Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epidemiological data have revealed that the progestogen in oral contraceptives (OCs) is involved in hypertension, ischemic heart diseases, and stroke. Atherosclerotic lesions were implicated owing to the androgenic properties of progestogens. However, atherosclerosis did not develop despite reduced high density lipoprotein (HDL) and elevated low density lipoprotein (LDL), presumably because of the strong effect of ethinyl estradiol (EE) upon induction of hepatic LDL- and remnant-receptors. A series of findings indicate that vasospasms caused by the effect of progestogens are involved in arterial thromboses. In postmenopausal women, the addition of progestogens to the estrogen treatment may trigger ischemic diseases. Estrogens exert a vasodilatory effect and stabilize the vascular tonus through the responsiveness of the endothelium, neurotransmitter release, and direct blocking of calcium channels. Progestogens increase the sensitivity of arteries to vasoconstrictory compounds and reduce blood flow. In women treated with ovulation inhibitors, and EE-induced activation of the renin-angiotensin-aldosterone system was observed. Aldosterone acts vasodilatorily, while progestogens with high affinity to the aldosterone receptor may exert a strong vasoconstrictory effect. If vascular lesions are present, the vasoconstrictory action of progestogens may cause acute ischemic attacks. Therefore, the lowest effective dose of the progestogen has to be used for replacement therapy. In hysterectomized women, the extra administration of progestogens should be avoided and in women with arterial diseases they should be prescribed with discretion. Additional progestogens given for 14 days 3 months apart may suffice for the prevention of endometrial hyperplasia. Both the EE and progestogen doses in OCs should be reduced. Progestogen-dominant ovulation inhibitors should be restricted to cases with an additional indication.
 ...
PMID:[Hormonal contraception and substitution therapy: the importance of progestogen for cardiovascular diseases]. 145

ACE inhibitors have been shown to be effective in reducing the morbidity and mortality of patients with left ventricular systolic dysfunction, but their application to clinical practice in this situation is still limited. In part, the failure to prescribe an ACE inhibitor to a patient with left ventricular systolic dysfunction is due to perceptions regarding their side effects, such as cough and renal dysfunction. Relatively few patients with left ventricular systolic dysfunction and a serum creatinine > or = 2 mg/dl receive an ACE inhibitor in clinical practice. In this situation one should consider an agent such as fosinopril, which is metabolized by the liver as well as secreted by the kidney. In patients with moderate renal dysfunction, fosinopril has been well tolerated without an increase in serum creatinine. In patients who develop cough due to an ACE inhibitor, consideration should be given to an angiotensin II type 1 receptor blocking agent, such as losartan. The relative safety and efficacy of an ACE inhibitor compared with an angiotensin II type 1 receptor blocking agent is being explored in a prospective randomized trial (Evaluation of Losartan In The Elderly [ELITE]), as well as the safety and pharmacological effectiveness of adding an angiotensin II receptor antagonist to an ACE inhibitor (Randomized Angiotensin receptor antagonists-ACE-inhibitor Study [RAAS]). There may also be a role for the combination of an aldosterone receptor antagonists and an ACE inhibitor in patients with left ventricular systolic dysfunction. Once an ACE inhibitor is administered to a patient with left ventricular systolic dysfunction it should be continued indefinitely. ACE inhibitors may be of value not only in preventing the progression of heart failure but also in reversing endothelial dysfunction and preventing the development of atherosclerosis and its consequences, such as myocardial infarction.
 ...
PMID:ACE inhibitors in heart failure: prospects and limitations. 921 Oct 22

Mechanisms that control the balance between cell proliferation and death are important in the development of vascular lesions. Rat primary smooth muscle cells were 80% inhibited by low microgram doses of hydrocortisone (HC) and 50% inhibited by nanogram concentrations of transforming growth factor-beta1 (TGF-beta1), although some lines acquired resistance in late passage. However, comparable doses of HC, or TGF-beta1, failed to inhibit most human lesion-derived cell (LDC) lines. In sensitive LDC, HC (10 microg/mL) inhibited proliferation by up to 50%, with obvious apoptosis in some lines, and TGF-beta1 inhibited proliferation by more than 90%. Collagen production, as measured by [3H]proline incorporation or RIA for type III pro-collagen, was either unaffected or increased in the LDCs by HC. These divergent responses between LDC lines were partially explained by the absence of the glucocorticoid receptor (GR) and heat shock protein 90 mRNA in 10 of 12 LDC lines, but the presence of the mineralocorticoid receptor and 11beta-hydroxysteroid dehydrogenase type II. Western blot analysis confirmed the absence of the GR protein in cells lacking GR mRNA. Immunohistochemistry of human carotid lesions showed high levels of GR in the tunica media, but large areas lacking GR in the fibrous lesion. Considering the absence of the GR in most lines, the effects of HC may be elicited through the mineralocorticoid receptor. Functional resistance to the antiproliferative and antifibrotic effects of HC may contribute to excessive wound repair in atherosclerosis and restenosis.
 ...
PMID:Glucocorticoid resistance caused by reduced expression of the glucocorticoid receptor in cells from human vascular lesions. 1032 68

Mineralocorticoids mediate a number of effects besides regulation of fluid and electrolyte balance. Recent evidence has revealed several nontraditional roles, sites of synthesis, and action for these steroids. Aldosterone, the principal mineralocorticoid in humans, appears to be synthesized in physiologically relevant amounts in both the heart and the vasculature, and plays an important role in vessel wall and myocardial remodeling. The genomic effects of aldosterone are mediated through activation of the classic mineralocorticoid receptor, whereas rapid nongenomic effects seem to involve a distinct receptor and result in activation of multiple downstream signaling pathways. Recently, several lines of evidence seem to suggest an important interaction between the nitric oxide and the aldosterone pathway in the adrenal gland and vasculature. The evolution of selective aldosterone receptor antagonists will help us understand the role that mineralocorticoids play in the pathogenesis of hypertension, heart failure, and atherosclerosis.
 ...
PMID:Aldosterone antagonists in the treatment of hypertension and target organ damage. 1135 75

Based upon the results of the RALES trial and accumulating evidence about the role of aldosterone and aldosterone receptor antagonism in various disease states, the authors anticipate that aldosterone receptor antagonists will become standard therapy, along with ACE inhibitors and beta-adrenergic receptor blocking agents, in patients with heart failure that is caused by systolic left ventricular dysfunction. Furthermore, the prospect of the use of these agents in other disease states that have implicated an activated rennin-angiotensin-aldosterone cascade, such as diastolic dysfunction, aging, and atherosclerosis, remains to be tested. Until further data from well-designed, prospective, randomized trials are available, the use of aldosterone receptor antagonists should be restricted to patients with severe or progressive heart failure caused by systolic left ventricular dysfunction in whom serum creatinine level is < or = 2.0 mg/dL and serum potassium levels are < 5.0 meq/L at baseline.
 ...
PMID:Aldosterone as a target in congestive heart failure. 1269 33

Reactive oxygen species are profoundly important for many physiologic functions and are also pivotal to numerous disease processes, particularly those involving inflammation. Much evidence has accrued demonstrating that aldosterone acts locally in many cells aside from those in the cortical collecting duct. Peripheral blood monocytes and vascular smooth muscle cells are both influenced by aldosterone to produce reactive oxygen species. This production contributes to nuclear factor kappaB (NF-kappaB) activation and the genes regulated by this transcription factor. Aldosterone thereby plays an important role in atherosclerosis and hypertension-induced vascular injury. Aldosterone interacts with angiotensin (Ang) II-induced signaling. Both aldosterone and Ang II initiate ERK1/2 and JNK signaling; the effects of the two compounds is additive and involves the epidermal growth factor receptor. Recent data suggest that reactive oxygen species, might contribute to aldosterone production in nonadrenal tissues. A novel oxidized derivative of linoleic acid is a prime candidate in this regard. Oxidative stress may impair mineralocorticoid receptor function by inhibiting aldosterone binding. The latter finding has particularly important implications for elderly persons who exhibit increased oxidative stress and who are at risk for diminished aldosterone function in the distal nephron and subsequent hyperkalemia.
 ...
PMID:The mineralocorticoid receptor and oxidative stress. 1594 91

Aldosterone may be involved in the pathogenesis of atherosclerosis. We investigated the effect of eplerenone, a selective mineralocorticoid receptor blocker, on atherosclerosis in monkeys fed a high-cholesterol diet. Monkeys fed a high-cholesterol diet for 9 months were divided into 3 groups: those treated with a low dose of eplerenone (30 mg/kg per day); those treated with a high dose of eplerenone (60 mg/kg per day); and the placebo-treated group. The normal group consisted of monkeys fed a normal diet. There were no significant differences in blood pressure and cholesterol levels between the placebo- and eplerenone-treated groups. On the other hand, monocyte chemoattractant protein-1 and malondialdehyde-modified LDL were significantly higher in the placebo-treated group than in the normal group, whereas they were suppressed in the eplerenone-treated groups. The ratio of intimal volume to total volume by intravascular ultrasound analysis imaging of the aortas was dose-dependently lower in the eplerenone-treated groups than in the placebo-treated group. Acetylcholine-induced vasorelaxation was significantly weaker in the placebo-treated group than in the normal group, but the vasorelaxation was strengthened in the eplerenone-treated groups. A significant upregulation of angiotensin-converting enzyme activity was observed in the placebo-treated group, but the activity was suppressed in the eplerenone-treated groups. In conclusion, eplerenone may strengthen the endothelium-dependent relaxation and suppress angiotensin-converting enzyme activity in the vasculature, thus preventing the development of atherosclerosis in nonhuman primates.
 ...
PMID:Eplerenone inhibits atherosclerosis in nonhuman primates. 1643 23

The endothelium is critically involved in modulating vascular tone through the release of vasodilator (mainly nitric oxide; NO) and vasoconstrictor agents. Under normal conditions the endothelium induces NO-mediated vasodilation, and opposes cell adhesion and thrombosis. Angiotensin II-induced generation of reactive oxygen species plays a key role in the pathophysiology of endothelial dysfunction by reducing NO bioavailability. Endothelial dysfunction is associated with several pathologic conditions, including hypertension and diabetes, and is characterized by altered vascular tone, inflammation, and thrombosis in the vascular wall. Inhibition of the renin-angiotensin-aldosterone system has induced beneficial effects on endothelial function in animals and humans. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists have improved endothelial function in hypertension and diabetes, slowed the progression of atherosclerosis, and reduced the risk associated with cardiovascular disease.
 ...
PMID:Inhibition of the renin angiotensin system: implications for the endothelium. 1687 78

Corticosteroid hormones (aldosterone and glucocorticoids) and their receptors are now recognized as major modulators of cardiovascular pathophysiology, but their specific roles remain elusive. Glucocorticoid hormones (GCs), which are widely used to treat acute and chronic diseases, often have adverse cardiovascular effects such as heart failure, hypertension, atherosclerosis, or metabolic alterations. The direct effects of GC on the heart are difficult to evaluate, as changes in plasma GC concentrations have multiple consequences due to the ubiquitous expression of the glucocorticoid receptor (GR), resulting in secondary effects on cardiac function. We evaluated the effects of GR on the heart in a conditional mouse model in which the GR was overexpressed solely in cardiomyocytes. The transgenic mice displayed electrocardiogram (ECG) abnormalities: a long PQ interval, increased QRS and QTc duration as well as chronic atrio-ventricular block, without cardiac hypertrophy or fibrosis. The ECG alterations were reversible on GR expression shutoff. Isolated ventricular cardiomyocytes showed major ion channel remodeling, with decreases in I(Na), I(to), and I(Kslow) activity and changes in cell calcium homeostasis (increase in C(al), in Ca2+ transients and in sarcoplasmic reticulum Ca2+ load). This phenotype differs from that observed in mice overexpressing the mineralocorticoid receptor in the heart, which displayed ventricular arrhythmia. Our mouse model highlights novel effects of GR activation in the heart indicating that GR has direct and specific cardiac effects in the mouse.
 ...
PMID:Conditional glucocorticoid receptor expression in the heart induces atrio-ventricular block. 1751 20

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.
 ...
PMID:The role of aldosterone and mineralocorticoid receptors in cardiovascular disease. 1761 Mar 42


1 2 3 4 5 Next >>