Hope or hype: The obsession for tetrahydrobiopterin and GTP cyclohydrolase I (GTPCH I) in cardiovascular medicine

Abstract

It has been speculated that a reduction in nitric oxide (NO) bioavailability as a result of decreased NO synthase (NOS) cofactor tetrahydrobiopterin (BH₄) plays an essential role in cardiovascular pathologies including dilated cardiomyopathy, ischemia–reperfusion injury, endothelial dysfunction, atherosclerosis, hypertension and diabetes. Treatment remedies towards BH₄ or its rate-limiting enzyme GTP cyclohydrolase I (GTPCH I) have shown some unusual therapeutic promises against cardiovascular diseases. To the contrary, blockade of BH₄ synthesis antagonizes cerebral infarction via inhibition of inducible NOS and ONOO⁻. In addition, GTPCH I may be stimulated by cytokines including interferon-γ, tumor necrosis factor-α and inflammatory mediators, suggesting a possible role of double-edge sword for BH₄ in cardiovascular medicine. Accumulation of free radicals and oxidative stress has been indicated to oxidize BH₄, although the precise role of BH₄ deficiency in cardiovascular pathophysiology remains largely elusive. Recent pharmacological, gene transfer and transgenic studies have provided new insight towards the ultimate understanding of BH₄ in the pathogenesis and therapy of cardiovascular diseases. However, whether BH₄ should be considered as a panacea for NO deficiency is debatable. This review intends to update the picture of pathophysiology of BH₄ deficiency, pros and cons in therapeutics using BH₄ and its rate limiting enzyme GTP cyclohydrolase I (GTPCH I) against NO deficiency.