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)

The obese Zucker rat represents a model of obesity combined with insulin resistance and hyperlipidaemia, which over a period of several months develops spontaneous glomerulosclerosis. The present study addressed the question as to whether glomerular sclerosis was associated with alterations in the degradation of matrix components. In the early phase (up to 6 months) glomeruli from obese rats displayed increased total collagen content (+64%) and decreased gelatinolytic activity (-34%) as compared to lean control animals. This decline in glomerular gelatinolytic activity was due to a reduction in gelatinase B [matrix metalloproteinase (MMP)-9]. Glomerular MMP-9 mRNA was reduced 4.6 +/- 0.6-fold (n = 3; p < 0.05), MMP-9 protein was not detectable by Western blotting and MMP-9 activity was considerably suppressed in gelatin zymograms. MMP-2, in terms of mRNA expression and activity, was unchanged. Tissue inhibitor of metalloproteinases (TIMP)-1 mRNA expression, TIMP-1 protein (immunohistochemistry) and TIMP-1 activity (reverse zymography) were enhanced in glomeruli from obese rats, while TIMP-2 mRNA remained unchanged. Moreover, mRNA for the alpha 1 IV collagen chain was 2.1 +/- 0.8-fold higher in glomeruli isolated from obese animals (n = 3; p < 0.05). These findings indicate that matrix expansion in glomeruli from obese Zucker rats is due to both enhanced synthesis of matrix components as well as reduced degradation by matrix metalloproteinases. Apparently the latter effect is based on a reduction in MMP-9 and up-regulation of its inhibitor TIMP-1.
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PMID:Differential regulation of glomerular gelatinase B (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in obese Zucker rats. 930 Feb 40

Diabetic nephropathy is related to glomerular extracellular matrix (ECM) accumulation that leads to glomerulosclerosis. Fluvastatin as a lipid-lowering medicine significantly prevents diabetic nephropathy, probably not only through its lipid-lowering action, but also mainly through its direct suppression of glomerular ECM accumulation. To test this hypothesis, in the present study, a five-sixths nephrectomized (5/6Nx) rat model to induce a renal ECM accumulation without coexistence of hyperlipidemia was used to investigate the effect of fluvastatin on renal function, glomerular ECM accumulation and expression of connective tissue growth factor (CTGF). 5/6Nx induced a significant nephropathy in rats at 13 weeks, indicated by renal dysfunction including increases in blood urine nitrogen, creatinine and urinary protein excretion, and renal histopathological changes. Administration of fluvastatin significantly prevented the renal dysfunction and histological abnormalities in the 5/6Nx rats. Furthermore, both significant suppression of matrix metalloproteinases (MMPs) activity such as MMP-2 and significant activation of tissue inhibitors of MMP (TIMPs) such as TIMP-2 observed in the 5/6Nx rats were almost completely prevented by fluvastatin, resulting in a significant prevention of glomerular ECM accumulation. For upstream mediator of ECM accumulation, 5/6Nx significantly up-regulated CTGF mRNA expression, but fluvastatin treatment prevented CTGF up-regulation. These results suggest that fluvastatin, as one of well-known lipid-lowering agents, plays an important role in the prevention of nephropathy, likely through suppression of CTGF-mediated ECM accumulation. Therefore, fluvastatin may be a potential candidate for developing a pharmaceutical approach to the prevention of diabetic nephropathy due to its both lipid-lowering and direct anti-renal ECM accumulation actions.
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PMID:Fluvastatin prevents nephropathy likely through suppression of connective tissue growth factor-mediated extracellular matrix accumulation. 1473 71

Hyperlipidemia attenuates the cardioprotective effect of preconditioning via unknown mechanisms. We have reported previously that in normolipidemic rats, preconditioning decreased ischemia-induced activation and release of myocardial matrix metalloproteinase (MMP)-2 into the coronary perfusate. Here, we investigated whether hyperlipidemia interferes with the cardioprotective effect of preconditioning through modulation of MMP-2. Hearts isolated from male Wistar rats fed 2% cholesterol-enriched or control chow for 9 weeks were subjected to a preconditioning protocol (three intermittent periods of ischemia/reperfusion of 5-min duration each) or a time-matched nonpreconditioning protocol. This was followed by a test ischemia/reperfusion (30-min ischemia and 120-min reperfusion) in both groups. Preconditioning decreased infarct size in the control but not the cholesterol-fed group. Cardioprotection in the preconditioned control group but not in the cholesterol-fed group was associated with an 18 +/- 3% (p < 0.05) inhibition of test ischemia/reperfusion-induced activation and release of myocardial MMP-2 into the perfusate. Myocardial protein levels of tissue inhibitors of MMPs [tissue inhibitor of metalloproteinases (TIMP)-2 and TIMP-4] were not changed in either group. A reduction of infarct size in nonpreconditioned hearts from both control and cholesterol-fed group was produced by the MMP inhibitor ilomastat at 0.25 microM, a concentration producing MMP-2 inhibition comparable with that of preconditioning in the control group. We conclude that hyperlipidemia blocks preconditioning-induced cardioprotection, hyperlipidemia abolishes preconditioning-induced inhibition of myocardial MMP-2 activation and release, preconditioning-induced inhibition of MMP-2 activation and release is not mediated by TIMPs, and pharmacological inhibition of MMPs produces cardioprotection in both normal and hyperlipidemic rats.
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PMID:Hyperlipidemia attenuates the infarct size-limiting effect of ischemic preconditioning: role of matrix metalloproteinase-2 inhibition. 1616 72

Recent evidences suggest that modulation of vascular structure by matrix metalloproteinases (MMPs) could be a main determinant of acute cardiovascular events in high-risk subjects. The authors consecutively selected 46 subjects affected by familial combined hyperlipidemia (FCH), 44 by metabolic syndrome (MS), 44 by FCH and MS, and 40 healthy subjects. All these subjects were firstly diagnosed and not treated with lipid-lowering, antihypertensive, or antidiabetic drugs. A 12-h fasting blood sample was obtained from each patient, and plasma levels of MMP-2 and MMP-9 were measured together with their tissue inhibitors and a full set of laboratory cardiovascular disease markers. MMP-2 plasma levels were not significantly different among the considered groups. MMP-9, tissue inhibitor of MMP (TIMP)-1, and TIMP-2 are significantly higher in FCH (p < .001) and MS (p < .001) patients than in healthy controls, and they are also higher in MS patients than in FCH ones (p < .001). TIMP-1 (p < .001) and TIMP-2 (p < .001), but not MMP-9, are also significantly higher in subjects with MS associated to FCH than in patients with MS alone. No specific correlation among MMPs, TIMPs, and the other studied parameters has been observed in the whole sample and in the four above-defined subgroups. MMP-9, TIMP-1, and TIMP-2 plasma levels could be significant determinant and/or diagnostic markers of MS but not of FCH. However, the superposition of MS on FCH further increases the plasma level of these parameters. The prognostic value of this observation has to be evaluated.
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PMID:Vascular remodeling and prothrombotic markers in subjects affected by familial combined hyperlipidemia and/or metabolic syndrome in primary prevention for cardiovascular disease. 1792 35

The presence of hypertension and hyperlipidemia accelerates atherosclerosis and increases the risk of ocular disease. Since there were few rat models for atherosclerosis, spontaneously hypertensive rats (SHRs) and spontaneously hyperlipidemic rats (HLRs) were crossbred to obtain a new model: the spontaneously hypertensive hyperlipidemic rat (SHHR). Matrix metalloproteinases (MMPs) play an important role in ocular degeneration. The purpose of this study is to investigate changes in the MMP activities in vitreous and plasma as well as MMP expression in the retinas of SHHRs, which served as a model of vascular degeneration. We used 8-month-old Wistar-Kyoto (WKY) rats and Sprague-Dawley (SD) rats, SHRs, HLRs, and SHHRs. The MMP-2 and MMP-9 activities in plasma and vitreous were examined by zymography. The mRNA expression of MMP-2, MMP-9, and tissue inhibitor of metalloproteinases-3 (TIMP-3) in retina was examined by quantitative PCR. The localized expression of MMP-9 in the retinas was examined by immunostaining. The MMP-9 activity increased significantly in SHHRs compared with all other rats. MMP-9 was observed mainly at the superficial layer of the retina on immunostaining. The MMP-2, MMP-9, and TIMP-3 mRNA in retina was not significantly different in SHHRs as compared with all other rats. Increased MMP-9 activity in vitreous was influenced more intensely from plasma than retina because there was no change in MMP-9 expression in retina, and MMP-9 immunostaining was observed mainly at the surface of the retina, where blood vessels are present. In this study, the complications of hypertension and hyperlipidemia induced increased MMP-9 activity in vitreous and plasma. It is therefore suggested that MMP-9 may be involved in causing this result and in the development of retinal disease.
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PMID:Matrix metalloproteinase-9 in spontaneously hypertensive hyperlipidemic rats. 1848 57

By means of a degradomic approach applying proteomic techniques, we previously suggested that apolipoprotein E (apoE) is a substrate of matrix metalloproteinase-14 (MMP-14). Here we confirm that apoE is, in fact, a substrate of MMP-14 and also of MMP-7 and MMP-2 to a lesser extent. The 34 kDa apoE protein was initially processed by MMP-14 into fragments with molecular masses of 28, 23, 21, and 11 kDa. MMP-14 cleavage sites within the apoE protein were determined by C-terminal labeling of MMP-14-digested apoE fragments with isotope ((18)O/(16)O = 1:1) and identification of the doublet fragments or peptides showing 2 Da difference by MS, along with N-terminal sequencing of the fragments. It was determined that the primary MMP-14 cleavage sites were A(176)-I(177), P(183)-L(184), P(202)-L(203), and Q(249)-I(250). The MMP-14-mediated cleavage of apoE was consistent regardless of whether apoE existed in its lipid-bound or lipid-free form. Upon digestion with MMP-14, apoE loses its ability to suppress the platelet-derived growth factor-induced migration of rat vascular smooth muscle cells. Considering the important role of apoE for lipid metabolism and atherosclerosis protection, our findings suggest that MMP-14 plays an essential role for the development of hyperlipidemia and atherosclerosis as a result of degradation of apoE.
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PMID:Cleavage and functional loss of human apolipoprotein E by digestion of matrix metalloproteinase-14. 1865 30

Monocytes/macrophages are key players throughout atheroma development. The aim of this study was to determine the role of macrophages in lesion formation in heart valves in hyperlipidemia. We examined whether systemic depletion of monocytes/macrophages had a beneficial or adverse effect on the development of lesions in hyperlipemic hamsters injected twice weekly (for 2 months) with clodronate-encapsulated liposomes (H+Lclod), a treatment that selectively induces significant monocyte apoptosis. Hyperlipemic hamsters were employed as controls, as were hyperlipemic hamsters treated with plain liposomes. We assayed serum cholesterol (CH) and triglycerides (TG), the lipid and collagen contents and the size of the valve lesions, the matrix metalloproteinases (MMPs) in the serum and vessel wall, apolipoprotein E (ApoE), interleukin-1beta (IL-1beta), and superoxide anion production. In comparison with controls, H+Lclod hamsters exhibited: (1) increased lipid and collagen accumulation within the lesions, (2) decreased activity of MMP-9 and MMP-2 in sera and aortic homogenates, (3) decreased serum CH and TG and decreased expression of ApoE in sera and liver, (4) reduced expression of IL-1beta in aorta and liver homogenates, and (5) no change in the level of superoxide anion in the aorta. Thus, initially, the presence of the macrophages is beneficial in valvular lesion formation. Depletion of monocytes/macrophages is a two-edged sword having a beneficial effect by decreasing the expression of IL-1beta and MMP activities but an adverse effect by inducing a significant increase in the lipid and collagen content and expansion of valvular lesions.
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PMID:Effect of depletion of monocytes/macrophages on early aortic valve lesion in experimental hyperlipidemia. 1930 Oct 37

Hyperlipidemia of hamsters was induced by high-fat/cholesterol diets formulated by the addition of coconut oil (CO), butter (BU), and flaxseed oil (FX). Lower (p < 0.05) serum lipids, liver size, and hepatic cholesterol and triacylglycerol contents were observed in the FX group compared to both CO and BU groups. The liver damage indices [glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) values] in the FX group were lower (p < 0.05) than those in the CO and BU groups, which may result from higher (p < 0.05) glutathione (GSH) levels and a tendency toward lower malondialdehyde (MDA) levels in livers. Besides, lower (p < 0.05) gene expression and activity of hepatic matrix metalloproteinases-9 (MMP-9) in the FX group were lower (p > 0.05) compared to those in the CO and BU groups; however, no (p > 0.05) differences in gene expression activities of hepatic MMP-2 were observed among treatments. Those beneficial effects could explain the attenuation of FX on nonalcoholic fatty liver (NAFL) induced by a high-fat/cholesterol dietary habit.
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PMID:Flaxseed oil attenuates nonalcoholic fatty liver of hyperlipidemic hamsters. 1945 4

The most adequate way to experimentally reproduce the post-prandial lipemia condition appears to be the administration of a standardized oral fat load (OFL) to fasting patients. We studied the effects of a standardized OFL on markers of vascular remodelling in healthy subjects. We enrolled 286 Caucasians aged >or= 18 of either sex. The OFL was given after a 12-h fast. Blood samples were drawn before and 3, 6, 9 and 12h after the fat load. The following parameters were evaluated: body mass index (BMI), blood glucose (BG), systolic blood pressure (SBP), diastolic blood pressure (DBP), lipid profile, nitrites and nitrates, adiponectin (ADP), metalloproteinase-2 (MMP-2) and metalloproteinase-9 (MMP-9). High density lipoprotein-cholesterol (HDL-C) decrease was present in subjects after 6h. Triglycerides (Tg) change was observed after 6h. Nitrites/nitrates variation was observed after 6 and 9h during OFL. Adiponectin level was decreased after 6 and 9h during OFL. Both MMP-2 and MMP-9 levels were higher after 6h during OFL. We observed that nitrites/nitrates and ADP significantly decreased and MMP-2 and MMP-9 significantly increased after a standardized OFL. Other studies need to confirm the direct acute effects of post-prandial lipemia on vascular damage.
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PMID:Effects of a standardized oral fat load on vascular remodelling markers in healthy subjects. 2035 87

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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