Mineralocorticoid receptors in immune cells: emerging role in cardiovascular disease.
Mineralocorticoid receptors (MRs) contribute to the pathophysiology of hypertension and cardiovascular disease in humans. As such, MR antagonists improve cardiovascular outcomes but the molecular mechanisms remain unclear. The actions of the MR in the kidney to increase blood pressure are well known, but the recent identification of MRs in immune cells has led to novel discoveries in the pathogenesis of cardiovascular disease that are reviewed here. MR regulates macrophage activation to the pro-inflammatory M1 phenotype and this process contributes to the pathogenesis of cardiovascular fibrosis in response to hypertension and to outcomes in mouse models of stroke. T lymphocytes have recently been implicated in the development of hypertension and cardiovascular fibrosis in mouse models. MR activation in vivo promotes T lymphocyte differentiation to the pro-inflammatory Th1 and Th17 subsets while decreasing the number of anti-inflammatory T regulatory lymphocytes. The mechanism likely involves activation of MR in antigen presenting dendritic cells that subsequently regulate Th1/Th17 polarization by production of cytokines. Alteration of the balance between T helper and T regulatory lymphocytes contributes to the pathogenesis of hypertension and atherosclerosis and the associated complications. B lymphocytes also express the MR and specific B lymphocyte-derived antibodies modulate the progression of atherosclerosis. However, the role of MR in B lymphocyte function remains to be explored. Overall, recent studies of MR in immune cells have identified new mechanisms by which MR activation may contribute to the pathogenesis of organ damage in patients with cardiovascular risk factors. Conversely, inhibition of leukocyte MR may contribute to the protective effects of MR antagonist drugs in cardiovascular patients. Further understanding of the role of MR in leukocyte function could yield novel drug targets for cardiovascular disease.
Tufts University School of Medicine, Boston, MA, USA.
Nicholas C
NC
Bene
Tufts University School of Medicine, Boston, MA, USA; Sackler School of Graduate Biomedical Sciences, Boston, MA, USA; Tufts Medical Center, Molecular Cardiology Research Institute, Boston, MA, USA.
Pilar
P
Alcaide
Tufts University School of Medicine, Boston, MA, USA; Sackler School of Graduate Biomedical Sciences, Boston, MA, USA.
Henry H
HH
Wortis
Tufts University School of Medicine, Boston, MA, USA; Sackler School of Graduate Biomedical Sciences, Boston, MA, USA; Tufts Medical Center, Molecular Cardiology Research Institute, Boston, MA, USA. Electronic address: ijaffe@tuftsmedicalcenter.org.
Iris Z
IZ
Jaffe
D000818:Animals; D002318:Cardiovascular Diseases / Q000378:metabolism*; D006801:Humans; D007962:Leukocytes / Q000378:metabolism*; D008954:Models, Biological; D018161:Receptors, Mineralocorticoid / Q000378:metabolism*; D012084:Renin-Angiotensin System
D018161:Receptors, Mineralocorticoid
Aldosterone; Cardiovascular disease; Hypertension; Macrophage; Mineralocorticoid receptor; T lymphocyte