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Induction and reversal of cardiac phenotype of human hypertrophic cardiomyopathy mutation cardiac troponin T-Q92 in switch on–switch off bigenic mice

Silvia Lutucuta, MD^*, Natalia Tsybouleva, MD^*, Masukuni Ishiyama, MD^*, Gilberto DeFreitas, MS^*, Lei Wei, PhD, Blase Carabello, MD^* and A.J. Marian, MD^*,*

^* Section of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, Texas
Section of Cardiovascular Sciences, Department of Medicine, Baylor College of Medicine, Houston, Texas

Manuscript received July 6, 2004; revised manuscript received August 9, 2004, accepted September 2, 2004.

^* Reprint requests and correspondence: Dr. A. J. Marian, Associate Professor of Medicine, Section of Cardiology, One Baylor Plaza, 519D, Houston, Texas 77030 (Email: amarian{at}bcm.tmc.edu).

OBJECTIVES: The 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.

BACKGROUND: Advances 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.

METHODS: We 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.

RESULTS: We established six lines and in dose-titration studies showed that treatment with 1,000 µg/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-Z-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.

CONCLUSIONS: The 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.

Abbreviations and Acronyms   ANOVA = analysis of variance   ATPase = adenosine triphosphatase   cAMP = cyclic adenosine monophosphate   cDNA = complementary deoxyribonucleic acid   cTnT = cardiac troponin T   cTnT-Q92 = cardiac troponin T-Q92   CVF = collagen volume fraction   HCM = hypertrophic cardiomyopathy   LV = left ventricular   LVEF = left ventricular ejection fraction   mRNA = messenger ribonucleic acid   MyHC = myosin heavy chain   NTG = non-transgenic   PCR = polymerase chain reaction   PKC = protein kinase C   PR = progesterone receptor   RT-PCR = reverse transcription-polymerase chain reaction   UAS = upstream activating sequences

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