Effect of Hypercholesterolemia on Expression and Function of Vascular Soluble Guanylyl Cyclase

U. Laber
2002 Circulation  
Background-Vasorelaxation to endothelial NO is mediated by activation of soluble guanylyl cyclase (sGC) and impaired by hypercholesterolemia in animals and humans. We investigated whether hypercholesterolemia impacts expression and function of sGC. Methods and Results-White New Zealand rabbits (nϭ10 per group) received a standard diet for 16 weeks (SD16) (nϭ20) or 32 weeks (SD32) and a cholesterol diet (7.5 g/kg) for 16 weeks (CD16) (nϭ20) or 32 weeks (CD32), respectively. Another group
more » ... cholesterol diet for 16 weeks followed by standard diet for 16 weeks (CD/SD). Aortic expression of the ␣ 1 -subunit of sGC (sGC-␣ 1 ) and ␤ 1 -subunit of sGC (sGC-␤ 1 ) was assessed by Western blot. Function was measured by aortic relaxation to S-Nitroso-N-acetyl-D, L-penicillamine (SNAP) and sGC activity in aortic cytosols. Hypercholesterolemia induced an upregulation of sGC-␤ 1 in CD16 (3.5Ϯ0.4-fold, PϽ0.001 versus SD16) and CD32 (4.0Ϯ0.4-fold, PϽ0.001 versus SD32). A similar increase was found for sGC-␣ 1 . In striking contrast, basal and NO-stimulated sGC activities in aortic cytosols of CD16 were only slightly enhanced (1.4-fold, PϽ0.05). Furthermore, the vasodilator potency of SNAP (EC 50 in ϪlogM) was 10-fold lower in CD16 (6.76Ϯ0.09) than in SD16 (7.66Ϯ0.14, PϽ0.01). The increase of sGC expression was completely reversible, as indicated by comparable sGC-␤ 1 amounts in SD32 and CD/SD (1.2Ϯ0.1-fold, PϾ0.05). Immunohistochemical analysis suggests that a great portion of the overexpressed sGC is located in intimal lesions. Additional experiments showed that increased vascular superoxide production induced by 6-anilino-5,8quinolinedione (LY85385) reduces sGC-activity but increases sGC-expression. Conclusions-These results suggest that hypercholesterolemia induces a reversible overexpression of a dysfunctional vascular sGC, which may contribute to the pathogenesis of atherosclerosis. (Circulation. 2002;105:855-860.)
doi:10.1161/hc0702.103975 pmid:11854127 fatcat:ljd3deob2zda5nv67zg4yc62fi