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Abstract-Inhibition or blockade of the angiotensin-aldosterone system consistently decreases ischemic cardiovascular events in clinical trials. The steroid hormone aldosterone acts by binding to the mineralocorticoid receptor (MR), a ligand activated transcription factor that is a member of the nuclear hormone receptor superfamily. MR binds and is activated by aldosterone and cortisol with equal affinity, but MR activation by cortisol is diminished in tissues that express the cortisol-inactivating enzyme 11-␤-hydroxysteroid-dehydrogenase-2 (11␤HSD2 Key Words: hormones Ⅲ mineralocorticoid receptor Ⅲ nuclear receptors Ⅲ smooth muscle cells Ⅲ vascular biology D espite recent advances in our understanding of the biology of atherosclerosis, ischemic cardiovascular diseases remain the leading cause of morbidity and mortality in the developed world. Recent human clinical trials have shown that inhibition of the angiotensin-aldosterone system improves cardiovascular outcomes in patients with heart failure, 1-4 after myocardial infarction (MI), 5 and at high risk for MI. 6 In addition to predicted effects on blood pressure and end points such as ejection fraction and functional capacity, these studies revealed a surprising but consistent decrease in unstable angina, MI, and the need for coronary revascularization in those patients treated with angiotensin-converting enzyme-I or aldosterone antagonists. [1][2][3][4][5][6] The steroid hormone aldosterone is synthesized in the adrenal cortex in response to angiotensin II stimulation and functions to elevate systemic blood pressure through renal effects on electrolyte and volume balance. 7 Until recently, the effects of mineralocorticoids on vascular disease have been attributed solely to these renal effects on systemic blood pressure. However, the reduction in ischemic events in clinical trials of angiotensin-converting enzyme inhibition or aldosterone antagonism is significantly greater than that expected from the modest decrease in systemic blood pressure in treated patients. 3,4,6,8 In addition, in the RALES and EPHESUS studies of the aldosterone antagonists spironolactone and eplerenone, respectively, the doses of the antagonists used were below threshold for causing significant renal effects, 2,5 suggesting that the mechanism of protection by these compounds may involve effects of aldosterone on extrarenal tissues.In vitro and animal data support a direct role for mineralocorticoids in regulating vascular function and vascular smooth muscle cell (VSMC) proliferation. Spironolactone can directly relax isolated rat aortic rings. In rats with aldosterone-induced hypertension, the aldosterone antagonist eplerenone decreases carotid artery cross-sectional thickness. 12 These data are consistent with a direct effect of mineralocorticoids on VSMC function. However, the mechanism by which aldosterone may directly effect vascular pathophysiology is poorly understood. Aldosterone is a steroid hormone that binds to the mineralocorticoid receptor (MR), a ligand-activated trans...

Abstract-In

Atherosclerosis is a chronic inflammatory vascular disease and the predominant cause of heart attack and ischemic stroke. Despite the well-known sexual dimorphism in the incidence and complications of atherosclerosis, there are relatively limited data in the clinical and preclinical literature to rigorously address mechanisms underlying sex as a biological variable in atherosclerosis. In multiple histological and imaging studies, overall plaque burden and markers of inflammation appear to be greater in men than women and are predictive of cardiovascular events. However, while younger women are relatively protected from cardiovascular disease, by the seventh decade, the incidence of myocardial infarction in women ultimately surpasses that of men, suggesting an interaction between sex and age. Most preclinical studies in animal atherosclerosis models do not examine both sexes, and even in those that do, well-powered direct statistical comparisons for sex as an independent variable remain rare. This article reviews the available data. Overall, male animals appear to have more inflamed yet smaller plaques compared to female animals. Plaque inflammation is often used as a surrogate end point for plaque vulnerability in animals. The available data support the notion that rather than plaque size, plaque inflammation may be more relevant in assessing sex-specific mechanisms since the findings correlate with the sex difference in ischemic events and mortality and thus may be more reflective of the human condition. Overall, the number of preclinical studies directly comparing plaque inflammation between the sexes is extremely limited relative to the vast literature exploring atherosclerosis mechanisms. Failure to include both sexes and to address age in mechanistic atherosclerosis studies are missed opportunities to uncover underlying sex-specific mechanisms. Understanding the mechanisms driving sex as a biological variable in atherosclerotic disease is critical to future precision medicine strategies to mitigate what is still the leading cause of death of men and women worldwide.