Sex Differences in the Role of the Endothelial Mineralocorticoid Receptor in Vascular Inflammation in Atherosclerosis

Abstract

BackgroundAtherosclerosis is a vascular inflammatory condition that underlies nearly all myocardial infarctions (MI) and ischemic strokes and is the leading cause of death in America for men and women. Prior to menopause, women are protected relative to men from the rupture of atherosclerotic plaques that leads to MI, through unknown mechanisms. Inflammation of atherosclerotic plaques is a risk factor for rupture; therefore it is critical to understand the mechanisms driving plaque inflammation to prevent downstream adverse cardiovascular events. Clinical data indicate that serum levels of the hormone aldosterone correlate with risk of MI and death, and animal models demonstrate a role for the aldosterone‐binding mineralocorticoid receptor (MR) in atherosclerosis in males. However, the role of the MR in atherosclerosis in females has never been studied. This study explores the role of the MR in atherosclerosis in both sexes and characterizes a sex‐specific role of endothelial cell MR (EC‐MR) in vascular inflammation.ResultsIn a mouse atherosclerosis model induced by viral expression of active human PCSK9, MR inhibition with spironolactone reduced inflammation in males but not females. To investigate the mechanism for this sex difference, atherosclerosis and vascular inflammation were assessed in male and female mice with EC‐MR deletion compared to MR‐intact littermates. EC‐MR deletion did not affect plaque size in either sex but reduced plaque inflammation specifically in male mice, as quantified by flow cytometry of the aortic arch. Female MR‐intact mice had larger but less inflamed plaques relative to males, and the protection from inflammation was abolished with EC‐MR deletion in females. In human cultured ECs, spironolactone reduced leukocyte adhesion and promoter activity and protein expression of intracellular adhesion molecule‐1, only in the absence of estrogen. Further studies are underway to characterize the contribution of EC‐MR to leukocyte rolling and adhesion, using novel intravital microscopy methods.ConclusionMR inhibition attenuates atherosclerotic plaque inflammation specifically in male mice, with no effect in females. This is mediated by a sex difference in the role of EC‐MR in vascular inflammation. As inflammation is linked with risk of rupture and thrombosis of atherosclerotic plaques, leading to death from cardiovascular ischemia, this study supports targeting of EC‐MR in males to reduce the risk of plaque rupture. Further, this study suggests a new mechanism for differences in the incidence of MI between men and premenopausal women.Support or Funding InformationFunding from NIH/NHLBI HL095590 (to IZJ), AHA EIA18290005 (to IZJ), AHA 17PRE32910003 (to MEM), and NIH/NHLBI F30HL137255 (to MEM).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.