Adrenalectomy stimulates the formation of initial atherosclerotic lesions: Reversal by adrenal transplantation

Abstract

Long-term changes in the secretion of immunosuppressive adrenal-derived glucocorticoid hormones influence cardiovascular disease risk. Here we determined the consequences of changes in adrenal steroid metabolism for the development of atherosclerotic lesions in mice. Atherosclerosis-susceptible low-density-lipoprotein (LDL) receptor knockout mice were subjected to adrenalectomy (ADX) or a control (SHAM) operation and subsequently fed an atherogenic diet for 4 weeks. Atherogenic diet feeding raised plasma corticosterone levels in SHAM mice, but not adrenalectomized mice, resulting in an 83% lower (P<0.01) corticosterone level in adrenalectomized mice. Adrenalectomy was associated with a respectively 22% and 29% lower plasma level of cholesterol and triglycerides. In contrast, white blood cell counts were increased 2-fold (P<0.01) in adrenalectomized mice, which could be attributed to a significant 2.1- to 2.6-fold rise in lymphocyte (P<0.05) and monocyte (P<0.05) numbers. Probably as a result of the enhanced systemic inflammatory status, adrenalectomy was associated with a higher susceptibility for diet-induced atherosclerosis (321±18×10(3) μm(2) for ADX vs 240±31×10(3) μm(2) for SHAM; P<0.05) not withstanding the lowered cholesterol levels. Restoring adrenocortical steroid secretion - but not adrenal medulla function - and the associated downstream glucocorticoid receptor signaling in adrenalectomized mice through adrenal transplantation induced a reversal of the adrenalectomy-associated rise in white blood cell numbers, plasma monocyte chemoattractant protein 1 (MCP-1) levels, and atherosclerotic lesion development (lesion size in transplanted mice: 258±34×10(3) μm(2); P<0.05 vs ADX). In conclusion, our studies show that adrenal-derived steroids protect against the development of initial atherosclerotic lesions in LDL receptor knockout mice.

LCAT deficiency in mice is associated with a diminished adrenal glucocorticoid function

“…In contrast to the change in hepatic glucocorticoid action in LCAT KO mice, leukocyte-specifi c glucocorticoid signaling is apparently normal in these mice because the susceptibility to endotoxemia is unaffected. Such a difference in cell-specifi c glucocorticoid sensitivity (i.e., high glucocorticoid receptor sensitivity in leukocytes and low glucocorticoid receptor sensitivity in hepatocytes) has also been detected in our previous adrenalectomy and adrenal transplantation studies ( 30 ).…”

FXR agonist GW4064 increases plasma glucocorticoid levels in C57BL/6 mice

“…We recently observed that feeding mice a cholic acid-containing atherogenic diet for 4 weeks induced a sustained increase in plasma corticosterone levels (van der Sluis et al, 2012). Importantly, in the current study, we now also show that short-term treatment with the synthetic FXR agonist GW4064 induces an acute 45% increase in the plasma level of corticosterone.…”

Adrenal-Specific Scavenger Receptor BI Deficiency Induces Glucocorticoid Insufficiency and Lowers Plasma Very-Low-Density and Low-Density Lipoprotein Levels in Mice

“…Adrenaltransplanted C57BL/6 were fed an atherogenic semisynthetic cholic acid-containing high cholesterol/high fat diet (15% (wt/wt) cacao butter, 1% (wt/wt) cholesterol, and 0.5% (wt/wt) cholic acid; Hope Farms, Woerden, NL) for 10 weeks starting from 6 weeks after the adrenal transplantation to stimulate the general steroidogenic activity of the adrenals. 23 On the basis of visual examination of the residual amount present at the time of cage changes, no major difference in the average food intake was noted between the 2 experimental groups while feeding the atherogenic diet. At the end of the study, 16 weeks postadrenal transplantation, mice were fasted overnight, anesthetized, and euthanized.…”