Immunohistochemical and biochemical evidence for a cardiovascular mineralocorticoid receptor.

Abstract

The presence of mineralocorticoid receptors (MRs) and their physicochemical characteristics were investigated in the heart and blood vessels of rabbits. Immunohistochemical methods using the monoclonal anti-idiotypic antibody H10E, which interacts with the steroid binding domain of MRs, revealed the presence of immunoreactive material in the heart and large blood vessels. In the heart, a positive staining was observed in myocytes and endothelial cells of atria and ventricles. In vessels, MRs were detected in the aorta and pulmonary artery. They were localized in endothelial and vascular smooth muscle cells. No staining was present in the small vascular bed, arterioles, and capillaries. In all these studies, the mineralocorticoid specificity of the staining was assessed by in situ competition experiments with aldosterone and RU486, a glucocorticoid antagonist. The presence of MRs in the heart and vessels was further demonstrated by specific aldosterone binding to one class of high affinity binding sites in the cytosol of the adrenalectomized rabbit heart (Kd, 0.25 nM; maximum MR concentration, 15-20 fmol/mg protein), whose mineralocorticoid specificity has been clearly established by competition studies. Sedimentation gradient analyses revealed that the cardiovascular MR is an 8.5S hetero-oligomer that includes the heat shock protein 90. The physicochemical characteristics of the cardiovascular MRs are virtually identical to those of the renal MRs. Altogether, our results clearly demonstrate the presence of MRs in the cardiovascular system. This supports the possibility of direct aldosterone actions in the heart and blood vessels.

Spironolactone Modulates Expressions of Cardiac Mineralocorticoid Receptor and 11.BETA.-Hydroxysteroid Dehydrogenase 2 and Prevents Ventricular Remodeling in Post-Infarct Rat Hearts

“…In various epithelial cells, expression of 11β-HSD2 converts endogenous glucocorticoids to their receptor-inactive 11-keto analogs, thereby conferring aldosterone selectivity on MR (41). Although cardiac myocytes express MR with high affinities for aldosterone, corticosterone and cortisol (42,43), cardiac expression of 11β-HSD2 is reported to be extremely low, indicating that myocyte MR are primarily occupied by endogenous glucocorticoids (41). Moreover, previous reports suggest the possibility that glucocorticoids do not activate MR but act as antagonists in nonepithelial cells such as myocytes (44,45).…”

Human Endothelium: Target for Aldosterone

“…12,13 How is aldosterone-induced cell swelling and amilorideinduced cell shrinkage explained? HUVECs are known to express mineralocorticoid receptors 9 and plasma membrane sodium channels. 10 Generally, activation causes receptors to translocate into the nucleus where gene transcription is initiated.…”

“…7 A study applying atomic force microscopy (AFM) on living aortic endothelial cells showed transient cell swelling that occurred over minutes and that was prevented by a high dose of amiloride known to inhibit plasma membrane Na ϩ /H ϩ exchange. 8 Although the underlying mechanism and its physiological relevance were still unclear, attention was placed on data suggesting that endothelial cells not only synthesize aldosterone 3 but also express mineralocorticoid receptors 9 and the epithelial sodium channel. 10 In a recent article, we applied cariporide, a specific Na ϩ /H ϩ exchange inhibitor, to human umbilical venous endothelial cells (HUVECs).…”

Increased Carotid Wall Elastic Modulus and Fibronectin in Aldosterone-Salt–Treated Rats

“…6 The presence of mineralocorticoid receptors in smooth muscle cells and in endothelial cells provides strong evidence for a local action of Aldo in large vessels. 27,28 Potential mechanisms including activation of endothelin, angiotensin II, plasminogen activator inhibitor (PAI-1), transforming growth factor-␤ 1 , as well as inhibition of NO and norepinephrine uptake have been described. 29,30 Whereas aldosterone is able to increase ACE mRNA levels in neonatal rat cardiocyte cultures, 31 a reduction in plasma levels of Ang II has been reported in this model.…”