cyclic-gmp and Hyperlipoproteinemia-Type-IV

Increased production of reactive oxygen species and loss of endothelial nitric oxide (NO) bioactivity are key features of vascular disease states such as atherosclerosis. Tetrahydrobiopterin (BH4) is a required cofactor for NO synthesis by endothelial nitric oxide synthase (eNOS); pharmacologic studies suggest that reduced BH4 availability may be an important mediator of endothelial dysfunction in atherosclerosis. We aimed to investigate the importance of endothelial BH4 availability in atherosclerosis using a transgenic mouse model with endothelial-targeted overexpression of the rate-limiting enzyme in BH4 synthesis, GTP-cyclohydrolase I (GTPCH).. Transgenic mice were crossed into an ApoE knockout (ApoE-KO) background and fed a high-fat diet for 16 weeks. Compared with ApoE-KO controls, transgenic mice (ApoE-KO/GCH-Tg) had higher aortic BH4 levels, reduced endothelial superoxide production and eNOS uncoupling, increased cGMP levels, and preserved NO-mediated endothelium dependent vasorelaxations. Furthermore, aortic root atherosclerotic plaque was significantly reduced in ApoE-KO/GCH-Tg mice compared with ApoE-KO controls.. These findings indicate that BH4 availability is a critical determinant of eNOS regulation in atherosclerosis and is a rational therapeutic target to restore NO-mediated endothelial function and reduce disease progression.

Topics: Animals; Aorta; Aortic Diseases; Apolipoproteins E; Arteriosclerosis; Biopterins; Coenzymes; Crosses, Genetic; Cyclic GMP; Diet, Atherogenic; Endothelium, Vascular; GTP Cyclohydrolase; Humans; Hyperlipoproteinemia Type II; Hyperlipoproteinemia Type IV; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Nitric Oxide; Organ Specificity; Receptor, TIE-2; Recombinant Fusion Proteins; Superoxides; Vasodilation