Angiotensin II and aldosterone regulate gene transcription via functional mineralocortocoid receptors in human coronary artery smooth muscle cells.
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-beta-hydroxysteroid-dehydrogenase-2 (11betaHSD2). Although previous studies support that the vasculature is a target tissue of aldosterone, MR-mediated gene expression in vascular cells has not been demonstrated or systematically explored. We investigated whether functional MR and 11betaHSD2 are expressed in human blood vessels. Human coronary and aortic vascular smooth muscle cells (VSMCs) express mRNA and protein for both MR and 11betaHSD2. The endogenous VSMC MR mediates aldosterone-dependent gene expression, which is blocked by the competitive MR antagonist spironolactone. Inhibition of 11betaHSD2 in coronary artery VSMCs enhances gene transactivation by cortisol, supporting that the VSMC 11betaHSD2 is functional. Angiotensin II also activates MR-mediated gene transcription in coronary artery VSMCs. Angiotensin II activation of MR-mediated gene expression is inhibited by both the AT1 receptor blocker losartan and by spironolactone, but not by aldosterone synthase inhibition. Microarray and quantitative RT-PCR experiments show that aldosterone activates expression of endogenous human coronary VSMC genes, including several involved in vascular fibrosis, inflammation, and calcification. These data support a new MR-dependent mechanism by which aldosterone and angiotensin II influence ischemic cardiovascular events, and suggest that ACE inhibitors and MR antagonists may decrease clinical ischemic events by inhibiting MR-dependent gene expression in vascular cells.
Jaffe
Iris Z
IZ
Molecular Cardiology Research Institute, Department of Medicine, New England Medical Center Hospitals and Tufts University School of Medicine, Boston, Mass 02111, USA.
Mendelsohn
Michael E
ME
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000096:biosynthesis / Q000235:genetics; D000256:Adenoviridae / Q000235:genetics; D000450:Aldosterone / Q000494:pharmacology / Q000502:physiology*; D000804:Angiotensin II / Q000494:pharmacology / Q000502:physiology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D001011:Aorta / Q000166:cytology; D002461:Cell Line, Transformed / Q000187:drug effects / Q000378:metabolism; D003331:Coronary Vessels / Q000166:cytology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D017930:Genes, Reporter; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology; D019808:Losartan / Q000494:pharmacology; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D008954:Models, Biological; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000187:drug effects; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology; D018161:Receptors, Mineralocorticoid / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D013148:Spironolactone / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*; D014161:Transduction, Genetic
D047228:Angiotensin II Type 1 Receptor Blockers; D044140:Receptor, Angiotensin, Type 1; D018161:Receptors, Mineralocorticoid; D000804:Angiotensin II; D013148:Spironolactone; D000450:Aldosterone; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D019808:Losartan; D006854:Hydrocortisone