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

Abstract

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...

Aldosterone Potentiates Angiotensin II–Induced Signaling in Vascular Smooth Muscle Cells

“…Earlier, we studied a similar rat model using Spi. 21 In that study, we also found that Spi ameliorated cardiac hypertrophy and fibrosis, largely independently of blood pressure. Taken together, these studies support the notion that Ald induces cardiac fibrosis independently of other renin-angiotensin system components.…”

Cardioprotective Mechanisms of Eplerenone on Cardiac Performance and Remodeling in Failing Rat Hearts

“…27 Recent reports on MR inhibitors demonstrated that NF-B activation was suppressed by administration of an MR inhibitor spironolactone to rats treated with continuous infusion of aldosterone 25 or to double transgenic rats harboring human renin and angiotensinogen genes (dTGR). 28 These findings suggest the possibilities that activation of NF-B-mediated induction of iNOS from the oxidative stress-LOX-1 pathway plays important roles in the pathology of heart failure and that eplerenone suppresses iNOS induction via suppressing NF-B activation through oxidative stress-LOX-1, which may lead to improvements in cardiac function and remodeling.…”

High-Salt Diet Inhibits Expression of Angiotensin Type 2 Receptor in Resistance Arteries

“…This mechanism has been postulated for the aldosteronedependent induction of epidermal growth factor receptor expression 41 and for the cardiac actions of aldosterone. 42 Numerous potential AP1 binding sites were identified in the promoter region of the human, mouse, and rat AT2R genes. 43,44 Clarification of these or other potential mechanisms mediating AT2R mRNA abundance changes will need further studies.…”