David M Ryba1, Chad M Warren1, Chehade N Karam1, Robert T Davis1, Shamim A K Chowdhury1, Manuel G Alvarez1, Maximilian McCann1, Chong Wee Liew1, David F Wieczorek2, Peter Varga3, R John Solaro1, Beata M Wolska1,4. 1. Department of Physiology and Biophysics and the Center for Cardiovascular Research, College of Medicine, University of Illinois at Chicago (D.M.R., C.M.W., C.N.K., R.T.D., S.A.K.C., M.G.A., M.M., C.W.L., R.J.S., B.M.W.). 2. Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, OH (D.F.W.). 3. Department of Pediatrics, Section of Cardiology, University of Illinois at Chicago (P.V.). 4. Department of Medicine, Division of Cardiology, University of Illinois at Chicago, IL (B.M.W.).
Abstract
BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a genetic cardiovascular disorder, primarily involving mutations in sarcomeric proteins. HCM patients present with hypertrophy, diastolic dysfunction, and fibrosis, but there is no specific treatment. The sphingosine-1-phosphate receptor modulator, FTY720/fingolimod, is approved for treatment of multiple sclerosis. We hypothesize that modulation of the sphingosine-1-phosphate receptor by FTY720 would be of therapeutic benefit in sarcomere-linked HCM. METHODS: We treated mice with an HCM-linked mutation in tropomyosin (Tm-E180G) and nontransgenic littermates with FTY720 or vehicle for 6 weeks. Compared with vehicle-treated, FTY720-treated Tm-E180G mice had a significant reduction in left atrial size (1.99±0.19 [n=7] versus 2.70±0.44 [n=6] mm; P<0.001) and improvement in diastolic function (E/A ratio: 2.69±0.38 [n=7] versus 5.34±1.19 [n=6]; P=0.004) as assessed by echocardiography. RESULTS: Pressure-volume relations revealed significant improvements in the end-diastolic pressure volume relationship, relaxation kinetics, preload recruitable stroke work, and ejection fraction. Detergent-extracted fiber bundles revealed a significant decrease in myofilament Ca2+-responsiveness (pCa50=6.15±0.11 [n=13] versus 6.24±0.06 [n=14]; P=0.041). We attributed these improvements to a downregulation of S-glutathionylation of cardiac myosin binding protein-C in FTY720-treated Tm-E180G mice and reduction in oxidative stress by downregulation of NADPH oxidases with no changes in fibrosis. CONCLUSIONS: This is the first demonstration that modulation of S1PR results in decreased myofilament-Ca2+-responsiveness and improved diastolic function in HCM. We associated these changes with decreased oxidative modification of myofilament proteins via downregulation of NOX2. Our data support the hypothesis that modification of sphingolipid signaling may be a novel therapeutic approach in HCM.
BACKGROUND:Hypertrophic cardiomyopathy (HCM) is a genetic cardiovascular disorder, primarily involving mutations in sarcomeric proteins. HCMpatients present with hypertrophy, diastolic dysfunction, and fibrosis, but there is no specific treatment. The sphingosine-1-phosphate receptor modulator, FTY720/fingolimod, is approved for treatment of multiple sclerosis. We hypothesize that modulation of the sphingosine-1-phosphate receptor by FTY720 would be of therapeutic benefit in sarcomere-linked HCM. METHODS: We treated mice with an HCM-linked mutation in tropomyosin (Tm-E180G) and nontransgenic littermates with FTY720 or vehicle for 6 weeks. Compared with vehicle-treated, FTY720-treated Tm-E180Gmice had a significant reduction in left atrial size (1.99±0.19 [n=7] versus 2.70±0.44 [n=6] mm; P<0.001) and improvement in diastolic function (E/A ratio: 2.69±0.38 [n=7] versus 5.34±1.19 [n=6]; P=0.004) as assessed by echocardiography. RESULTS: Pressure-volume relations revealed significant improvements in the end-diastolic pressure volume relationship, relaxation kinetics, preload recruitable stroke work, and ejection fraction. Detergent-extracted fiber bundles revealed a significant decrease in myofilament Ca2+-responsiveness (pCa50=6.15±0.11 [n=13] versus 6.24±0.06 [n=14]; P=0.041). We attributed these improvements to a downregulation of S-glutathionylation of cardiac myosin binding protein-C in FTY720-treated Tm-E180Gmice and reduction in oxidative stress by downregulation of NADPH oxidases with no changes in fibrosis. CONCLUSIONS: This is the first demonstration that modulation of S1PR results in decreased myofilament-Ca2+-responsiveness and improved diastolic function in HCM. We associated these changes with decreased oxidative modification of myofilament proteins via downregulation of NOX2. Our data support the hypothesis that modification of sphingolipid signaling may be a novel therapeutic approach in HCM.
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