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, valsartan (VAL; 10 mg · kg Ϫ1 · d Ϫ1 ), 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-␤ 1 , and the transcription factors AP-1 and nuclear factor (NF)-B. 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-␤ 1 were little changed. VAL and SPIRO suppressed this upregulation. Both AP-1 and NF-B 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-B, and bFGF. Mineralocorticoid receptor blockade downregulates these effectors and reduces angiotensin II-induced cardiac damage. Key Words: angiotensin Ⅲ nuclear factors Ⅲ receptors, mineralocorticoid Ⅲ spironolactone I n a recent study, patients with heart failure after myocardial infarction exhibited a 30% reduced mortality rates with mineralocorticoid receptor blockade compared with control subjects. 1 A direct relationship has been shown between death and serum aldosterone concentrations in heart failure patients. 2 After myocardial infarction, the renin-angiotensin-aldosterone system contributes to cardiac remodeling; local tissue angiotensin (Ang) II and aldosterone are increased. 3,4 The effects of aldosterone on the kidney are well recognized; however, less appreciated are the facts that aldosterone also induces collagen, fibronectin, and laminin and contributes directly to fibrosis. 5-7 Vascular smooth muscle and endothelial cells respond to aldosterone with increased ITP, [Ca 2ϩ ] i , and protein kinase C activity, as well as with ion channel activation. Aldosterone-induced genes include the G protein K-Ras and several serum glucocorticoid kinase proteins. 8 Furthermore, genes important for cell cycle progression, such as c-myc, c-fos, and c-jun, are upregulated by aldosterone. 8 Aldosterone-induced cardiac fibrosis can be prevented with spironolactone (SPIRO), as well as with Ang II type 1 receptor (AT 1 ) blockade. 9 We investigated the effect of SPIRO in rats harboring the human renin and angiotensinogen genes (dTGR). They produce Ang II locally and develop hypertension and severe end-organ damage. 10 M...

Cerivastatin reduced inflammation, cell proliferation, and iNOS induction, which led to a reduction in cellular damage. Our findings suggest that 3-hydroxy-3-methylglutaryl coenzyme (HMG-CoA) reductase inhibition ameliorates Ang II-induced end-organ damage. We suggest that these effects were independent of cholesterol.

Background-3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have effects that extend beyond cholesterol reduction. We used an angiotensin (Ang) II-dependent model to test the hypothesis that cerivastatin ameliorates cardiac injury. Methods and Results-We treated rats transgenic for human renin and angiotensinogen (dTGR) chronically from weeks 4 to 7 with cerivastatin (0.5 mg/kg by gavage). We used immunohistochemistry, electrophoretic mobility shift assays, and reverse transcription-polymerase chain reaction techniques. Compared with control dTGR, dTGR treated with cerivastatin had reduced mortality, blood pressure, cardiac hypertrophy, macrophage infiltration, and collagen I, laminin, and fibronectin deposition. Basic fibroblast growth factor mRNA and protein expression were markedly reduced, as was interleukin-6 expression. The transcription factors NF-B and AP-1 were substantially less activated, although plasma cholesterol was not decreased. Conclusions-These