STIMULATION OF SOLUBLE GUANYLATE-CYCLASE BY ENDOTHELIUM-DERIVED RELAXING FACTOR IS ANTAGONIZED BY OXIDIZED LOW-DENSITY-LIPOPROTEIN

Atherosclerosis is associated with a diminished dilatory response of blood vessels to endothelium-derived relaxing factor (EDRF). To clarify whether this impaired response may be due to a reduced biosynthesis of EDRF or a diminished responsiveness of the smooth muscle guanylate cyclase to EDRF, we investigated the effects of oxidized low-density lipoprotein (LDLox), a lipoprotein with atherogenic properties, on the activation of purified soluble guanylate cyclase by EDRF, as well as on the activity of the partially purified EDRF-forming enzyme. In the presence of LDLox, the effects of EDRF and other nitrocompounds on soluble guanylate cyclase were dose-dependently diminished, whereas no effect of LDLox on basal guanylate cyclase activity was observed. The inhibitory effect could be potentiated by preincubation of the enzyme with LDLox, indicating a direct interaction between the lipoprotein and guanylate cyclase. In contrast to its inhibitory effect on guanylate cyclase, LDLox did not affect the activity of the EDRF-forming enzyme. These data indicate that the impaired response of atherosclerotic blood vessels may be due to a diminished responsiveness of the smooth muscle guanylate cyclase rather than a reduced biosynthesis of EDRF.