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Query: UMLS:C0007222 (cardiovascular disease)
 65,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The roles of aldosterone and mineralocorticoid receptors in cardiovascular disease have been expanded, refined, and distinguished over the past decade. Primary aldosteronism has been shown to represent 8-13% (rather than <1%) of unselected hypertensive patients, and patients with primary aldosteronism to have higher indices of cardiovascular damage than controls of the same age, sex, and BP status. While this represents a clearly expanded role for aldosterone, it is improbable that the hormone (as opposed to the mineralocorticoid receptor) plays a major role in other instances of essential hypertension, in cardiac failure, or in atherosclerosis. Evidence from studies in these conditions supports a substantial role for mineralocorticoid receptor activation; low baseline aldosterone levels, and evidence from experimental in vivo studies, support a role for normal levels of physiologic glucocorticoids in activating mineralocorticoid receptors (MR) in the context of tissue damage and reactive oxygen species generation. These relatively recent insights suggest the potential therapeutic role for MR antagonists across a spectrum of cardiovascular disease, as vascular protectants even when circulating levels of aldosterone are low.
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PMID:The role of aldosterone and mineralocorticoid receptors in cardiovascular disease. 1761 Mar 42

In recent years, it has become increasingly clear that the extra-renal effects of aldosterone play an important role in the pathogenesis of cardiovascular disease. Stroke is one of the leading causes of death in the Western world, and MR (mineralocorticoid receptor) antagonism is a potential preventative therapy for patients at risk of both ischaemic and haemorrhagic strokes. This protective effect of MR antagonism appears to occur at the level of the cerebral vasculature and may be related to the expression and activation of the EGFR (epidermal growth factor receptor) and the degree of vessel wall collagen deposition.
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PMID:Is the mineralocorticoid receptor a potential target for stroke prevention? 1804 68

The last decade has witnessed tremendous progress in the understanding of the mineralocorticoid receptor (MR), its molecular mechanism of action, and its implications for physiology and pathophysiology. After the initial cloning of MR, and identification of its gene structure and promoters, it now appears as a major actor in protein-protein interaction networks. The role of transcriptional coregulators and the determinants of mineralocorticoid selectivity have been elucidated. Targeted oncogenesis and transgenic mouse models have identified unexpected sites of MR expression and novel roles for MR in non-epithelial tissues. These experimental approaches have contributed to the generation of new cell lines for the characterization of aldosterone signaling pathways, and have also facilitated a better understanding of MR physiology in the heart, vasculature, brain and adipose tissues. This review describes the structure, molecular mechanism of action and transcriptional regulation mediated by MR, emphasizing the most recent developments at the cellular and molecular level. Finally, through insights obtained from mouse models and human disease, its role in physiology and pathophysiology will be reviewed. Future investigations of MR biology should lead to new therapeutic strategies, modulating cell-specific actions in the management of cardiovascular disease, neuroprotection, mineralocorticoid resistance, and metabolic disorders.
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PMID:The mineralocorticoid receptor: insights into its molecular and (patho)physiological biology. 1817 20

Angiotensin II (Ang II) is considered the main final mediator of the renin-angiotensin-aldosterone system (RAAS). The actions of Ang II have been implicated in many cardiovascular conditions, such as hypertension, atherosclerosis, coronary heart disease, restenosis after injury, and heart failure. The Ang II type 1 receptor (AT(1)R), a G-protein-coupled receptor, mediates most of the physiological and pathophysiological actions of Ang II. This receptor is predominantly expressed in cardiovascular cells, such as vascular smooth muscle cells where it activates various signaling cascades leading to vascular remodeling and inflammation. Besides Ang II, aldosterone has emerged as an important component and mediator of the effects of the RAAS. Aldosterone-induced genomic effects mediated through binding to the mineralocorticoid receptor (MR), a member of the steroid hormone receptor superfamily, which functions as a ligand-dependent transcription factor, are characterized by a delay of minutes to hours corresponding to a long series of subcellular events that include gene activation and protein synthesis. Besides its well-known genomic actions, there is evidence of aldosterone-mediated rapid effects which lead to the activation of ion channels and other signaling pathways. Some of the effects of aldosterone occur through similar pathways as Ang II-induced signaling events. Indeed, recent studies suggest complex interactions between Ang II and aldosterone: it has become evident that aldosterone may influence the signaling or trafficking of the AT(1)R. Thus, growing evidence demonstrates the existence of cross-talk between Ang II and aldosterone which could potentially modulate Ang II signal transduction. These interactions between Ang II and aldosterone activate specific signaling pathways, sometimes in ways distinct from those that they induce on their own, one which may lead to pathogenic effects on target organs. Here we focus on recent findings and concepts that suggest the existence of novel signaling mechanisms whereby the cross-talk between Ang II and aldosterone plays a role in cardiovascular disease. We also discuss the importance of investigating Ang II/aldosterone cross-talk as a mean of developing new therapeutic strategies to combat cardiovascular disease.
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PMID:New insights on signaling cascades induced by cross-talk between angiotensin II and aldosterone. 1836 82

Metabolic syndrome is a highly predisposing condition for cardiovascular disease and could be a cause of excess salt-induced organ damage. Recently, several investigators have demonstrated that salt loading causes left ventricular diastolic dysfunction associated with increased oxidative stress and mineralocorticoid receptor activation. We, therefore, investigated whether excess salt induces cardiac diastolic dysfunction in metabolic syndrome via increased oxidative stress and upregulation of mineralocorticoid receptor signals. Thirteen-week-old spontaneously hypertensive rats and SHR/NDmcr-cps, the genetic model of metabolic syndrome, were fed a normal salt (0.5% NaCl) or high-salt (8% NaCl) diet for 4 weeks. In SHR/NDmcr-cps, salt loading induced severe hypertension, abnormal left ventricular relaxation, and perivascular fibrosis. Salt-loaded SHR/NDmcr-cps also exhibited overproduction of reactive oxygen species and upregulation of mineralocorticoid receptor-dependent gene expression, such as Na(+)/H(+) exchanger-1 and serum- and glucocorticoid-inducible kinase-1 in the cardiac tissue. However, in spontaneously hypertensive rats, salt loading did not cause these cardiac abnormalities despite a similar increase in blood pressure. An antioxidant, tempol, prevented salt-induced diastolic dysfunction, perivascular fibrosis, and upregulation of mineralocorticoid receptor signals in SHR/NDmcr-cps. Moreover, a selective mineralocorticoid receptor antagonist, eplerenone, prevented not only diastolic dysfunction but also overproduction of reactive oxygen species in salt-loaded SHR/NDmcr-cps. These results suggest that metabolic syndrome is a predisposed condition for salt-induced left ventricular diastolic dysfunction, possibly via increased oxidative stress and enhanced mineralocorticoid receptor signals.
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PMID:Salt excess causes left ventricular diastolic dysfunction in rats with metabolic disorder. 1860 4

The role of mineralocorticoids in the development of cardiovascular disease (CVD), cardiometabolic syndrome, type 2 diabetes mellitus, chronic kidney disease (CKD), and hypertension is a growing field of interest. Aldosterone, mainly through nongenomic actions that result in proliferation, fibrosis, inflammation, and tissue remodeling, has been linked to CVD and CKD. Increased circulating aldosterone is also associated with insulin resistance and impaired glucose homeostasis that contribute to the development of endothelial dysfunction, atherosclerosis, and kidney disease. Aldosterone-induced oxidative stress and inflammation play a key role in impairing insulin signaling. Mineralocorticoid receptor blockade restores insulin sensitivity, counterbalances the deleterious cardiovascular and renal effects of aldosterone, and emerges as an alternative to improve blockade of the renin-angiotensin-aldosterone system, which potentially could contribute to reduce the burden of CVD and CKD.
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PMID:The role of aldosterone in cardiovascular disease in people with diabetes and hypertension: an update. 1862 17

Hyperaldosteronism is associated with endothelial dysfunction and impaired vascular reactivity in patients with hypertension or congestive heart failure. When present, endothelial dysfunction is an independent predictor of adverse cardiovascular events. The mineralocorticoid receptor (MR) antagonists spironolactone and eplerenone reduce morbidity and mortality, and it has been suggested that this occurs, in part, as a result of improved vascular function. The routine use of MR antagonists in patients with cardiovascular disease, however, is limited by the development of gynecomastia with spironolactone use and hyperkalemia with the use of both agents. Therefore, the development of newer agents with more favorable side-effect profiles is needed.
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PMID:Mineralocorticoid receptor antagonists and endothelial function. 1872 3

The mineralocorticoid receptor (MR) plays a critical role in the maintenance of electrolyte homeostasis and blood pressure via direct effects on the distal nephron and the cardiovascular system. The MR also has an important role in the pathology of cardiovascular disease, particularly heart failure, and is therefore an attractive therapeutic target. However, renal side effects limit its use in the clinic. Previous studies of MR molecular pharmacology have been performed on its isolated ligand-binding domain (LBD); however, current evidence suggests that nuclear receptor LBDs behave differently in isolation, than in the context of the full-length receptor. To date, technical issues have precluded production of full-length MR, thereby preventing molecular and structural studies of the MR LBD in its natural context. Here, we describe expression and purification of full-length human MR (hMR). hMR was expressed in Sf9 insect cells with an N-terminal biotinylated (bt)-tag, and stabilised by addition of ligand. bt-hMR exhibited ligand-binding and transactivation properties similar to that of the native protein. Affinity purification using an avidin matrix yielded approximately 120mug MR protein from 0.5lt Sf9 culture, and the receptor was purified bound to either aldosterone or cortisol. Recombinant hMR had a molecular weight of 110-130kDa, bound an MR DNA response element in vitro and interacted with a known co-regulator, PGC-1alpha, in GST pull-down assays, indicating its functional activity. Availability of this reagent will now enable analysis of MR structure and ligand interactions in the context of the full-length receptor, a prerequisite for future development of ligand-selective MR antagonists for the treatment of cardiovascular disease.
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PMID:Purification and characterization of recombinant human mineralocorticoid receptor. 1911 86

Aldosterone is an adrenal hormone that regulates sodium, fluid, and potassium balance. Jerome Conn first described the syndrome of autonomous and excessive aldosterone secretion or "primary aldosteronism." Contrary to the historical belief, recent studies indicate that primary aldosteronism is a common cause of hypertension with a prevalence of 5-10% among general hypertensive patients. Various animal models have demonstrated that aldosterone in association with a high salt diet results in target-organ inflammation and fibrosis. Similarly, cross-sectional and observational human studies have demonstrated the association of aldosterone with development and severity of hypertension, congestive heart failure, coronary artery disease, chronic kidney disease, and metabolic syndrome. Several interventional studies have also demonstrated the beneficial effects of mineralocorticoid receptor antagonists in these disease processes, particularly hypertension, heart failure, and post myocardial infarction, further supporting the role of aldosterone in their pathogenesis. We review the role of aldosterone in these various cardiovascular disease processes along with potential mechanisms and treatment.
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PMID:Aldosterone and cardiovascular disease. 1913 16

The mineralocorticoid receptor (MR) and glucocorticoid receptor are ligand-activated transcription factors that have important physiological and pathophysiological actions in a broad range of cell types including monocytes and macrophages. While the glucocorticoids cortisol and corticosterone have well-described anti-inflammatory actions on both recruited and tissue resident macrophages, a role for the mineralocorticoid aldosterone in these cells is largely undefined. Emerging evidence, however, suggests that MR signalling may promote pro-inflammatory effects. This review will discuss the current understanding of the role of corticosteroid receptors in macrophages and their effect on diseases involving inflammation, with a particular focus on cardiovascular disease.
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PMID:Corticosteroid receptors, macrophages and cardiovascular disease. 1915 33


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