Mineralocorticoid receptor affects AP-1 and nuclear factor-kappa B activation in angiotensin II-Induced cardiac injury

Aldosterone is implicated in cardiac hypertrophy and fibrosis. We tested th e role of the mineralocorticoid receptor in a model of angiotensin II-induc ed 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 investi gated basic fibroblast growth factor (bFGF), platelet-derived growth factor , transforming growth factor-beta (1), and the transcription factors AP-1 a nd nuclear factor (NF)-kappaB. We used immunohistochemistry, electrophoreti c mobility shift assays, and TaqMan RT-PCR. Untreated dTGR developed hypert ension, cardiac hypertrophy, vasculopathy, and fibrosis with a 50% mortalit y rates at 7 weeks. SPIRO and VAL prevented death and reversed cardiac hype rtrophy, while only VAL normalized blood pressure. Both drugs prevented vas culopathy. 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 transc ription factors and reduced bFGF, collagen I, fibronectin, and laminin in t he interstitium. These findings show that aldosterone promotes hypertrophy, cardiac remodeling, and fibrosis, independent of blood pressure. The effec ts involve AP-1, NF-kappaB, and bFGF. Mineralocorticoid receptor blockade d ownregulates these effecters and reduces angiotensin II-induced cardiac dam age.