Induction of Cardiac Fibrosis by Aldosterone

Lijnen, Paul; Petrov, Victor

doi:10.1006/jmcc.2000.1129

Cited by 234 publications

(133 citation statements)

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“…Collectively, different animal 35 and clinical 4 studies have emphasized the pathophysiological cardiac role of MRs. One of the more striking results of the resurgent use of the aldosterone-blocking agent spironolactone or its analogue eplerenone to treat patients with systolic LV dysfunction has been a reduction in the incidence of arrhythmias, which have been mainly related to fibrosis. 4,8,9,35 However, other protective mechanisms have been underscored. Aldosterone is the major regulator of body ion homeostasis.…”

Section: Discussionmentioning

confidence: 99%

“…The mechanisms of this action in cardiac remodeling are not fully understood. The antiarrhythmogenic benefits of MR antagonists might be linked to their role in ameliorating reactive fibrosis 8,9 and/or, alternatively, to their electrophysiological effects. Recently, we showed that aldosterone treatment of isolated myocytes mimics the electrophysiological changes that occur during cardiac remodeling.…”

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confidence: 99%

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Mineralocorticoid Receptor Antagonism Prevents the Electrical Remodeling That Precedes Cellular Hypertrophy After Myocardial Infarction

et al. 2004

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Background-Cardiac hypertrophy underlies arrhythmias and sudden death, for which mineralocorticoid receptor (MR) activity has recently been implicated. We sought to establish the sequence of ionic events that link the initiating insult and MR to hypertrophy development. Methods and Results-Using whole-cell, patch-clamp and quantitative reverse transcription-polymerase chain reaction techniques on right ventricular myocytes of a myocardial infarction (MI) rat model, we examined the cellular response over time. One week after MI, no sign of cellular hypertrophy was found, but action potential duration (APD) was lengthened. Both an increase in Ca 2ϩ current (I Ca ) and a decrease in K ϩ transient outward current (I to ) underlay this effect. Consistently, the relative expression of mRNA coding for the Ca 2ϩ channel ␣1C subunit (Ca v 1.2) increased, and that of the K ϩ channel K v 4.2 subunit decreased. Three weeks after MI, AP prolongation endured, whereas cellular hypertrophy developed. I Ca density, Ca v 1.2, and K v 4.2 mRNA levels regained control levels, but I to density remained reduced. Long-term treatment with RU28318, an MR antagonist, prevented this electrical remodeling. In a different etiologic model of abdominal aortic constriction, we confirmed that APD prolongation and modifications of ionic currents precede cellular hypertrophy. Conclusions-Electrical remodeling, which is triggered at least in part by MR activation, is an initial, early cellular response to hypertrophic insults.

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Section: Discussionmentioning

confidence: 99%

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Mineralocorticoid Receptor Antagonism Prevents the Electrical Remodeling That Precedes Cellular Hypertrophy After Myocardial Infarction

et al. 2004

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“…12,13 Renin itself has been identified as a mediator of profibrotic effects via binding to specific receptors. 14 These non-hemodynamic effects also have a role in renal kidney damage during chronic renal ischemia.…”

Section: Introductionmentioning

confidence: 99%

Aliskiren reduced renal fibrosis in mice with chronic ischemic kidney injury—beyond the direct renin inhibition

et al. 2011

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Chronic renal ischemia leads to renal fibrosis and atrophy. Activation of the renin-angiotensin-aldosterone system is one of the main mechanisms driving chronic renal ischemic injury. The aim of the present study was to define the effect of aliskiren in chronic ischemia of the kidney. Two-kidney, one-clip mice were used to study chronic renal ischemia. Aliskiren significantly lowered the blood pressure in mice with renal artery constriction (92.1±1.1 vs. 81.0±1.8 mm Hg, Po0.05). Renin expression was significantly increased in ischemic kidneys when treated with aliskiren. In addition, (Pro)renin receptor expression was decreased by aliskiren in ischemic kidneys. Aliskiren treatment significantly increased klotho expression and reduced the expression of fibrogenic cystokines, caspase-3 and Bax in ischemic kidneys. Histological examination revealed that aliskiren significantly reduced the nephrosclerosis score (4.5±1.9 vs. 7.3±0.4, Po0.05). Immunofluorescence staining also showed that aliskiren decreased the deposition of interstitial collagen I in ischemic kidneys. In conclusion, direct renin inhibition significantly reduced renal fibrosis and apoptosis following chronic renal ischemia.

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“…3 At these locations, it is regulated by similar mechanisms comparable to the renin-angiotensin aldosterone system. 4,5 Because of the fact that aldosterone acts on cardiomyocytes, cardiac fibroblasts, and endothelial cells, this hormone plays a major role in the development of heart failure, myocardial fibrosis, and endothelial dysfunction. 6 Moreover, there is much interest in the possibility of the use of aldosterone receptor blockade in patients to diminish pathological effects that can be produced by this hormone.…”

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Human Endothelium: Target for Aldosterone

et al. 2004

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Abstract-Aldosterone has long been known to control water and electrolyte balance by acting on mineralocorticoid receptors in kidney. However, recent studies demonstrated the presence of these receptors in nonclassical locations, including the cardiovascular system. We tested the hypothesis whether endothelial cells respond to aldosterone with changes in cell volume, a measure for ion-mediated water movement across the cell membrane. By means of atomic force microscopy in fluid, we measured volume of adherent human umbilical venous endothelial cells exposed for 72 hours to 10 nmol/L aldosterone. Over this period of time, cells swell by Ϸ18%. Aldosterone-induced swelling is prevented by 100 nmol/L of the mineralocorticoid receptor antagonist spironolactone, added to the primary endothelial cell culture. Aldosterone-treated cells dramatically shrink when 1 mol/L of the diuretic amiloride is applied. Cells deprived of aldosterone do not respond to amiloride. Our conclusions are: (1) aldosterone leads to sustained cell swelling inhibited by administration of spironolactone or the sodium channel blocker amiloride; (2) cells respond to amiloride after aldosterone exposure; (3) renal diuretics act on endothelial cells; and (4) Key Words: endothelium Ⅲ mineralocorticoids T he kidney is known to be the major target for aldosterone, a mineralocorticoid hormone synthesized in the adrenal cortex that acts on electrolyte transport in the distal nephron. 1 However, there is strong evidence that this hormone is also synthesized in heart 2 and blood vessels. 3 At these locations, it is regulated by similar mechanisms comparable to the renin-angiotensin aldosterone system. 4,5 Because of the fact that aldosterone acts on cardiomyocytes, cardiac fibroblasts, and endothelial cells, this hormone plays a major role in the development of heart failure, myocardial fibrosis, and endothelial dysfunction. 6 Moreover, there is much interest in the possibility of the use of aldosterone receptor blockade in patients to diminish pathological effects that can be produced by this hormone. 7 A study applying atomic force microscopy (AFM) on living aortic endothelial cells showed transient cell swelling that occurred over minutes and that was prevented by a high dose of amiloride known to inhibit plasma membrane Na ϩ /H ϩ exchange. 8 Although the underlying mechanism and its physiological relevance were still unclear, attention was placed on data suggesting that endothelial cells not only synthesize aldosterone 3 but also express mineralocorticoid receptors 9 and the epithelial sodium channel. 10 In a recent article, we applied cariporide, a specific Na ϩ /H ϩ exchange inhibitor, to human umbilical venous endothelial cells (HUVECs). 11 To our surprise, we found that the specific Na ϩ /H ϩ exchange inhibitor did not prevent aldosterone-induced cell swelling, whereas, in contrast, a low dose of amiloride known to block plasma membrane sodium channels was most effective. Taken together, these observations indicated that aldosterone triggers the "c...

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Induction of Cardiac Fibrosis by Aldosterone

Cited by 234 publications

References 87 publications

Mineralocorticoid Receptor Antagonism Prevents the Electrical Remodeling That Precedes Cellular Hypertrophy After Myocardial Infarction

Mineralocorticoid Receptor Antagonism Prevents the Electrical Remodeling That Precedes Cellular Hypertrophy After Myocardial Infarction

Aliskiren reduced renal fibrosis in mice with chronic ischemic kidney injury—beyond the direct renin inhibition

Human Endothelium: Target for Aldosterone

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