Auto-inhibitory regulation of angiotensin II functionality in hamster aorta during the early phases of dyslipidemia

Emerging data point the crosstalk between dyslipidemia and renin-angiotensin system (RAS). Advanced dyslipidemia is described to induce RAS activation in the vasculature. However, the interplay between early dyslipidemia and the RAS remains unexplored. Knowing that hamsters and humans have a similar lipid profile, we investigated the effects of early and advanced dyslipidemia on angiotensin II-induced contraction. Cumulative concentration-response curves for angiotensin II (1.0pmol/l to 1.0µmol/l) were obtained in the hamster thoracic aorta. We also investigated the modulatory action of NAD(P)H oxidase on angiotensin II-induced contraction using ML171 (Nox-1 inhibitor, 0.5µmol/l) and VAS2870 (Nox-4 inhibitor, 5µmol/l). Early dyslipidemia was detected in hamsters treated with a cholesterol-rich diet for 15 days. Early dyslipidemia decreased the contraction induced by angiotensin II and the concentration of Nox-4-derived hydrogen peroxide. Advanced dyslipidemia, observed in hamsters treated with cholesterol-rich diet for 30 days, restored the contractile response induced by angiotensin II by compensatory mechanism that involves Nox-4-mediated oxidative stress. The hyporresponsiveness to angiotensin II may be an auto-inhibitory regulation of the angiotensinergic function during early dyslipidemia in an attempt to reduce the effects of the upregulation of the vascular RAS during the advanced stages of atherogenesis. The recovery of vascular angiotensin II functionality during the advanced phases of dyslipidemia is the result of the upregulation of redox-pro-inflammatory pathway that might be most likely involved in atherogenesis progression rather than in the recovery of vascular function. Taken together, our findings show the early phase of dyslipidemia may be the most favorable moment for effective atheroprotective therapeutic interventions.

Hamsters fed with cholesterol (1%)-rich diet for 15 days develop early dyslipidemia (increased levels of LDL-C). The moderate hypercholesterolemia evoked by early dyslipidemia impairs the aortic generation of eNOS-derived NO, which impairs catalase activity. Initially, the downregulation of catalase leads to a transient increase in O2−-derived H2O2 levels, which persistently inhibits its self generation by Nox-4 upon the inhibition of SOD and Rac-1 interaction during an auto-regulatory mechanism. The reduced levels of H2O2 contribute to the vascular contractile hyporresponsiveness to Ang II. Hamsters fed with cholesterol (1%)-rich diet for 30 days develop advanced dyslipidemia (increased LDL-cholesterol and TG levels). The advanced dyslipidemia impairs aortic SOD activity upon the vascular accumulation of oxLDL. SOD downregulation increases O2- levels but reduces H2O2 levels. By Fenton-like reactions, high levels of
• OH are directly generated from O2-.
• OH induces PGH2, which contributes to the recovery of local Ang II functionality. The contractile hyporresponsiveness to Ang II may be elicited as an auto-inhibitory regulation of the RAS during early dyslipidemia in an attempt to reduce the effects of the upregulation of vascular RAS during the advanced stages of atherogenesis. In turn, the recovery of vascular Ang II functionality during the advanced phases of dyslipidemia is reached upon the upregulation of a redox-pro-inflammatory pathway that might be most likely involved in atherogenesis progression rather than in the rescue of vascular function. Taken together, these findings suggest that the early phases of dyslipidemia may be the most favorable moment for effective atheroprotective therapeutic interventions. LDL-C (low density lipoprotein-cholesterol); TG (triglycerides); oxLDL (oxidized low density lipoproteins); eNOS (endothelial nitric oxide synthase); NO (nitric oxide); SOD (superoxide dismutase); O2- (superoxide anion); H2O2 (hydrogen peroxide);
• OH (hydroxyl radical); PGH2 (prostaglandin H2); Ang II (angiotensin II); RAS (renin-angiotensin system).Figure optionsDownload high-quality image (177 K)Download as PowerPoint slide