Mineralocorticoid Receptor Affects AP-1 and Nuclear Factor-κB Activation in Angiotensin II–Induced Cardiac Injury

• Published in: Hypertension (Dallas, Tex. 1979) Tex. 1979), 2001-02, Vol.37 (2, Part 2 Suppl), p.787-793
• Main Authors: Fiebeler, Anette, Schmidt, Folke, Müller, Dominik N, Park, Joon-Keun, Dechend, Ralf, Bieringer, Markus, Shagdarsuren, Erdenechimeg, Breu, Volker, Haller, Hermann, Luft, Friedrich C
• Format: Article
• Language: English
• Subjects: Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Clinical manifestations. Epidemiology. Investigative techniques. Etiology; Medical sciences
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/01.hyp.37.2.787

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 · d), valsartan (VAL; 10 mg · kg · d), 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-β1, and the transcription factors AP-1 and nuclear factor (NF)-κB. 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-β1 were little changed. VAL and SPIRO suppressed this upregulation. Both AP-1 and NF-κB 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-κB, and bFGF. Mineralocorticoid receptor blockade downregulates these effectors and reduces angiotensin II–induced cardiac damage.