Oral Tetrahydrobiopterin Treatment Prevents Accelerated Atherosclerosis Caused by Oscillatory Shear Stress

Abstract

Tetrahydrobiopterin (BH4) is a critical cofactor for NO synthesis by endothelial NO synthase (eNOS). BH4 synthesis is regulated by phosphorylation of the rate‐limiting enzyme, GTP cyclohydrolase I (GTPCH‐1). We previously found that laminar, but not oscillatory shear stress stimulates GTPCH‐1 phosphorylation and markedly increases BH4 levels. A recent study showed that disturbed blood flow in vivo induced by partial carotid ligation results in endothelial dysfunction and accelerated atherosclerosis in ApoE−/− mice. We have now found that oscillatory shear in vivo is associated with reduced GTPCH‐1 phosphorylation and markedly lower levels of BH4. We therefore aimed to test the hypothesis that atherosclerosis induced by oscillatory shear is due to low levels of BH4 and eNOS uncoupling, and that increasing BH4 will prevent atherosclerosis. We found that oral BH4 treatment at 10 mg/kg/day in drinking water virtually eliminated atherosclerotic lesion formation in ApoE−/− mice after 3 weeks of ligation. Furthermore, BH4 treatment preserved the decline of NO production induced by oscillatory shear. We also showed that BH4 treatment abolished the marked increase in superoxide production induced by disturbed flow. Thus, BH4 treatment appears to prevent eNOS uncoupling and atherosclerosis in this model of rapid lesion development caused by disturbed flow. Supported by HL39006 and an AHA predoctoral fellowship.