Mineralocorticoid receptor activation promotes vascular cell calcification.
OBJECTIVE
Clinical studies demonstrate that mineralocorticoid receptor (MR) antagonism improves outcomes in cardiovascular patients and that vascular calcification correlates with adverse cardiac events. We have recently demonstrated that human vascular smooth muscle cells (VSMCs) express functional MRs that, in response to aldosterone, modulate expression of osteogenic genes including alkaline phosphatase (ALP) and bone morphogenetic protein-2 (BMP2). This study examines the effects of MR activation by aldosterone on the process of in vitro vascular calcification.


RESULTS
Using immunoblotting and adenoviral promoter-reporter assays, we demonstrated that calcifying vascular cells (CVCs), an in vitro model of vascular calcification, express MRs that mediate both aldosterone- and cortisol-stimulated gene transcription. In this model, aldosterone stimulated ALP activity, an early marker of osteoblastic differentiation, as well as mineralization. Aldosterone antagonism with spironolactone abolished both effects implicating CVC MRs in the mechanism of aldosterone-stimulated vascular calcification. Inhibition of BMP2 signaling by overexpression of dominant negative BMP2 receptor did not attenuate aldosterone-induced osteoblastic differentiation.


CONCLUSIONS
Aldosterone activation of MR promotes osteoblastic differentiation and mineralization of VSMCs independent of BMP2 signaling. These data provide a mechanistic link between hormone-mediated VSMC MR activation and vascular calcification, two processes associated with increased risk of cardiovascular ischemic events in humans.
Jaffe
Iris Z
IZ
Tufts University School of Medicine, New England Medical Center, Molecular Cardiology Research Institute, 750 Washington St, Box 80, Boston, MA 02111, USA. ijaffe@tufts-nemc.org
Tintut
Yin
Y
Newfell
Brenna G
BG
Demer
Linda L
LL
Mendelsohn
Michael E
ME
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000378:metabolism; D000305:Adrenal Cortex Hormones / Q000494:pharmacology; D000450:Aldosterone / Q000494:pharmacology; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001011:Aorta; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002114:Calcinosis / Q000201:enzymology / Q000209:etiology* / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D003331:Coronary Vessels; D006801:Humans; D008903:Minerals / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000201:enzymology / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014652:Vascular Diseases / Q000201:enzymology / Q000209:etiology* / Q000378:metabolism
D000305:Adrenal Cortex Hormones; C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D008903:Minerals; D018161:Receptors, Mineralocorticoid; D016212:Transforming Growth Factor beta; D000450:Aldosterone; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D000469:Alkaline Phosphatase