Expression and modulation of steroidogenic acute regulatory protein messenger ribonucleic acid in rat cardiocytes and after myocardial infarction.
We examined whether the mRNA for steroidogenic acute regulatory (StAR) protein, a crucial factor in the rate-limiting step of aldosterone biosynthesis, is expressed and regulated in rat heart. We performed quantitative RT-PCR for StAR mRNA in an in vitro and an in vivo model: purified rat neonatal cardiomyocytes in primary culture and myocardial infarction (MI) in the rat. StAR mRNA was expressed in cultured cardiomyocytes, and angiotensin II (10 nM) increased it in a time-dependent fashion (132 +/- 2.7% of controls after 24 h; n = 3; P < 0.05). Concomitantly, angiotensin II stimulated aldosterone production in the culture medium from 32.6 +/- 6.1 to 54 +/- 12.7 fmol/mg protein after 24 h (n = 8; P < 0.05). StAR mRNA levels in cardiomyocytes were dramatically reduced after 24-h treatment with dexamethasone in a concentration-dependent manner (50% inhibitory concentration, 10 nM); maximal inhibition (to 15 +/- 6% of control; P < 0.001; n = 6) was achieved with 100 nM dexamethasone. This inhibition was prevented by RU486. In the rat MI model, StAR mRNA was also present in control heart tissue and was increased 2.4-fold in the noninfarcted area of the left ventricle after MI (n = 6; P < 0.01). This effect was completely prevented by treatment with losartan (8 mg/kg per d) and spironolactone (80 mg/kg per d), which reduced StAR mRNA levels to values not different from those in non-MI controls. Thus, the mRNA for an indispensable factor in aldosterone biosynthesis, the StAR protein, is expressed in the rat heart and is up-regulated after MI. These results support the view of a local synthesis of aldosterone in the heart and of intracrine/paracrine deleterious effects of the mineralocorticoid in heart failure.
Casal
Andrés J
AJ
Division of Endocrinology and Diabetology, University Hospital, CH-1211 Geneva 14, Switzerland.
Silvestre
Jean-Sébastien
JS
Delcayre
Claude
C
Capponi
Alessandro M
AM
D000450:Aldosterone / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D005938:Glucocorticoids / Q000494:pharmacology; D008297:Male; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009203:Myocardial Infarction / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D000098682:Steroidogenic Acute Regulatory Protein
D005938:Glucocorticoids; D010750:Phosphoproteins; D012333:RNA, Messenger; D000098682:Steroidogenic Acute Regulatory Protein; D000804:Angiotensin II; D000450:Aldosterone; D003907:Dexamethasone; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases