Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020473 (hyperlipidemia)
 15,891 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously demonstrated that urokinase-type plasminogen activator (uPA) is highly expressed in the aneurysmal segment of the abdominal aorta (AAA) in apolipoprotein E-deficient (apoE-/-) mice treated with angiotensin II (Ang II). In the present study, we tested the hypothesis that uPA is essential for AAA formation in this model. An osmotic minipump containing Ang II (1.44 mg/kg per day) was implanted subcutaneously into 7- to 11-month-old male mice for 1 month. Ang II induced AAA in 9 (90%) of 10 hyperlipidemic mice deficient in apoE (apoE-/-/uPA+/+ mice) but in only 2 (22%) of 9 mice deficient in both apoE and uPA (apoE-/-/uPA-/- mice) (P<0.05). Although the expansion of the suprarenal aorta was significantly less in apoE-/-/uPA-/- mice than in apoE-/-/uPA+/+ mice, the aortic diameters of the aorta immediately above or below the suprarenal aorta were similar between the 2 groups. Ang II induced AAA in 7 (39%) of 18 strain-matched wild-type C57 black/6J control mice. The incidence was significantly higher in atherosclerotic apoE-deficient (apoE-/-) mice, in which 8 (100%) of 8 mice developed AAA. Only 1 (4%) of 27 uPA-/- mice developed AAA after Ang II treatment. We conclude the following: (1) uPA plays an essential role in Ang II-induced AAA in mice with or without preexisting hyperlipidemia and atherosclerosis; (2) uPA deficiency does not affect the diameter of the nonaneurysmal portion of the aorta; and (3) atherosclerosis and/or hyperlipidemia promotes but is not essential for Ang II-induced AAA formation in this model.
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PMID:Urokinase-type plasminogen activator plays a critical role in angiotensin II-induced abdominal aortic aneurysm. 1260 Aug 80

Risk factors for progression of kidney disease include hypertension, proteinuria, male sex, obesity, diabetes mellitus, hyperlipidemia, smoking, high-protein diets, phosphate retention, and metabolic acidosis. Angiotensin II production upregulates the expression of transforming growth factor-beta1, tumor necrosis factor-alpha, nuclear factor-kappaB, and several adhesion molecules and chemoattractants. In addition to angiotensin, other vasoactive compounds, such as thromboxane A(2), endothelin, and prostaglandins, are upregulated. Treatment with one of several growth factors may ameliorate the progression of kidney disease: insulin-like growth factor-1, hepatocyte growth factor, and bone morphogenetic protein-7.
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PMID:Progression of chronic renal disease. 1261 42

The endothelial cell layer displays the features of a distributed organ and has a variety of biological functions such as keeping the balance between coagulation and fibrinolysis, expression of adhesion molecules for cells in the immune system, metabolism of noradrenaline and 5-hydroxytryptamine, and conversion of angiotensin I and bradykinin. The endothelium also regulates the underlying smooth muscle layer and vascular tone by release of endothelium-derived relaxing factors such as nitric oxide (NO), prostaglandins, and endothelium-derived hyperpolarizing factor (EDHF) as well as vasoconstricting factors such as endothelin, superoxide (O(2)(-)), and thromboxane. We have reviewed the nature, mechanisms of action, and role of these factors in regulation of vascular tone, with special emphasis on NO. By a process catalyzed by NO synthase, NO and citrulline is formed from the substrates molecular O(2) and L-arginine. The main receptor for NO is guanylyl cyclase leading to formation of smooth muscle cyclic guanosinmonophosphate and relaxation. EDHF is an endothelium-derived factor causing vasorelaxation of the underlying smooth muscle layer by hyperpolarization. The nature of EDHF is still unknown, but several candidates for EDHF have been proposed such as potassium ions, hydrogen peroxide, and epoxyeicosatrienoic acids. Prostaglandins such as prostacyclin and prostaglandin E2 binds to specific receptors followed by increases in cyclic adenosinmonophosphate and vasorelaxation, while contractile prostaglandins constrict vessels by activation of thromboxane and endoperoxidase receptors. Superoxide anions induce contraction of vascular smooth muscles cells by scavenging NO. Endothelin is a potent endothelium-derived contractile factor. The synthesis of endothelin-1 is induced by hypoxia, thrombin, interleukin-1, transforming growth factor-beta1, vasopressin, and catecholamines. Cardiovascular risk factors like age, hypertension, and hyperlipidemia are associated with impaired endothelium-dependent vasodilation either as a consequence of increased inactivation of endothelium-derived vasodilators or increased formation of endothelium-derived contracting factors. This imbalance of endothelium-derived factors plays a role for development of atheroslerosis and ischemic vascular diseases.
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PMID:[Role of nitric oxide and other endothelium-derived factors]. 1273 1

1. Overproduction of superoxide anions in the vascular wall contributes to endothelial dysfunction in vascular disease. A superoxide-generating reduced beta-nicotinamide adenine dinucleotide phosphate (NADPH) oxidase has recently been identified as a major source of oxidative radicals in vascular tissues. We studied the effects of a synthetic manganese-containing superoxide dismutase (SOD) mimetic, M40403, on NADPH oxidase-dependent superoxide generation and on endothelial dysfunction. 2. In rat aortic smooth muscle cells, NADPH (100 micro M) markedly stimulated superoxide production as detected by lucigenin (5 micro M)-enhanced chemiluminescence. M40403 reduced NADPH oxidase-dependent superoxide production in a concentration-dependent manner, with IC(50) being 31.6 micro M. In contrast, native Cu/Zn SOD (up to 300 U ml(-1)) had no effect. Angiotensin II (100 nM) increased the NADPH oxidase activity by 70%, and treatment with M40403 (10 micro M) reduced this increased superoxide to the control level. 3. In aortae from apolipoprotein(E)-deficient mice (apoE(0)) with hyperlipidemia and atherosclerosis, superoxide production is largely derived from NADPH oxidase. The attenuation of endothelial nitric oxide vasodilator function parallels the increase in vascular superoxide production at different stages of the disease. Acute incubation of such aortic rings with M40403 significantly suppressed superoxide production and improved endothelium-dependent vasorelaxation to a level comparable to that in wildtype control mice. 4. In summary, the cell-permeable SOD mimetic M40403 was found to reverse endothelial dysfunction in apoE(0) aorta ex vivo by decreasing NADPH oxidase-dependent superoxide levels. The advantages of synthetic SOD mimetics over the native Cu/Zn SOD enzyme, such as greater cell permeability and stability, confer significant therapeutic potential in vascular disease.
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PMID:Superoxide dismutase mimetic M40403 improves endothelial function in apolipoprotein(E)-deficient mice. 1287 23

Diseases such as hypertension, atherosclerosis, hyperlipidemia, and diabetes are associated with vascular functional and structural changes including endothelial dysfunction, altered contractility and vascular remodeling. Cellular events underlying these processes involve changes in vascular smooth muscle cell (VSMC) growth, apoptosis/anoikis, cell migration, inflammation, and fibrosis. Many factors influence cellular changes, of which angiotensin II (Ang II) appears to be amongst the most important. The physiological and pathophysiological actions of Ang II are mediated primarily via the Ang II type 1 receptor. Growing evidence indicates that Ang II induces its pleiotropic vascular effects through NADPH-driven generation of reactive oxygen species (ROS). ROS function as important intracellular and intercellular second messengers to modulate many downstream signaling molecules, such as protein tyrosine phosphatases, protein tyrosine kinases, transcription factors, mitogen-activated protein kinases, and ion channels. Induction of these signaling cascades leads to VSMC growth and migration, regulation of endothelial function, expression of pro-inflammatory mediators, and modification of extracellular matrix. In addition, ROS increase intracellular free Ca2+ concentration ([Ca2+]i), a major determinant of vascular reactivity. ROS influence signaling molecules by altering the intracellular redox state and by oxidative modification of proteins. In physiological conditions, these events play an important role in maintaining vascular function and integrity. Under pathological conditions ROS contribute to vascular dysfunction and remodeling through oxidative damage. The present review focuses on the biology of ROS in Ang II signaling in vascular cells and discusses how oxidative stress contributes to vascular damage in cardiovascular disease.
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PMID:Reactive oxygen species and angiotensin II signaling in vascular cells -- implications in cardiovascular disease. 1527 29

Diffuse atherosclerosis entails a 15-30% risk of plaques on renal arteries (ARAS), with a correlation with coronary atherosclerosis. Ischemia induces generation of angiotensin II (Ang II) that maintains sufficient hydrostatic pressure within the tuft to preserve the GFR. Ang II inhibition suppresses this protective mechanism. In fact, any antihypertensive drug may lead to reaching a "critical perfusion pressure". ARAS should be suspected in case of renal asymmetry. It should also be envisaged in case of "flash pulmonary edemas". Ultrasonography and renal tomography show aortic calcifications and often the outline of an abdominal aortic aneurysm. Tomodensitometry may detect large aorto-renal plaques. Spiral scanner tomography represents a progress, in terms of renal artery imaging and of renal cortical atrophy. Magnetic resonance imaging is less accurate but avoids iodine toxicity. The best noninvasive method is pulsed echo-doppler. It is particularly useful for evaluating stenoses progression. Some stenoses progress to renal atrophy and renal artery thrombosis, whereas others follow a stable course. Pulsed Doppler helps predict whether revascularization will improve renal function, according to the resistance index. Renal arteriography entails a high risk of cholesterol crystal embolism. However, it is the obligatory first step for angioplasty and stent positioning, indicated when the kidney is not atrophic. The indication for revascularization essentially depends on evaluation of the benefits vs risks of angioplasty or surgery. Some publications underscore the frequent stability of renal function and the fact that, revascularized or not, most patients will shortly die of myocardial infarction. Renal cholesterol crystal embolism (CCE) is a severe condition, which occurs when large arteries undergo surgery, aortography or interventional radiology. Anticoagulants are a frequent cause of CCE. CCE may also occur spontaneously, resulting in slowly progressive renal insufficiency. Migration of crystals in small caliber intrarenal arteries induces obstruction, followed by an inflammatory reaction. The clinical picture resembles angiitis, with laboratory evidence of inflammation along with high eosinophil counts and hypocomplementemia. Diagnosis rests on: 1) a iatrogenic event in a patient with an atherosclerotic background; 2) examination of the skin disclosing purple toes, small necrotic lesions and livedo of the lower limbs. Crystals may also be found by funduscopy. Skin or muscle biopsy are contributive in showing crystals and help avoid renal biopsy; 3) other localizations involve the mesenteric circulation and the central nervous system. Until recently, the prognosis was considered disastrous. However, a recently published treatment schedule proved efficient in reducing mortality. A last issue regarding the relationships between atherosclerosis and the kidney deserves mention. In an autopsy-based study it was shown that atherosclerosis per se is accompanied by an increase in the glomerular surface area along with a greater proportion of obsolescent glomeruli by comparison with matched controls. Finally, it should be recalled that atherogenic hyperlipidemia usually aggravates the course of any renal disease, including ARAS. Treatment with statins is indicated in all forms of atherosclerotic renal disease.
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PMID:[Atherosclerosis and the kidney]. 1689 85

The Japan Hypertension Evaluation with Angiotensin II Antagonist Losartan Therapy (J-HEALTH) study is a nationwide, prospective, multicenter observational study that was designed to enroll hypertensive Japanese patients (>30,000 subjects). The patients in this study received treatment with open-label losartan, an angiotensin II receptor antagonist, for a maximum of 5 years. This report summarizes the study protocol and the baseline characteristics of the patients. Between June 2000 and May 2002, patients were screened in all 47 prefectures around Japan. Among the 31,515 patients screened, 31,048 patients were enrolled in this study and treated with losartan at a daily dose of 25-50 mg. These patients were 62.4 +/- 12.1 years old (mean +/- SD) and the mean clinic systolic/diastolic blood pressure (BP) values were 165.3 +/- 17.3/94.3 +/- 11.7 mmHg (mean +/- SD). The complications of hyperlipidemia, diabetes mellitus, cardiovascular disease, and cerebrovascular disease were also present in 38.5%, 13.1%, 8.0%, and 4.4% of patients, respectively. Regarding the World Health Organization classification, grade 2 hypertension was most frequent in this patient cohort. Nearly 10,000 patients agreed to perform home BP monitoring and report details regarding their lifestyles at baseline. Among the patients, 4.2% had white coat hypertension at the baseline. The J-HEALTH study is expected to provide valuable information about the significance of clinic and home BP control and home BP monitoring for the management of hypertension in Japanese patients.
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PMID:Design and baseline characteristics of an observational study in Japanese patients with hypertension: Japan Hypertension Evaluation with Angiotensin II Antagonist Losartan Therapy (J-HEALTH). 1803 73

Substantial evidence suggests that the intrarenal renin-angiotensin system (RAS) plays a role in the pathogenesis of diabetic nephropathy. Although the glomerular RAS is activated in the streptozotocin (STZ)-diabetic rat, the status of the glomerular RAS in the Zucker diabetic fatty (ZDF) rat, which is a commonly used genetic model of diabetes, is not known. Angiotensinogen (AGT), angiotensin II (Ang II), angiotensin converting enzyme (ACE), and angiotensin converting enzyme 2 (ACE2) were measured in glomeruli isolated from 4-week-old STZ-diabetic rats and 32-week-old ZDF rats. Glomerular injury was evaluated by histopathologic methods. Both STZ-diabetic and ZDF rats exhibited marked hyperglycemia and renal hypertrophy, but only ZDF rats demonstrated proteinuria and glomerulosclerosis. Glomerular AGT and Ang II levels were increased significantly in STZ-diabetic compared with nondiabetic control rats, accompanied by a reduction in ACE2 activity. In contrast, glomerular AGT, Ang II, and ACE2 were similar in ZDF rats and lean controls. ACE levels were not affected by diabetes in either diabetic model. In conclusion, the glomerular RAS is activated in the STZ diabetic rat but not in the ZDF rat despite a similar degree of hyperglycemia. The mechanism of nephropathy in the ZDF rat may involve factors other than hyperglycemia and RAS activation, such as hypertension and hyperlipidemia.
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PMID:Glomerular renin angiotensin system in streptozotocin diabetic and Zucker diabetic fatty rats. 1835 68

The kidney is one of the major organs involved in whole-body homeostasis while chronic renal impairment usually leads to fat redistribution and hyperlipidemia. The aim of this study was to elucidate the role of tissue renal renin-angiotensin system (RAS) components, lipogenic peroxisome proliferator-activated receptor-gamma (PPARgamma), and cytokine TNF-alpha in the development of ectopic adipogenesis and lipid deposition. Adult male Sprague-Dawley rats were randomized into three groups: untreated uninephrectomized (UNX) rats, UNX rats treated with an angiotensin-converting enzyme inhibitor (ACEI), lisinopril, and sham-operated rats. All animals were euthanized at 10 mo postoperation. The untreated UNX rats showed increased protein expression of renin, angiotensinogen, PPARgamma, and the angiotensin II type 2 receptor (AT2R) but reduced protein expression of AT1R and TNF-alpha in their remnant kidneys. Immunofluorescence staining revealed increased reactivity of angiotensinogen and angiotensin I/II in renal tubular cells and adipocytes of the untreated UNX rats. ACEI treatment largely prevented these disorders in association with restored normolipidemia and normalized renal adipogenesis and lipid deposition. These findings support the notion that tissue RAS, PPARgamma, and TNF-alpha collectively play an important role in the renal adipogenesis and lipid metabolism.
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PMID:Renin-angiotensin system activation in renal adipogenesis. 1994 35

Cigarette smoke, hyperlipidemia, and hypertension with the risk of development and progression of atherosclerosis and associated pathologies such as abdominal aortic aneurysm (AAA) are correlated. We examined the interaction of cigarette mainstream smoke (MS) and angiotensin-II (Ang II)-induced hypertension in the atherosclerotic process using hyperlipidemic apolipoprotein E-knockout (ApoE(-/-)) mice. ApoE(-/-) mice were treated with Ang II for 4 weeks and then further exposed to MS or to fresh air for 4 weeks. AAA formation was observed in all mice treated with Ang II, regardless of smoke exposure; however, smoke exposure increased the incidence of AAA in these mice. Ang II treatment resulted in higher gene expression of matrix metalloproteinases (MMP)-2, -3, -8, -9, and -12 in the abdominal aortas, which was further increased by MS exposure. The proteolytic activity of MMP-2 and MMP-9 was also enhanced in Ang II-treated mice exposed to MS, but only minor changes were seen with either smoke exposure or Ang II treatment alone. This study shows for the first time that both formation and severity of AAA in hypertensive ApoE(-/-) mice are accelerated by exposure to MS and that the proteolytic activity of MMPs is enhanced by the combination of Ang II and MS.
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PMID:Cigarette smoke enhances abdominal aortic aneurysm formation in angiotensin II-treated apolipoprotein E-deficient mice. 2093 66


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