by nuclear plakoglobin recapitulates phenotype of arrhythmogenic right ventricular cardiomyopathy.The Journal of clinical investigation · 2006Article
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7 authors at 1 institution in 1 country.
Funding
Abstract
objectivesThe aim of this study was to establish reversibility of cardiac phenotypes in hypertrophic cardiomyopathy (HCM) by generating bigenic mice in which expression of the mutant transgene could be turned on and off as needed.
backgroundAdvances in molecular therapeutics could ultimately lead to therapies aimed at correcting the causal mutations. However, whether cardiac phenotypes, once established, are permanent, or could be reversed, if expression of the mutant protein is turned off, is unknown.
methodsWe generated ligand-inducible bigenic mice, turned on and off expression of cardiac troponin T-Q92 (cTnT-Q92), responsible for human HCM, and characterized molecular, histologic, and functional phenotypes.
resultsWe established six lines and in dose-titration studies showed that treatment with 1,000 mug/kg of mifepristone consistently switched on cTnT-Q92 expression in the heart. Short-term (16 days) induced expression enhanced myocardial systolic function without changing myocardial cyclic adenosine monophosphate levels. Levels of PTEN, a regulator of cardiac function, phospho-protein kinase C-Zetalambda-Thr538 and phosphor-protein kinase D-Ser744-748 were reduced, whereas messenger ribonucleic acid (mRNA) levels of NPPA, NPPB, and sarcoplasmic reticulum calcium adenine triphosphatase 2 (ATP2A2) (hypertrophic markers) and procollagen COL1A1, COL1A2, and COL3A1 were unchanged. Long-term (70 days) induced expression increased COL1A1 and COL1A3 mRNAs levels and collagen volume fraction and reduced levels of NPPA and NPPB. Switching off expression of the cTnT-Q92 reversed functional, molecular, and histologic phenotypes completely.
conclusionsThe initial phenotype induced by cTnT-Q92 is enhanced myocardial systolic function followed by changes in signaling kinases and interstitial fibrosis. Established phenotypes in HCM reverse upon turning off expression of the mutant protein. These findings provoke pursuing specific therapies directed at correcting the underlying the genetic defect in HCM.
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