Aldosterone Stimulates Elastogenesis in Cardiac Fibroblasts via Mineralocorticoid Receptor-independent Action Involving the Consecutive Activation of Gα13, c-Src, the Insulin-like Growth Factor-I Receptor, and Phosphatidylinositol 3-Kinase/Akt

Bunda, Severa; Wang, Yanting; Mitts, Thomas F.; Liu, Peter; Arab, Sara; Arabkhari, Majid; Hinek, Aleksander

doi:10.1074/jbc.m109.008748

Cited by 48 publications

(35 citation statements)

References 75 publications

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“…It has been well documented that the persistent excessive actions of aldosterone, commonly by a combination of salt loading, cause adverse cardiovascular effects primarily via MR-dependent pathways (Matsui et al 2008. On the other hand, ourselves and others have recently reported that aldosterone exerts transient but favorable effects on cardiocytes in vitro, mainly via rapid MR-independent actions (Yamamuro et al 2006, Bunda et al 2009, Nagoshi et al 2012. In agreement with these findings, the present ex vivo study demonstrated the rapid, favorable effects of aldosterone on cardiac functional recovery and injury during ischemia-reperfusion, although aldosterone did not affect the baseline cardiac function (Table 1), congruent with the findings of previous reports by other groups (Fujita et al 2005, Matsui et al 2007).…”

Section: Discussionmentioning

confidence: 99%

Preconditioning actions of aldosterone through p38 signaling modulation in isolated rat hearts

Yoshino¹,

Nagoshi²,

Anzawa³

et al. 2014

Journal of Endocrinology

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Although persistent excessive actions of aldosterone have unfavorable effects on the cardiovascular system, primarily via mineralocorticoid receptor (MR)-dependent pathways, the pathophysiological significance of aldosterone cascade activation in heart diseases has not yet been fully clarified. We herein examined the effects of short-term aldosterone stimulation at a physiological dose on cardiac function during ischemia-reperfusion injury (IRI). In order to study the effects of aldosterone preconditioning, male Wistar rat Langendorff hearts were perfused with 10 K9 mol/l of aldosterone for 10 min before ischemia, and the response to IRI was assessed. Although aldosterone did not affect the baseline hemodynamic parameters, preconditioning actions of aldosterone significantly improved the recovery in left ventricular contractility and left ventricular end-diastolic pressure associated with a reduced activity of creatine phosphokinase released into the perfusate after ischemia-reperfusion. Notably, the MR inhibitor eplerenone did not abrogate these beneficial effects. Biochemical analyses revealed that p38MAPK phosphorylation was significantly increased during aldosterone preconditioning before ischemia, whereas its phosphorylation was substantially attenuated during sustained ischemiareperfusion, compared with the results for in the non-preconditioned control hearts. This dual regulation of p38MAPK was not affected by eplerenone. The phosphorylation levels of other MAPKs were not altered by aldosterone preconditioning. In conclusion, the temporal induction of the aldosterone cascade, at a physiological dose, has favorable effects on cardiac functional recovery and injury following ischemia-reperfusion in a MR-independent manner. Phasic dynamism of p38MAPK activation may play a key role in the physiological compensatory pathway of aldosterone under severe cardiac pathological conditions.

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Section: Discussionmentioning

confidence: 99%

Preconditioning actions of aldosterone through p38 signaling modulation in isolated rat hearts

Yoshino¹,

Nagoshi²,

Anzawa³

et al. 2014

Journal of Endocrinology

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“…This effect of Gal-3 on aldosterone actions was confirmed in human cardiac fibroblasts where aldosterone and Gal-3 showed proinflammatory and profibrotic properties in cardiac fibroblasts, increasing inflammatory markers, MMP activities, and ECM components, as it has been previously published in other cell types. 19,25 Moreover, in cardiac fibroblasts, Gal-3 silencing was able to prevent the increase in inflammatory and fibrotic markers induced by aldosterone.…”

Section: Discussionmentioning

confidence: 99%

Galectin-3 Blockade Inhibits Cardiac Inflammation and Fibrosis in Experimental Hyperaldosteronism and Hypertension

et al. 2015

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Hypertensive cardiac remodeling is accompanied by molecular inflammation and fibrosis, 2 mechanisms that finally affect cardiac function. At cardiac level, aldosterone promotes inflammation and fibrosis, although the precise mechanisms are still unclear. Galectin-3 (Gal-3), a β-galactoside–binding lectin, is associated with inflammation and fibrosis in the cardiovascular system. We herein investigated whether Gal-3 inhibition could block aldosterone-induced cardiac inflammation and fibrosis and its potential role in cardiac damage associated with hypertension. Aldosterone-salt–treated rats presented hypertension, cardiac inflammation, and fibrosis that were prevented by the pharmacological inhibition of Gal-3 with modified citrus pectin. Cardiac inflammation and fibrosis presented in spontaneously hypertensive rats were prevented by modified citrus pectin treatment, whereas Gal-3 blockade did not modify blood pressure levels. In the absence of blood pressure modifications, Gal-3 knockout mice were resistant to aldosterone-induced cardiac inflammation. In human cardiac fibroblasts, aldosterone increased Gal-3 expression via its mineralocorticoid receptor. Gal-3 and aldosterone enhanced proinflammatory and profibrotic markers, as well as metalloproteinase activities in human cardiac fibroblasts, effects that were not observed in Gal-3–silenced cells treated with aldosterone. In experimental hyperaldosteronism, the increase in Gal-3 expression was associated with cardiac inflammation and fibrosis, alterations that were prevented by Gal-3 blockade independently of blood pressure levels. These data suggest that Gal-3 could be a new molecular mechanism linking cardiac inflammation and fibrosis in situations with high-aldosterone levels, such as hypertension.

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“…1995), fibroblasts (Bunda et al. 2009), vascular smooth muscle cells (Jaffe and Mendelsohn 2005), endothelial cells (EC) (Caprio et al. 2008), and infiltrated immune cells (Bene et al.…”

Section: Introductionmentioning

confidence: 99%

Endothelial mineralocorticoid receptor contributes to systolic dysfunction induced by pressure overload without modulating cardiac hypertrophy or inflammation

et al. 2017

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Heart Failure (HF) is associated with increased circulating levels of aldosterone and systemic inflammation. Mineralocorticoid receptor (MR) antagonists block aldosterone action and decrease mortality in patients with congestive HF. However, the molecular mechanisms underlying the therapeutic benefits of MR antagonists remain unclear. MR is expressed in all cell types in the heart, including the endothelial cells (EC), in which aldosterone induces the expression of intercellular adhesion molecule 1 (ICAM‐1). Recently, we reported that ICAM‐1 regulates cardiac inflammation and cardiac function in mice subjected to transverse aortic constriction (TAC). Whether MR specifically in endothelial cells (EC) contributes to the several mechanisms of pathological cardiac remodeling and cardiac dysfunction remains unclear. Basal cardiac function and LV dimensions were comparable in mice with MR selectively deleted from ECs (EC‐MR −/−) and wild‐type littermate controls (EC‐MR +/+). MR was specifically deleted in heart EC, and in EC‐containing tissues, but not in leukocytes of TAC EC‐MR −/− mice. While EC‐MR −/− TAC mice showed preserved systolic function and some alterations in the expression of fetal genes, the proinflammatory cytokine TNF α and the endothelin receptors in the LV as compared to EC‐MR +/+ TAC mice, no difference was observed between both TAC groups in overall cardiac hypertrophy, ICAM‐1 LV expression and leukocyte infiltration, cardiac fibrosis or capillary rarefaction, all hallmarks of pathological cardiac remodeling. Our data indicate that EC‐MR contributes to the transition of cardiac hypertrophy to systolic dysfunction independently of other maladaptive changes induced by LV pressure overload.

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Aldosterone Stimulates Elastogenesis in Cardiac Fibroblasts via Mineralocorticoid Receptor-independent Action Involving the Consecutive Activation of Gα13, c-Src, the Insulin-like Growth Factor-I Receptor, and Phosphatidylinositol 3-Kinase/Akt

Cited by 48 publications

References 75 publications

Preconditioning actions of aldosterone through p38 signaling modulation in isolated rat hearts

Preconditioning actions of aldosterone through p38 signaling modulation in isolated rat hearts

Galectin-3 Blockade Inhibits Cardiac Inflammation and Fibrosis in Experimental Hyperaldosteronism and Hypertension

Endothelial mineralocorticoid receptor contributes to systolic dysfunction induced by pressure overload without modulating cardiac hypertrophy or inflammation

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