Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242339 (dyslipidemia)
 13,927 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Calcium channel blockers and HMG-CoA reductase inhibitors are widely used for the management of hypertension and dyslipidemia, respectively. The use of these agents in the prevention and treatment of cardiovascular disease remains largely based on their actions in lowering blood pressure and lipids. Recent clinical trials, however, indicate that certain members of these two drug classes may slow progression of disease to an extent that cannot be solely attributed to risk factor reduction. The proposed mechanisms for such pleiotropic actions include enhancement of endothelial-dependent nitric oxide bioavailability, anti-inflammatory activity, and inhibition of oxidative stress. To understand the basis for such effects, along with potential synergies, we will review the basic and clinical evidence that indicate a broader opportunity for treatment and protection of cardiovascular events by atheroprotection with these agents beyond risk factor management.
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PMID:A rationale for combined therapy with a calcium channel blocker and a statin: evaluation of basic and clinical evidence. 1650 69

There is a major defect in skin blood flow (SkBF) in people with type 2 diabetes (T2DM). This defect is associated with relatively normal nitric oxide (NO) production in the skin. The abnormal blood flow cosegregates with hypertension, dyslipidemia, abnormal fatty acid composition, a proinflammatory state, and insulin resistance. Since these covariates are an integral part of the insulin resistance syndrome, we examined the effects of the thiazoledindiones (TZDs) as insulin sensitizers for their ability to correct the abnormal blood flow. The PPARgamma rosiglitazone improved NO production to normal levels, but had a small effect on SKBF. In contrast, pioglitazone had a small effect on skin neurovascular function but a dramatic effect on reducing nitrosative stress. These effects do not appear to be due to the insulin sensitizing properties of these compounds but are associated with a reduction in indices of inflammation, hemodilution, and are likely to be due to one of the many "vascular" effects of TZDs. The role of inflammation in the disordered neurovascular function in diabetes cannot be underplayed and the possible contribution of PPARalpha agonists to alter the inflammatory state needs to be explored further. Since blood flow regulation is mediated by mechanisms other than NO, such as prostaglandins and endothelial derived hyperpolarizing factor, which, in turn, are compromised by the inflammatory state, we anticipate that activation of both the PPARgamma as well as PPARalpha should ameliorate the disordered blood flow in type 2 diabetes. While it now appears that the PPARs may have a major role to play in protection from macrovascular disease, their contribution to amelioration of the microvascular defects in type 2 diabetes has fallen short of spectacular success. In this respect, the combinations of PPARalpha, PPARbeta and PPARgamma may better serve the unique requirements for improving the microvascular defect in diabetes.
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PMID:The role of PPARs in the microvascular dysfunction in diabetes. 1678 97

Identification and management of cardiovascular risk factors, such as hypertension, diabetes mellitus, and dyslipidemia, is essential not only for prevention of cardiovascular disease, but also for slowing the progression of existing cardiovascular disease. A major underlying mechanism that links various cardiovascular risk factors and manifestations of cardiovascular disease is endothelial dysfunction, characterized by impaired nitric oxide bioactivity. Oxidative stress is an important cause of impaired nitric oxide bioactivity, and a major pathogenic mechanism of atherosclerosis. Several pharmacologic therapies, including angiotensin-converting enzyme inhibitors, calcium channel blockers, statins, and the vasodilating beta blocker nebivolol, have been shown to enhance nitric oxide bioactivity and improve endothelial function. This effect may help explain the cardioprotective benefits of these agents and may stimulate further use of nitric oxide modulation for the treatment of cardiovascular risk factors and manifestations of cardiovascular disease.
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PMID:Nitric oxide mechanisms in the pathogenesis of global risk. 1689 46

Resistance to the actions of insulin is strongly associated with the microvascular complications of diabetes. To the extent that insulin resistance leads to hyperglycemia, dyslipidemia and hypertension, this association is not surprising. It is now clear that insulin also has direct actions in the microvasculature that influence the development and progression of microvascular disease. In the healthy state, insulin appears to have only minor effects on vascular function, because of the activation of opposing mediators such as nitric oxide and endothelin-1. Diabetes and obesity, however, are associated with selective insulin resistance in the phosphatidylinositol-3-kinase signaling pathway, which leads to reduced synthesis of nitric oxide, impaired metabolic control and compensatory hyperinsulinemia. By contrast, insulin signaling via extracellular signal-regulated kinase dependent pathways is relatively unaffected in diabetes, tipping the balance of insulin's actions so that they favor abnormal vasoreactivity, angiogenesis, and other pathways implicated in microvascular complications and hypertension. In addition, preferential impairment of nonoxidative glucose metabolism leads to increased intracellular formation of advanced glycation end products, oxidative stress and activation of other pathogenic mediators. Despite a strong temporal association, a causal link between pathway-selective insulin resistance and microvascular damage remains to be established. It is possible that this association reflects a common genotype or phenotype. Nonetheless, insulin resistance remains an important marker of risk and a key target for intervention, because those patients who achieve a greater improvement of insulin sensitivity achieve better microvascular outcomes.
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PMID:Mechanisms of disease: Pathway-selective insulin resistance and microvascular complications of diabetes. 1692 78

The endothelial function declines with age, and dyslipidemia (DL) has been shown to hasten this process by favoring the generation of reactive oxygen species (ROS). Cyclooxygenase-2 (COX-2) can be induced by ROS, but its contribution to the regulation of the endothelial function is unknown. Since COX-2 inhibitors may be deleterious to the cardiovascular system, we hypothesized that DL leads to ROS-dependent endothelial damage and a protective upregulation of COX-2. Dilations to acetylcholine (ACh) of renal arteries isolated from 3-, 6-, and 12-mo-old wild-type (WT) and DL mice expressing the human ApoB-100 were recorded with or without COX inhibitors and the antioxidant N-acetyl-l-cystein (NAC). Nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) were inhibited using N(omega)-nitro-l-arginine (l-NNA) and a depolarizing solution, respectively. In WT mice, the dilation to ACh declined at 12 mo but was insensitive to COX-1/2 inhibition alone or with NAC. DL led to an early endothelial dysfunction at 6 mo, normalized, however, by NAC. At 12 mo, vascular sensitivity to ACh was further reduced by DL. At this age, selective COX-2 inhibition reduced the dilation, whereas addition of NAC improved it. In 3- and 6-mo-old WT mice, l-NNA significantly reduced the dilation, whereas it limited the dilation only in 3-mo-old DL mice. EDHF-dependent dilation remains identical in both groups. These data suggest that COX-2 activity confers endothelium-dependent vasodilatory function in aged DL mice in the face of a pro-oxidative environment. Upregulation of this pathway compensates for the early loss of the contribution of NO in DL mice.
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PMID:Aging associated with mild dyslipidemia reveals that COX-2 preserves dilation despite endothelial dysfunction. 1698 Mar 43

Lipid metabolism can modulate structural and functional characteristics of the vascular system. Recent studies suggested that dyslipidemia may also affect the hemodynamic response to salt intake through the impairment of intravascular volume regulation and cellular sodium handling. Indeed, dyslipidemia may affect sodium homeostasis through several pathways, including defective nitric oxide and eicosanoid production, enhanced renin-angiotensin system activity and increased sympathetic response. Moreover, dyslipidemia directly affects cellular membrane viscosity and modifies membrane ion transport activity. In line with this evidence, attenuation of the above mentioned mechanisms has been demonstrated after lipid-lowering treatment. From the clinical point of view, such interaction between plasma lipids and sodium homeostasis may adversely affect the clinical presentation of diseases such as salt-sensitive hypertension, congestive heart failure, renal diseases with proteinuria or sodium retention. This review considers the interplay between plasma lipids and sodium homeostasis and its potential clinical implication.
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PMID:Lipid modulation of intravascular and cellular sodium handling: mechanistic insights and potential clinical implications. 1707 5

Type 2 diabetes (DM-2) has become a major global health problem that has been fueled mainly by increasing obesity and aging of the population. Most studies show that arterial stiffening occurs across all age groups in both type 1 diabetes and DM-2, and among those with impaired fasting glucose, impaired glucose tolerance, and the metabolic syndrome. Arterial stiffening in DM-2 results, in part, from the clustering of hyperglycemia, dyslipidemia and hypertension, all of which may promote insulin resistance, oxidative stress, endothelial dysfunction, and the formation of pro-inflammatory cytokines and advanced glycosylation end-products. Likewise, aging may increase arterial stiffening by altering the proportions of elastin and collagen in the aorta. The consequences of arterial stiffening are increased pulse pressure, hypertension, and a greater risk of cardiovascular disease. Treatment strategies to reduce or prevent arterial stiffening include pharmacologic agents that block the renin-angiotensin-aldosterone system, relax vascular smooth muscle, enhance release of nitric oxide from endothelial cells, and break glycosylation end-product cross-links, and fish oil supplementation.
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PMID:Diabetes and arterial stiffening. 1707 13

Endothelium has many important functions including the control of blood-tissue permeability and vascular tonus, regulation of vascular surface properties for homeostasis and inflammation. Nitric oxide is the chief molecule in regulation of endothelial functions. Nitric oxide deficiency, which is also known as endothelial dysfunction, is the first step for the occurrence of many disease states in cardiovascular system including heart failure, hypertension, dyslipidemia, insulin resistance, diabetes mellitus, hyperhomocysteinemia and smoking. This review deals with the importance of nitric oxide for cardiovascular system. It also includes the latest improvements in the diagnosis and treatment of endothelial dysfunction.
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PMID:Nitric oxide and cardiovascular system. 1716 86

The endothelium plays a crucial role in modulating vascular function and structure. In healthy conditions, nitric oxide produced by endothelial cells exerts not only vasodilating properties, but also several other protective actions toward the vessel wall against the development of atherosclerosis and thrombosis. Traditional cardiovascular risk factors are characterized by endothelial dysfunction caused by an enhanced production of oxidative stress leading to destroy nitric oxide, thus reducing its availability. Abdominal obesity is associated with endothelial dysfunction, through direct mechanisms, such as insulin resistance and the association with risk factors (including diabetes mellitus, hypertension and dyslipidemia), and direct, by the production of adipokines and pro-inflammatory cytokines, which in turn induce oxidative stress leading to a reduced nitric oxide availability. A reduced endothelium-dependent relaxation is a predictor of cardiovascular events in high-risk patients and represents a putative clinical parameter to stratify the cardiovascular risk and a useful marker for therapy efficacy. Weight loss and a modification of lifestyle ameliorate endothelial function in obese patients, an effect due not only to a better glycemic profile, but also secondary to reduced plasma levels of inflammatory markers and adipokines. At present, whether an improvement of endothelial dysfunction secondary to weight loss is significantly associated with a better cardiovascular prognosis is still unknown. (G Ital Cardiol 2006; 7 (11): 715-723)
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PMID:[Obesity and endothelial dysfunction]. 1721 13

Dyslipidemia increases the risks for atherosclerosis in part by impairing endothelial integrity; endothelial progenitor cells (EPCs) play a pivotal role in reendothelialization. In this study, we investigated the mechanism whereby oxidized low-density lipoprotein (oxLDL) affects the function of differentiated EPCs (EDCs). In EDCs expanded in vitro from EPCs isolated from human cord blood, we measured EDC responses to both copper-oxidized LDL and L5, an electronegative LDL minimally oxidized in vivo in patients with hypercholesterolemia. OxLDL induced apoptosis of EDCs and impaired their response to nitric oxide. We found that the key to oxLDL-induced apoptosis in both EDCs and endothelial cells is the induction of a conformational change of Bax, leading to Bax activation without altering its expression. The conformationally changed Bax translocated to the mitochondria and stimulated apoptosis, as Bax knockdown prevented oxLDL-induced apoptosis in EDCs. The activation of Bax is mediated by an increase in p53 and knockdown of p53 abolished oxLDL-induced activation of Bax and apoptosis. OxLDL activated p53 through production of mitochondria-derived reactive oxygen species. In EDCs treated with a recombinant adenovirus expressing superoxide dismutase or N-acetyl-cysteine (but not catalase), the p53-Bax pathway activated by oxLDL was blocked, and apoptosis was prevented. Of importance, treatment of EDC with low-concentration L5 stimulated superoxide dismutase expression, which significantly attenuated apoptosis in EDCs exposed to high-concentration L5. These findings suggest that exposure of EDCs and endothelial cells to either experimentally prepared or naturally occurring modified LDL results in an increased transfer of mitochondria-derived superoxide anion to p53, which stimulates a conformational change in Bax favoring its translocation to the mitochondria with resultant apoptosis of these cells.
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PMID:Oxidized low-density lipoprotein stimulates p53-dependent activation of proapoptotic Bax leading to apoptosis of differentiated endothelial progenitor cells. 1728 42


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