Tetrahydrobiopterin Protects Against Hypertrophic Heart Disease Independent of Myocardial Nitric Oxide Synthase Coupling

Background Nitric oxide synthase uncoupling occurs under conditions of oxidative stress modifying the enzyme's function so it generates superoxide rather than nitric oxide. Nitric oxide synthase uncoupling occurs with chronic pressure overload, and both are ameliorated by exogenous tetrahydrobiopterin ( BH 4)—a cofactor required for normal nitric oxide synthase function—supporting a pathophysiological link. Genetically augmenting BH 4 synthesis in endothelial cells fails to replicate this benefit, indicating that other cell types dominate the effects of exogenous BH 4 administration. We tested whether the primary cellular target of BH 4 is the cardiomyocyte or whether other novel mechanisms are invoked. Methods and Results Mice with cardiomyocyte‐specific overexpression of GTP cyclohydrolase 1 ( mGCH 1) and wild‐type littermates underwent transverse aortic constriction. The mGCH 1 mice had markedly increased myocardial BH 4 and, unlike wild type, maintained nitric oxide synthase coupling after transverse aortic constriction; however, the transverse aortic constriction–induced abnormalities in cardiac morphology and function were similar in both groups. In contrast, exogenous BH 4 supplementation improved transverse aortic constricted hearts in both groups, suppressed multiple inflammatory cytokines, and attenuated infiltration of inflammatory macrophages into the heart early after transverse aortic constriction. Conclusions BH 4 protection against adverse remodeling in hypertrophic cardiac disease is not driven by its prevention of myocardial nitric oxide synthase uncoupling, as presumed previously. Instead, benefits from exogenous BH 4 are mediated by a protective effect coupled to suppression of inflammatory pathways and myocardial macrophage infiltration.