Non-Hypertensive Deoxycorticosterone-Salt Treatment Accelerates Atherosclerosis Progression in Watanabe Heritable Hyperlipidemic Rabbit

Abstract

Epidemiological studies have indicated that hypertension enhances the development of atherosclerosis in patients with lipid disorders. However, it was still unclear whether this promoting effect resulted only from hemodynamic changes or whether part of it was mediated by humoral or neurogenic factors independent of blood pressure alteration. The aim of this study was to determine whether mineralocorticoids, which are known to be involved in the pathogenesis of hypertension, could be implicated in the atherosclerotic process independent of pressure changes. For this purpose, the effect of deoxycorticosterone (DOCA, 200 mg/kg s.c.) on aortic atherosclerosis was studied in Watanabe heritable hyperlipidemic (WHHL) rabbits in comparison with New Zealand rabbits. After 4 weeks of treatment, DOCA significantly increased the size of atherosclerotic lesions in the arch and thoracic aorta (+115%) in parallel with the aortic cholesterol ester content (+83%). The vascular free cholesterol and triglyceride content remained unchanged on DOCA treatment, as were arterial pressure and plasma cholesterol levels. None of these effects was observed in New Zealand rabbits. DOCA did not accentuate the alteration of endothelial function usually found in WHHL rabbits. The sensitivity to serotonin was not altered, but the maximal contraction to this agonist was decreased in both strains by mineralocorticoid treatment.

Metyrapone Treatment Protects Low-Density Lipoprotein Receptor Knockout Mice against Hypercorticosteronemia Development without Changing Atherosclerosis Susceptibility

“…Raven et al have shown that, in a small cohort of mentally depressed human subjects, metyrapone treatment was associated with a striking >5-fold increase in the urinary output of 11-deoxycortisol (deoxycortisol) metabolites [ 21 ]. Treatment with deoxycorticosterone stimulates atherogenesis in Watanabe heritable hyperlipidemic rabbits [ 22 ] as well as in hyperlipidemic apolipoprotein E knockout mice [ 23 ]. Lother et al have shown that deoxycorticosterone executes its pathological vascular effects through activation of the mineralocorticoid receptor (MR) [ 24 ].…”