Regulation of 11β-hydroxylase cytochrome P450 expression by cholesterol in spontaneously hypertensive rats

Objective: To investigate whether hypercholesterolaemia interferes with the expressionof the enzymes involved in steroid biosynth esis in the adrenal cortex. Methods: Twenty-fou r 5-week-old male spontaneously hypertensive rats (SHR) were randomly assigned to a high (1%) cholesterol diet (n = 8) or to a matchedcholesterol-free diet (n =8) for 6 weeks. A third group (n =8) was studied after 2weeks of washout from the high-cholesterol intake. A cohort of age- and sex-matchednormotensive Wi star-Kyoto (WKY) rats (n =24) und erwent the same treatments and was used as a control. Results: In SHR cholesterol feedin g reduced urinary sodium excretion (0.8±0.1 versus1.4 ± 0.1 mmol/24 h in the cholesterol-free group), increased plasma aldosteronelevels (299 ±60 versus 154 ± 24) and reduced plasma co rtic osterone levels (1 42 ±21versus 278 ±35 ng/ml). Those responses were associated with a reducti on of1113-hydro xyl ase cytochrome P450 messenger RNA (mRNA) in the adrenal cortex (-52.3 ± 3.4%) whereas aldosterone synthase mRNA remain ed unchanged. That effect and the changes in electro lyte excretion and steroid levels were no longer detectable after withdrawal of the diet. In WKY rats high-cholesterol diet induced no significant changes in urinary electrolyte excretion, steroid levels and expression of 1113-hydr oxyl ase cytoc hrome P450 and aldosterone synthase in the adrenals. Conclusions: The present results indicate that in SHR hypercholesterolaemia selectively interferes with the adrenal steroid biosynthetic pathway by reducin g the expression of 1113-hydroxylase, leading to accumulation of min eralocorticoids and sodium retention.