Published Online
on May 12, 2008

A more recent version of this article appeared on May 20, 2008

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Submitted on September 4, 2007
Accepted on March 7, 2008

Reversal of Cardiac Hypertrophy and Fibrosis From Pressure Overload by Tetrahydrobiopterin. Efficacy of Recoupling Nitric Oxide Synthase as a Therapeutic Strategy

An L. Moens MD, Eiki Takimoto MD, PhD, Carlo G. Tocchetti MD, PhD, Khalid Chakir PhD, Djahida Bedja MS, Gianfranco Cormaci MD, Elizabeth A. Ketner MS, Maulik Majmudar MD, Kathleen Gabrielson DVM, PhD, Marc K. Halushka MD, James B. Mitchell PhD, Shyam Biswal PhD, Keith M. Channon MD, PhD, Michael S. Wolin PhD, Nicholas J. Alp MD, PhD, Nazareno Paolocci MD, PhD, Hunter C. Champion MD, PhD, and David A. Kass MD^*

From the Division of Cardiology, Department of Medicine (A.L.M., E.T., C.G.T., K.C., D.B., G.C., E.A.K., M.M., K.G., N.P., H.C.C., D.A.K.), and Department of Pathology (M.K.H.), Johns Hopkins Medical Institutions, Baltimore, Md; Department of Environmental Health Sciences, Bloomberg School of Public Health (S.B.), John Hopkins University, Baltimore, Md: Department of Physiology, New York Medical College, Valhalla (M.S.W.); Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Md (J.B.M.); and Department of Cardiovascular Medicine, University of Oxford, Oxford, UK (K.M.C., N.J.A.).

^* To whom correspondence should be addressed. E-mail: dkass{at}jhmi.edu.

Background—Sustained pressure overload induces pathological cardiac hypertrophy and dysfunction. Oxidative stress linked to nitric oxide synthase (NOS) uncoupling may play an important role. We tested whether tetrahydrobiopterin (BH4) can recouple NOS and reverse preestablished advanced hypertrophy, fibrosis, and dysfunction.

Methods and Results—C57/Bl6 mice underwent transverse aortic constriction for 4 weeks, increasing cardiac mass (190%) and diastolic dimension (144%), lowering ejection fraction (-46%), and triggering NOS uncoupling and oxidative stress. Oral BH4 was then administered for 5 more weeks of pressure overload. Without reducing loading, BH4 reversed hypertrophy and fibrosis, recoupled endothelial NOS, lowered oxidant stress, and improved chamber and myocyte function, whereas untreated hearts worsened. If BH4 was started at the onset of pressure overload, it did not suppress hypertrophy over the first week when NOS activity remained preserved even in untreated transverse aortic constriction hearts. However, BH4 stopped subsequent remodeling when NOS activity was otherwise declining. A broad antioxidant, Tempol, also reduced oxidant stress yet did not recouple NOS or reverse worsened hypertrophy/fibrosis from sustained transverse aortic constriction. Microarray analysis revealed very different gene expression profiles for both treatments. BH4 did not enhance net protein kinase G activity. Finally, transgenic mice with enhanced BH4 synthesis confined to endothelial cells were unprotected against pressure overload, indicating that exogenous BH4 targeted myocytes and fibroblasts.

Conclusions—NOS recoupling by exogenous BH4 ameliorates preexisting advanced cardiac hypertrophy/fibrosis and is more effective than a less targeted antioxidant approach (Tempol). These data highlight the importance of myocyte NOS uncoupling in hypertrophic heart disease and support BH4 as a potential new approach to treat this disorder.

Key words: antioxidants • heart failure • hypertrophy • nitric oxide synthase • reactive oxygen species • remodeling • therapeutics

Related Article:

Clinical Summaries
Circulation 2008 117: 2567-2569. [Extract] [Full Text]

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