Alteration of Cardiac and Renal Functions in Transgenic Mice Overexpressing Human Mineralocorticoid Receptor

Menuet, Damien Le; Isnard, Richard; Bichara, M.; Viengchareun, Say; Muffat-Joly, Martine; Walker, Francine; Zennaro, Maria-Christina; Lombès, Marc

doi:10.1074/jbc.m103984200

Cited by 109 publications

(73 citation statements)

References 35 publications

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“…While overexpression of MR in cardiomyocytes induces spontaneous development of classical features of HF such as cardiac hypertrophy and fibrosis (Le Menuet et al. 2001; Ouvrard‐Pascaud et al. 2005), cell‐specific deletion of MR has provided divergent results depending on the cell targeted and the HF model used.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Moreover, inflammatory cells were present in the cardiac fibrosis obtained after experimental hyperaldosteronism (15), which is not the case here. Transgenic mice with overexpression of human MR in heart and kidney exhibit mild cardiopathy without cardiac fibrosis (29). These observations raise further questions about the role of the cardiac MR in the aldosteronesalt model.…”

Section: Down-expression Of Endogenous Mr Mrna Leads To Cardiac Remod-mentioning

confidence: 89%

“…A targeted approach, as used in this study, is critical to determine the role of the transgene in heart independent of its function in other cell types. This model allows analysis of the specific contribution of MR in heart, and therefore differs from previous models, in which MR expression has been altered constitutively in multiple organs by overexpression (29) or gene inactivation (10), leading to both local and systemic effects. Here we observe that decreased cardiac MR without hyperaldosteronism dramatically affects cardiac structure and function in mice, leading to cardiac hypertrophy, ventricular dysfunction, interstitial fibrosis, and heart failure.…”

Section: Heart Failure and Cardiac Remodeling Are Reversible When Mmrmentioning

confidence: 97%

Reversible cardiac fibrosis and heart failure induced by conditional expression of an antisense mRNA of the mineralocorticoid receptor in cardiomyocytes

Beggah

Escoubet

Puttini

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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Cardiac failure is a common feature in the evolution of cardiac disease. Among the determinants of cardiac failure, the reninangiotensin-aldosterone system has a central role, and antagonism of the mineralocorticoid receptor (MR) has been proposed as a therapeutic strategy. In this study, we questioned the role of the MR, not of aldosterone, on heart function, using an inducible and cardiac-specific transgenic mouse model. We have generated a conditional knock-down model by expressing solely in the heart an antisense mRNA directed against the murine MR, a transcription factor with unknown targets in cardiomyocytes. Within 2-3 mo, mice developed severe heart failure and cardiac fibrosis in the absence of hypertension or chronic hyperaldosteronism. Moreover, cardiac failure and fibrosis were fully reversible when MR antisense mRNA expression was subsequently suppressed.C ardiac failure is a major health problem with increasing incidence with aging of the population. Cardiac fibrosis is a marker of cardiac failure and a crucial determinant of myocardial heterogeneity, increasing diastolic stiffness, systolic dysfunction, and the propensity for reentry arrhythmias (1). Animal models are necessary to investigate the mechanisms of appearance and regression of cardiac remodeling and to improve therapeutic strategies. In this paper, we report on a conditional mouse transgenic model in which cardiac fibrosis can be induced and reversed. This was achieved by regulating the expression of the mineralocorticoid receptor (MR) in cardiomyocytes.Studies in both experimental animals and humans have suggested that aldosterone excess may have deleterious effects on cardiac function (2). Recently, the Randomized Aldactone Evaluation Study (RALES) showed that treatment of patients experiencing severe heart failure with spironolactone, an antagonist of the aldosterone receptor (mineralocorticoid receptor) used in the treatment of hypertension, improved both morbidity and mortality (3). These findings have resulted in the recommendation of spironolactone use in the treatment of severe heart failure (4). In RALES, the mechanisms and cellular targets involved in the beneficial effect of spironolactone action are largely unknown. Because MR is expressed in both cardiomyocytes (5) and the kidney (6), it has been difficult to separate the direct effects of signaling through the cardiac MR and indirect effects resulting from actions of the drug on renal MR. MR is a ligand-dependent transcription factor of the steroid receptor superfamily (7). In the kidney, aldosterone binding to MR increases sodium reabsorption and potassium excretion (6). Inactivating mutations of MR result in chronic renal salt wasting, and activating mutation of MR causes hypertension, underscoring the essential role of this pathway in sodium balance and the control of blood pressure (8, 9). In the heart, however, the role of MR in physiologic and pathologic situations has not been defined. A MR knockout mouse model is available (10), but these animals die in the first ...

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“…To examine the possible involvement of Ang II or other active products of the renin-angiotensin system, such as Ang [1][2][3][4][5][6][7] , in cardiac aldosterone synthesis through receptors other than AT 1A , we examined the effects of lisinopril, an ACE inhibitor. As shown in Figure 5A, treatment with lisinopril (20 mg/kg per day) significantly attenuated LV hypertrophy observed in WT mice but did not further reduce LV weight in AT 1A -KO MI mice.…”

Section: Mechanism Underlying Renin-angiotensin System-independent Almentioning

confidence: 99%

“…5,6 Although one of the primary targets of aldosterone is the kidney, there is also evidence that aldosterone directly affects cardiac tissues and causes the development of cardiac hypertrophy, fibrosis, and heart failure. 7,8 Accumulating evidence suggests production of aldosterone in cardiac tissues, particularly under pathological conditions. Aldosterone synthase (CYP11B2) is detected in the hearts of several species, including rats 9,10 and humans.…”

mentioning

confidence: 99%

Persistent Cardiac Aldosterone Synthesis in Angiotensin II Type 1A Receptor–Knockout Mice After Myocardial Infarction

et al. 2005

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Background-The renin-angiotensin-aldosterone system is implicated in the pathogenesis of heart failure. Pharmacological blockade of angiotensin II (Ang II)-dependent signaling is clinically effective in reducing cardiovascular events after myocardial infarction (MI) but still fails to completely prevent remodeling. The molecular basis underlying this Ang II-independent remodeling is unclear. Methods and Results-Acute MI was induced by coronary ligation in wild-type (WT) and angiotensin II type IA receptor-knockout (AT 1A -KO) mice. Left ventricular (LV) geometry, hemodynamics, and cardiac gene expression were evaluated on day 28. Severe LV remodeling and resultant cardiac dysfunction were observed in WT mice, whereas less marked, but still significant, LV remodeling and cardiac dysfunction were induced in AT 1A -KO mice. Gene expression levels of aldosterone synthase and the cardiac aldosterone content were both elevated in the MI hearts, even in AT 1A -KO mice. In AT 1A -KO mice treated with spironolactone (20 mg/kg per day), LV remodeling, cardiac dysfunction, and cardiac gene expression of collagens and natriuretic peptides were almost normalized. Conclusions-Our results indicate that genetic blockade of AT 1A signaling fails to arrest aldosterone production in cardiac tissues and that cardiac aldosterone plays a critical role in post-MI LV remodeling. The results suggest that spironolactone could be potentially effective in patients with MI, when used in combination with renin-angiotensin system blockade, by blocking the actions of aldosterone produced by Ang II-independent mechanisms. (Circulation. 2005;111:2157-2164.)

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Alteration of Cardiac and Renal Functions in Transgenic Mice Overexpressing Human Mineralocorticoid Receptor

Cited by 109 publications

References 35 publications

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

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

Reversible cardiac fibrosis and heart failure induced by conditional expression of an antisense mRNA of the mineralocorticoid receptor in cardiomyocytes

Persistent Cardiac Aldosterone Synthesis in Angiotensin II Type 1A Receptor–Knockout Mice After Myocardial Infarction

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