title: Mineralocorticoid receptor expression in human venous smooth muscle cells: a potential role for aldosterone signaling in vein graft arterialization.
abstract: Experimental studies have suggested a role for the local renin-angiotensin-aldosterone system in the response to vascular injury. Clinical data support that aldosterone, via activation of the mineralocorticoid receptor (MR), is an important mediator of vascular damage in humans with cardiovascular disease. In mineralocorticoid-sensitive target tissue, aldosterone specificity for MR is conferred enzymatically by the cortisol-inactivating enzyme 11β-hydroxysteroid-dehydrogenase-2 (11βHSD2). However, the role of MR/aldosterone signaling in the venous system has not been explored. We hypothesized that MR expression and signaling in venous smooth muscle cells contributes to the arterialization of venous conduits and the injury response in vein bypass grafts. MR immunostaining was observed in all samples of excised human peripheral vein graft lesions and in explanted experimental rabbit carotid interposition vein grafts, with minimal staining in control greater saphenous vein. We also found upregulated transcriptional expression of both MR and 11βHSD2 in human vein graft and rabbit vein graft, whereas control greater saphenous vein expressed minimal MR and no detectable 11βHSD2. The expression of MR and 11βHSD2 was confirmed in cultured human saphenous venous smooth muscle cells (hSVSMCs). Using an adenovirus containing a MR response element-driven reporter gene, we demonstrate that MR in hSVSMCs is capable of mediating aldosterone-induced gene activation. The functional significance for MR signaling in hSVSMCs is supported by the aldosterone-induced increase of angiotensin II type-1 receptor gene expression that was inhibited by the MR antagonist spironolactone. The upregulation of MR and 11βHSD2 suggests that aldosterone-mediated tissue injury plays a role in vein graft arterialization.
authors.affiliation: Div. of Vascular and Endovascular Surgery, Univ. of California San Francisco, 400 Parnassus Ave., Ste. A581, San Francisco, CA 94143-0222, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Bafford
authors.forename: Xin Xin
authors.initials: XX
authors.lastname: Sui
authors.forename: Min
authors.initials: M
authors.lastname: Park
authors.forename: Takuya
authors.initials: T
authors.lastname: Miyahara
authors.forename: Brenna G
authors.initials: BG
authors.lastname: Newfell
authors.forename: Iris Z
authors.initials: IZ
authors.lastname: Jaffe
authors.forename: Jose R
authors.initials: JR
authors.lastname: Romero
authors.forename: Gail K
authors.initials: GK
authors.lastname: Adler
authors.forename: Gordon H
authors.initials: GH
authors.lastname: Williams
authors.forename: Raouf A
authors.initials: RA
authors.lastname: Khalil
authors.forename: Michael S
authors.initials: MS
authors.lastname: Conte
mesh_terms: D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000096:biosynthesis / Q000235:genetics; D000450:Aldosterone / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D001158:Arteries / Q000502:physiology*; D002339:Carotid Arteries / Q000502:physiology; D015870:Gene Expression / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000502:physiology*; D011817:Rabbits; D044140:Receptor, Angiotensin, Type 1 / Q000096:biosynthesis; D018161:Receptors, Mineralocorticoid / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012501:Saphenous Vein / Q000166:cytology / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology; D014680:Veins / Q000502:physiology* / Q000637:transplantation*
chemical_list: D044140:Receptor, Angiotensin, Type 1; D018161:Receptors, Mineralocorticoid; D000450:Aldosterone; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2