Mineralocorticoid modulation of cardiac ryanodine receptor activity is associated with downregulation of FK506-binding proteins.
ABSTRACT The mineralocorticoid pathway is involved in cardiac arrhythmias associated with heart failure through mechanisms that are incompletely understood. Defective regulation of the cardiac ryanodine receptor (RyR) is an important cause of the initiation of arrhythmias. Here, we examined whether the aldosterone pathway might modulate RyR function.
Using the whole-cell patch clamp method, we observed an increase in the occurrence of delayed afterdepolarizations during action potential recordings in isolated adult rat ventricular myocytes exposed for 48 hours to aldosterone 100 nmol/L, in freshly isolated myocytes from transgenic mice with human mineralocorticoid receptor expression in the heart, and in wild-type littermates treated with aldosterone. Sarcoplasmic reticulum Ca(2+) load and RyR expression were not altered; however, RyR activity, visualized in situ by confocal microscopy, was increased in all cells, as evidenced by an increased occurrence and redistribution to long-lasting and broader populations of spontaneous Ca(2+) sparks. These changes were associated with downregulation of FK506-binding proteins (FKBP12 and 12.6), regulatory proteins of the RyR macromolecular complex.
We suggest that in addition to modulation of Ca(2+) influx, overstimulation of the cardiac mineralocorticoid pathway in the heart might be a major upstream factor for aberrant Ca(2+) release during diastole, which contributes to cardiac arrhythmia in heart failure.
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ABSTRACT: Pulmonary arterial hypertension (PAH) is associated with aberrant pulmonary vascular remodeling that leads to increased pulmonary artery pressure, pulmonary vascular resistance, and right ventricular dysfunction. There is now accumulating evidence that the renin-angiotensin-aldosterone system is activated and contributes to cardiopulmonary remodeling that occurs in PAH. Increased plasma and lung tissue levels of angiotensin and aldosterone have been detected in experimental models of PAH and shown to correlate with cardiopulmonary hemodynamics and pulmonary vascular remodeling. These processes are abrogated by treatment with angiotensin receptor or mineralocorticoid receptor antagonists. At a cellular level, angiotensin and aldosterone activate oxidant stress signaling pathways that decrease levels of bioavailable nitric oxide, increase inflammation, and promote cell proliferation, migration, extracellular matrix remodeling, and fibrosis. Clinically, enhanced renin-angiotensin activity and elevated levels of aldosterone have been detected in patients with PAH, which suggests a role for angiotensin and mineralocorticoid receptor antagonists in the treatment of PAH. This review will examine the current evidence linking renin-angiotensin-aldosterone system activation to PAH with an emphasis on the cellular and molecular mechanisms that are modulated by aldosterone and may be of importance for the pathobiology of PAH.Pulmonary circulation. 06/2014; 4(2):200-10.
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ABSTRACT: The first aldosterone blocker, spironolactone, initially was used as a diuretic but was accompanied by a significant amount of side effects that necessitated the withdrawal of the drug in a relevant number of patients. The discovery of the many receptor-mediated actions of aldosterone in several different organs greatly contributed to expand the indications of aldosterone blockers. Eplerenone was the second component of this class of drugs and differed from spironolactone because of its significantly better safety, albeit this was accompanied by a lower potency when used at equinumeric doses. Although these two drugs were being used in clinical practice, the epithelial sodium channel blockers, amiloride and triamterene, with a similar antialdosterone action, continued to be used in clinical practice in combination with thiazides and loop diuretics. New members of the third and fourth generation of mineralocorticoid receptor antagonists and aldosterone synthase inhibitors are in development. These new compounds, which include the new nonsteroidal mineralocorticoid-receptor antagonists and aldosterone synthase inhibitors, try to maintain adequate efficacy, avoiding the drawbacks of spironolactone and eplerenone. Ongoing studies will show the certainty of the capacities of these new compounds to override the virtues of the first mineralocorticoid-receptor spironolactone while avoiding the side effects leading so frequently to the withdrawal of the drug, including a significantly lower prevalence of hyperkalemia when chronic kidney disease is present.Seminars in Nephrology 01/2014; · 2.83 Impact Factor
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ABSTRACT: Cardiac toxicity is a side-effect of anti-cancer treatment including radiotherapy and this translational study was initiated to characterize radiation-induced cardiac side effects in a population of breast cancer patients and in experimental models in order to identify novel therapeutic target. The size of the heart was evaluated in CO-HO-RT patients by measuring the Cardiac-Contact-Distance before and after radiotherapy (48months of follow-up). In parallel, fibrogenic signals were studied in a severe case of human radiation-induced pericarditis. Lastly, radiation-induced cardiac damage was studied in mice and in rat neonatal cardiac cardiomyocytes. In patients, time dependent enhancement of the CCD was measured suggesting occurrence of cardiac hypertrophy. In the case of human radiation-induced pericarditis, we measured the activation of fibrogenic (CTGF, RhoA) and remodeling (MMP2) signals. In irradiated mice, we documented decreased contractile function, enlargement of the ventricular cavity and long-term modification of the time constant of decay of Ca(2+) transients. Both hypertrophy and amyloid deposition were correlated with the induction of Epac-1; whereas radiation-induced fibrosis correlated with Rho/CTGF activation. Transactivation studies support Epac contribution in hypertrophy stimulation and showed that radiotherapy and Epac displayed specific and synergistic signals. Epac-1 has been identified as a novel regulator of radiation-induced hypertrophy and amyloidosis but not fibrosis in the heart.Radiotherapy and Oncology 04/2014; · 4.52 Impact Factor