Mineralocorticoid receptor affects AP-1 and nuclear factor-kappab activation in angiotensin II-induced cardiac injury.

Abstract

Aldosterone is implicated in cardiac hypertrophy and fibrosis. We tested the role of the mineralocorticoid receptor in a model of angiotensin II-induced cardiac injury. We administered spironolactone (SPIRO; 20 mg. kg(-1). d(-1)), valsartan (VAL; 10 mg. kg(-1). d(-1)), or vehicle to rats double transgenic for the human renin and angiotensinogen genes (dTGR). We investigated basic fibroblast growth factor (bFGF), platelet-derived growth factor, transforming growth factor-beta(1), and the transcription factors AP-1 and nuclear factor (NF)-kappaB. We used immunohistochemistry, electrophoretic mobility shift assays, and TaqMan RT-PCR. Untreated dTGR developed hypertension, cardiac hypertrophy, vasculopathy, and fibrosis with a 50% mortality rates at 7 weeks. SPIRO and VAL prevented death and reversed cardiac hypertrophy, while only VAL normalized blood pressure. Both drugs prevented vasculopathy. bFGF was markedly upregulated in dTGR, whereas platelet-derived growth factor-B and transforming growth factor-beta(1) were little changed. VAL and SPIRO suppressed this upregulation. Both AP-1 and NF-kappaB were activated in dTGR compared with controls. VAL and SPIRO reduced both transcription factors and reduced bFGF, collagen I, fibronectin, and laminin in the interstitium. These findings show that aldosterone promotes hypertrophy, cardiac remodeling, and fibrosis, independent of blood pressure. The effects involve AP-1, NF-kappaB, and bFGF. Mineralocorticoid receptor blockade downregulates these effectors and reduces angiotensin II-induced cardiac damage.

• Authors: A Fiebeler, F Schmidt, D N Müller, J K Park, R Dechend, M Bieringer, E Shagdarsuren, V Breu, H Haller, F C Luft
• Journal: Hypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 37 Issue 2 Pt 2 Pg. 787-93 (Feb 2001) ISSN: 1524-4563 [Electronic] United States
• PMID: 11230374 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Mineralocorticoid Receptor Antagonists
• NF-kappa B
• Platelet-Derived Growth Factor
• RNA, Messenger
• Receptors, Mineralocorticoid
• Tetrazoles
• Transcription Factor AP-1
• Transforming Growth Factor beta
• Fibroblast Growth Factor 2
• Angiotensin II
• Spironolactone
• Aldosterone
• Valsartan
• Renin
• Valine

Topics

• Aldosterone (blood)
• Angiotensin II (genetics)
• Animals
• Animals, Genetically Modified
• Blood Pressure (drug effects)
• Body Weight
• Cardiovascular Diseases (chemically induced, metabolism, prevention & control)
• Fibroblast Growth Factor 2 (genetics, metabolism)
• Heart (drug effects)
• Immunohistochemistry
• Mineralocorticoid Receptor Antagonists
• NF-kappa B (metabolism)
• Organ Size
• Platelet-Derived Growth Factor (metabolism)
• RNA, Messenger (metabolism)
• Rats
• Receptors, Mineralocorticoid (physiology)
• Renin (genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Spironolactone (pharmacology)
• Tetrazoles (pharmacology)
• Transcription Factor AP-1 (metabolism)
• Transforming Growth Factor beta (metabolism)
• Valine (analogs & derivatives, pharmacology)
• Valsartan