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

Studied nature of the "blood vessels relaxing factor" derived from endothelium that was identified as nitric oxide caused intensive scientific research on nitric oxide regarding some aspects of its impact on human physiological and pathological processes. The objective of this short review is to discuss widely used (in the clinical practice) direct and indirect donors of nitric oxide and/or other agents, increasing nitric oxide concentration in human body, and their beneficial role for the prevention of atherosclerosis. Under physiological conditions, endothelium regulates the tone of blood vessels, homeostasis of which is maintained by endothelium-generated vasoconstrictors and vasodilators. The most important vasodilator and the main substance produced by the endothelium is nitric oxide. The failure of synthesis and/or the lost of nitric oxide bioavailability is the major feature of endothelial dysfunction and key factor initiating progression of atherosclerosis. The endothelial dysfunction initiates the series of events, which stimulate and aggravate the course of atherosclerosis by increasing endothelial permeability, platelet aggregation, and leukocyte adhesion, and cytokine expression. Further, the review deals with the mechanisms of action of statins, angiotensin-converting enzyme inhibitors, L-arginine, direct nitric oxide donors (nitroglycerin, isosorbide mononitrate and isosorbide dinitrate), and indirect nitric oxide donors (phosphodiesterase-V inhibitors, K(ATP) openers).
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PMID:[Endothelium and nitric oxide]. 1869 54

A 34-year-old African American woman with sickle cell disease and history of relatively severe hemolysis, chronic leg ulcers, and mild pulmonary hypertension presented with a new ischemic stroke. Recent research has suggested a syndrome of hemolysis-associated vasculopathy in patients with sickle cell disease, which features severe hemolytic anemia and leads to scavenging of nitric oxide and its biochemical precursor l-arginine. This diminished bioavailability of nitric oxide promotes a hemolysis-vascular dysfunction syndrome, which includes pulmonary hypertension, cutaneous leg ulceration, priapism, and ischemic stroke. Additional correlates of this vasculopathy include activation of endothelial cell adhesion molecules, platelets, and the vascular protectant hemeoxygenase-1. Some known risk factors for atherosclerosis are also associated with sickle cell vasculopathy, including low levels of apolipoprotein AI and high levels of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase. Identification of dysregulated vascular biology pathways in sickle vasculopathy has provided a focus for new clinical trials for therapeutic intervention, including inhaled nitric oxide, sodium nitrite, L-arginine, phosphodiesterase-5 inhibitors, niacin, inhaled carbon monoxide, and endothelin receptor antagonists. This article reviews the pathophysiology of sickle vasculopathy and the results of preliminary clinical trials of novel small-molecule therapeutics directed at abnormal vascular biology in patients with sickle cell disease.
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PMID:Evolution of novel small-molecule therapeutics targeting sickle cell vasculopathy. 1906 84

Internalization of modified low-density lipoprotein (LDL) via macrophage scavenger receptors (e.g. scavenger receptor A and CD36) is thought to play a crucial role in the development of atherosclerotic lesions. Cilostazol, an antiplatelet agent with selective phosphodiesterase 3 inhibitory action, has been reported to ameliorate atherosclerosis in mouse models. However, the effect of cilostazol on modified LDL uptake in macrophages is not known. Thus, we investigated the effect of cilostazol on LDL uptake in mouse peritoneal macrophages (MPM). Cilostazol significantly inhibited oxidized and acetylated LDL uptake in MPM, while cyclic AMP (cAMP)-elevating agents, db-cAMP and other phosphodiesterase 3 or 4 inhibitors, did not inhibit the uptake. Cilostazol did not change cytosolic cAMP levels in MPM, and a protein kinase A (PKA) inhibitor did not influence the inhibitory effects of cilostazol. Cilostazol decreased scavenger receptor A but not CD36 expression. Moreover, cilostazol significantly inhibited foam cell formation, which was represented by an increase in esterified cholesterol content. In conclusion, cilostazol significantly inhibits the uptake of modified LDL and foam cell formation in mouse peritoneal macrophages, and the inhibitory effect of cilostazol can be induced in a cAMP- and PKA-independent manner.
Atherosclerosis 2009 Jun
PMID:Cilostazol inhibits modified low-density lipoprotein uptake and foam cell formation in mouse peritoneal macrophages. 1910 34

Erectile dysfunction (ED) and endothelial dysfunction are common in individuals with multiple cardiovascular risk factors (CRFs) and are longitudinal predictors of cardiovascular events. ED is associated with systemic endothelial cell activation/dysfunction independent from CRFs or from diffuse, unrecognized vascular damage. The pathogenesis of endothelial dysfunction and ED is intimately linked through decreased expression and activation of endothelial nitric oxide (NO) synthase and the subsequent physiologic actions of NO. Furthermore, reduced biologic activity of endothelium-derived NO links atherosclerosis to ED and underscores the role of altered endothelium in the pathogenesis of both conditions. Evidence-based data suggest that daily use of phosphodiesterase type-5 inhibitors (PDE5-i) improves endothelial and erectile functions and that this benefit is lost upon drug withdrawal. Daily PDE5-i may also improve lower tract urinary symptoms related to benign prostatic hyperplasia through a reduction of adrenergic overtone. The relevance for these drugs in the prevention of complications in internal medicine diseases, i.e. cardiovascular disease, clotting disorders and autoimmune disease is uncertain. Finally, endothelial dysfunction is present in testosterone deficiency syndromes and replacement therapy is able to revert ED and to improve endothelial function. Aim of the present review is to discuss the systemic effects of drugs designed to treat ED, such as testosterone and PDE5-i, with regard to safety, unwanted effects and efficacy in improving endothelial function; finally, a goal-oriented approach to rehabilitation using daily vs. on-demand PDE5-i in difficult patients is discussed.
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PMID:Endothelial effects of drugs designed to treat erectile dysfunction. 1912 29

Intracellular cAMP is an ubiquitous intracellular second messenger that regulates important cellular functions. Intracellular cAMP levels are regulated by the enzymes adenylyl cyclase and phosphodiesterases. The role of cAMP in atherosclerosis is not widely accepted and incompletely characterized. Several reports support a role of cAMP in atherogenesis by modulating the function of vascular endothelium, the production of reactive oxygen species, the recruitment of circulating monocytes to the artery wall and their differentiation into macrophages- foam cells, by controlling the expression of pro- and anti-inflammatory interleukins, and regulating serum levels of triglycerides and cholesterol. Previous reports suggested an important role of cAMP in the modulation of atherosclerotic plaque progression by removal of excess free cholesterol from macrophages by inducing the ABCA1 secretory pathway and reducing circulating levels of cholesterol. Studies suggested a crucial role of cAMP on the development of acute coronary syndromes [(ACS); unstable angina, and acute myocardial infarction] and stroke, by modulating platelet aggregation and thrombus formation and the expression of metalloproteinases. This review focuses on the identified mechanisms and roles of cAMP in the prevention of atherosclerosis, atherogenesis, and progression of atherosclerosis and the development of ACS. Finally, it provides evidence that showed the beneficial effects that may derive from the inhibition of phosphodiesterase III and activation of adenylyl cyclase and subsequent elevation of cAMP levels. Thus, cAMP may be a possible target for the prevention and treatment of atherosclerosis.
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PMID:The role of intracellular 3'5'-cyclic adenosine monophosphate (cAMP) in atherosclerosis. 1948 5

Erectile dysfunction (ED) is observed in up to 81% of men with systemic sclerosis (SSc) and therefore should be counselled as a common complaint in this disorder. Whereas ED is frequently associated with atherosclerosis in the general population in which it is also a harbinger of cardiovascular events, ED has a different aetiology in SSc. In SSc the penile blood flow is impaired due to both myointimal proliferation of small arteries and corporal fibrosis. Data on the prevention of ED in SSc are not available. On-demand phosphodiesterase type 5 (PDE-5) inhibitors are not effective in improving erectile function, but fixed daily or alternate day regimens of long acting PDE-5 inhibitors provide a measurable, although often limited, clinical benefit. When intracavernous injections of prostaglandin E1 (alprostadil) are ineffective, the implantation of a penile prosthesis may be considered. Complex treatment options may require the involvement of urology.
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PMID:Erectile dysfunction in systemic sclerosis. 1952 6

Female sexual dysfunction (FSD) is a prevalent problem, afflicting approximately 40% of women and there are few treatment options. FSD is more typical as women age and is a progressive and widespread condition. Common symptoms associated with FSD include diminished vaginal lubrication, pain and discomfort upon intercourse, decreased sense of arousal and difficulty in achieving orgasm. Only a small percentage of women seek medical attention. In comparison to the overwhelming research and treatment for erectile dysfunction in males, specifically with the development of phosphodiesterase type 5 inhibitors, significantly less has been explored regarding FSD and treatment is primarily limited to psychological therapy. Several cardiovascular diseases have been linked with FSD including atherosclerosis, peripheral arterial disease and hypertension, all of which are also pathological conditions associated with aging and erectile dysfunction in men. Using animal models, we have expanded our understanding of FSD, however a tremendous amount is still to be learned in order to properly treat women suffering from FSD. The aim of this review is to provide the most current knowledge on FSD, advances in basic science addressing this dysfunction, and explore developing therapeutic options.
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PMID:Female sexual dysfunction: therapeutic options and experimental challenges. 1953 61

Increased expression of plasminogen activator inhibitor-1 (PAI-1) in vascular tissues is a potential factor linking diabetes to restenosis after percutaneous coronary intervention. Recent studies have shown that cilostazol, a selective type 3 phosphodiesterase inhibitor, prevents neointimal hyperplasia and in-stent thrombosis in patients with diabetes after coronary angioplasty and stent implantation. However, the molecular mechanism of this drug has not been fully elucidated. We examined whether cilostazol inhibits PAI-1 expression in vascular smooth muscle cells (VSMCs) and neointimal hyperplasia. We found that cilostazol effectively inhibits angiotensin II-, high glucose- and TGF-beta-stimulated PAI-1 expression in vivo and in vitro. Cilostazol attenuated PAI-1 expression in neointimal regions and inhibited neointimal hyperplasia after balloon injury. Cilostazol inhibited PAI-1 expression by multiple mechanisms including downregulation of TGF-beta, JNK and p38 signaling pathways. Cilostazol also inhibited transactivating activity at the PAI-1 promoter by Smad3, leading to a suppression of PAI-1 gene transcription. Taken together with its antiproliferative effect on VSMCs, this may explain how cilostazol exerts its antithrombogenic effects after angioplasty and stent implantation.
Atherosclerosis 2009 Dec
PMID:Cilostazol inhibits high glucose- and angiotensin II-induced type 1 plasminogen activator inhibitor expression in artery wall and neointimal region after vascular injury. 1958 29

Stroke is the third largest cause of death and a major cause of adult disability and mortality worldwide. Experimental evidence suggests that genetic determinants do contribute a large part to stroke risk. The identification of phosphodiesterase 4D gene as a risk factor for stroke caused a great deal of interest in stroke genetics. Many of the studies of PDE4D gene have focused on the original Icelandic findings but the association between specific SNPs and haplotypes has been inconsistent. The aim of the present study was to investigate the association of three SNPs 32 (rs 456009), 83 (rs 966221) and 87 (rs 2910829), originally described by deCODE group; with stroke in a South Indian population from Andhra Pradesh. Two hundred and fifty ischemic stroke patients and two hundred and fifty controls were included in the study. The stroke patients were sub typed according to TOAST classification. SNP 83 showed significant association with stroke in the population under study while SNPs 87 and 32 were monomorphic. Further SNP 83 was found to be significantly associated with two stroke subtypes, intracranial large artery atherosclerosis (the most frequent subtype in the population) and small artery occlusion. The association with other subtypes was found to be insignificant. Further, SNP 83 was found to be associated significantly with some conventional stroke risk factors like diabetes and smoking.
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PMID:Phosphodiesterase 4D (PDE4D) gene variants and the risk of ischemic stroke in a South Indian population. 1960 1

In 1983, a delayed and prolonged cardioprotection induced by drugs was described. This pharmacologically induced adaptation to stress represents a new trend in cardioprotection as opposed to the classical drug treatment that was based on the presence of drug-receptor binding. Such a long-lasting, delayed adaptation can be induced by non-injurious pharmacological stimuli (eg, prostacyclin and its stable analogues, catecholamines and other substances) and manifests as a marked protection against the severe consequences of ischemia; attenuation of early morphological changes (limitation in infarct size) and reduction in ventricular arrhythmias as results of coronary artery occlusion and reperfusion or ouabain toxication. The protection is time- and dose-dependent; the maximum effects occur 24 h and 48 h after drug treatment. These effects can be prolonged for a longer period by the periodic administration of maintenance doses. Concerning the mechanism of this marked delayed protection, the findings show that these adaptive stresses stimulate the adenylate cyclase/cyclic AMP (cAMP) system and result in elevation in cardiac cAMP level. This triggers the induction of Na(+)/K(+)-ATPase and activates phosphodiesterase (PDE) isoforms, most likely PDE1 and PDE4. The increased amount of PDE isoforms and activated Na(+)/K(+)-ATPase moderates ischemic myocardial potassium loss, and reduces sodium and calcium accumulation during myocardial ischemia. This also attenuates ouabain toxicity. Induction of PDE isoforms may lead to a reduction in the accumulation of excess cAMP and contribute to a lessened response to beta-adrenergic stimuli. The antiarrhythmic effects can be explained by electrophysiological changes, such as prolongations of the effective refractory period and the action potential duration during ischemia and reperfusion. The advantages of pharmacologically induced adaptation to stress in preventive therapy are that an exact dosage can be applied, the risk of the harmful effects is minimal, the protection can be prolonged, and it can be induced under pathological conditions (eg, atherosclerosis, hypercholesterolemia). Pharmacologically induced long-term protection may represent a new approach in the therapy of cardiovascular diseases.
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PMID:Pharmacological induction of delayed and prolonged cardiac protection: The role of prostanoids. 1964 89


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