Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypercholesterolemia impairs arteriolar dilatation, but whether the vascular abnormalities accompanying this condition include large artery function is unknown. We addressed this issue in 13 normotensive subjects with familial hypercholesterolemia (serum cholesterol 401.6 +/- 16.9 mg/dl, mean +/- S.E., FHC) and no evidence of atherosclerotic lesions, in whom radial artery (RA) diameter and blood pressure (BP) were measured beat to beat by an echotracking and a Finapres device, respectively. RA compliance (RAC) was derived from the diameter/BP relationship and expressed over the systo-diastolic BP range, both at baseline and after a 12-min brachial artery occlusion. RAC was expressed also as the area under the RAC/BP curve divided for pulse BP. Measurements included maximal forearm blood flow (plethysmography) and minimal forearm vascular resistance (FVR) which were obtained from the values following the 12-min brachial arterial occlusion. Data were collected before and after 6- and 24-month lipid lowering treatment (simvastatin 40 mg/day). Ten age-matched normotensive normocholesterolemic healthy subjects (N) served as controls. Compared to N, baseline RAC was strikingly reduced in FHC (-53.5%, P < 0.01). After ischemia RAC increased significantly and markedly in N (+38.7, P < 0.01), while only a modest and non-significant increase was observed in FHC. Minimal FVR was markedly higher in FHC than in N (3.5 +/- 0.9 vs 1.6 +/- 0.1 units, P < 0.01). In FHC (7 subjects) RAC remained unchanged after 6 months of lipid lowering treatment, but increased markedly (+55.2%, p < 0.05) when treatment was prolonged to 24 months. Lipid lowering treatment also reduced minimal FVR, the effect being significant both after 6 and after 24 months. No changes in RAC and minimal FVR were seen after 6 months in controls. Thus, in subjects with a marked increase in serum cholesterol due to FHC, not only arteriolar dilatation, but also RAC and distensibility are markedly impaired. This impairment can be favourably affected by an effective lipid lowering treatment of long duration.
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PMID:Impaired radial artery compliance in normotensive subjects with familial hypercholesterolemia. 883 Sep 37

An asymptomatic 36-year-old woman had high cholesterol levels due to heterozygous familial hypercholesterolemia (FHC) and a family history of coronary artery disease (CAD) but no other risk factors. Exercise testing showed no signs of ischemia. Conventional drug therapy did not lower lipid levels adequately. However, low-density lipoprotein (LDL) apheresis, which effectively reduces cholesterol levels in patients with heterozygous FHC, was not indicated, according to current guidelines. Electron beam computed tomography demonstrated exceptionally high amounts of coronary calcium for the patient's age and sex. A subsequent coronary angiogram revealed advanced CAD, which justified the initiation of LDL apheresis to reduce her cholesterol levels. In patients with heterozygous FHC refractory to conventional lipid-lowering therapy, the presence of coronary calcium in the highest percentiles for age and sex (i.e., > 75th percentile) may warrant aggressive clinical management to improve prognosis, even if no symptoms or signs of ischemia are present.
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PMID:Improved coronary risk assessment with electron beam computed tomography in an asymptomatic female with familial hypercholesterolemia. 1091 68

Gene therapy for atherosclerosis-related disorders of lipoprotein metabolism is primarily directed to liver and aims at long-lasting correction of familial hypercholesterolemia, lipoprotein / hepatic lipase deficiency, and Apolipoprotein A, B, or E -related diseases. Treatment of complications of atherosclerosis (eg, restenosis, ischemia) requires local gene transfer to arterial wall or ischemic muscle with transient gene expression. Catheter-mediated approach or direct injections have been used in clinical trials for the treatment of restenosis and for the induction of angiogenesis in ischaemic limb and myocardium. Other possible applications of local gene transfer include antithrombotic treatment and stabilization of vulnerable plaques.
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PMID:Gene therapy for atherosclerosis and atherosclerosis-related diseases. 1112 1

This article summarizes the clinical and biochemical evidence for maximal treatment of atherosclerosis by a simultaneous 60% to 70% reduction of plasma low-density lipoprotein cholesterol (LDL cholesterol), fibrinogen, and lipoprotein a concentrations with heparin-mediated extracorporeal LDL/fibrinogen precipitation (HELP) apheresis and statins. Apheresis has proven efficient and safe in the treatment of more than 1,000 patients since 1984 and has been applied in children and adults for the treatment of homozygous and heterozygous familial hypercholesterolemia, coronary artery disease, ischemic cardiomyopathy, generalized atherosclerosis, or transplant-associated arteriosclerosis after cardiac transplantation. Simultaneous removal of the main atherogenic plasma compounds has an immediate impact on myocardial and peripheral vasomotion by increasing myocardial blood flow, coronary flow reserve, cerebral CO2-reactivity, and muscle oxygen tension. Removal of fibrinogen and cholesterol reduces plasma viscosity by 20% and erythrocyte aggregation by 60% which gives rise to applying the HELP apheresis in various microcirculatory disorders. Pilot studies on acute retinal ischemia, critical limb ischemia, and sudden hearing loss confirm this observation.
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PMID:Evidence for maximal treatment of atherosclerosis: drastic reduction of cholesterol and fibrinogen restores vascular homeostasis. 1146 57

To investigate if spontaneous ischemic events in mice with severe multi-organ atherosclerosis could adapt to ischemia, apolipoprotein E/LDL receptor knockout mice were fed an atherogenic diet for 7 to 9 months. Signs of spontaneous ischemia occurred. One to two days later, hearts were excised, Langendorff-perfused with induced global ischemia, and compared with mice without signs of disease. In vivo heart or brain infarctions were verified by heart histology and/or increased serum levels of cardiac troponin T and S100B. Hearts of mice with spontaneous ischemic events had improved function and reduced Langendorff-induced infarctions. To investigate the remote preconditioning effect of brain ischemia, bilateral ligation of the internal carotid arteries was performed in C57BL6 mice. Twenty-four hours later, their isolated hearts were protected against induced global ischemia. A possible role of inducible NO synthase (iNOS) was studied in iNOS knock out mice, who were not preconditioned by induced brain ischemia. Cardiac iNOS was unchanged 24 hours after preconditioning, suggesting that NO is a trigger rather than a mediator of protection. These findings suggest that spontaneous ischemic events in the brain and heart adapt the heart to ischemia. This can be mimicked by induced brain ischemia, with iNOS as a key factor of protection.
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PMID:Spontaneous ischemic events in the brain and heart adapt the hearts of severely atherosclerotic mice to ischemia. 1206 10

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear receptors which regulate the expression of target genes. Three types of PPAR have been identified: PPAR alpha, PPAR beta/delta and PPAR gamma. The known endogenous PPAR ligands are polyunsaturated fatty acids and eicosanoids, such as 15-deoxy-delta 12,14-prostaglandin J2 and leukotriene B4. Two classes of drugs, fibrates and thiazolidinediones, bind to PPAR alpha and PPAR gamma, respectively. PPARs are involved in the regulation of the lipid metabolism and adipogenesis but are also expressed in the vasculature. PPARs activators inhibit inflammatory reactions within the vascular wall, inhibit vascular smooth muscle cells migration and proliferation and affect foam cells formation by changing the expression of scavenger receptors. PPAR agonists lower blood pressure and improve endothelial function in different animal models of hypertension as well as in humans. PPAR gamma ligands inhibit the development of atherosclerosis in LDL receptor deficient and apolipoprotein E deficient mice and in diabetic humans. PPAR gamma agonists have also been shown to attenuate myocardial hypertrophy and protect against ischemia-reperfuion injury.
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PMID:[Peroxisome proliferator-activated receptors (PPAR) in pathophysiology of the circulatory system and prospective use of agonists of these receptors in therapy]. 1286 56

Biotin-cysteine was used to study protein S-thiolation in isolated rat kidneys subjected to ischemia and reperfusion. After 40 min of ischemia, total protein S-thiolation increased significantly (P < 0.05), by 311%, and remained significantly elevated (P < 0.05), 221% above control, after 5 min of postischemic reperfusion. Treatment of protein samples with 2-mercaptoethanol abolished the S-thiolation signals detected, consistent with the dependence of the signal on the presence of a disulfide bond. With the use of gel filtration chromatography followed by affinity purification with streptavidin-agarose, S-thiolated proteins were purified from CHAPS-soluble kidney homogenate. The proteins were then separated by SDS-PAGE and stained with Coomassie blue. With a combination of matrix-assisted laser desorption ionization time of flight mass spectrometry and LC/MS/MS analysis of protein bands digested with trypsin, a number of S-thiolation substrates were identified. These included the LDL receptor-related protein 2, ATP synthase alpha chain, heat shock protein 90 beta, hydroxyacid oxidase 3, serum albumin precursor, triose phosphate isomerase, and lamin. These represent proteins that may be functionally regulated by S-thiolation and thus could undergo a change in activity or function after renal ischemia and reperfusion.
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PMID:Reversible cysteine-targeted oxidation of proteins during renal oxidative stress. 1287 48

The regulation of cerebrovascular permeability is critical for normal brain homeostasis, and the "breakdown" of the blood-brain barrier (BBB) is associated with the development of vasogenic edema and intracranial hypertension in a number of neurological disorders. In this study we demonstrate that an increase in endogenous tissue-type plasminogen activator (tPA) activity in the perivascular tissue following cerebral ischemia induces opening of the BBB via a mechanism that is independent of both plasminogen (Plg) and MMP-9. We also show that injection of tPA into the cerebrospinal fluid in the absence of ischemia results in a rapid dose-dependent increase in vascular permeability. This activity is not seen with urokinase-type Plg activator (uPA) but is induced in Plg-/- mice, confirming that the effect is Plg-independent. However, the activity is blocked by antibodies to the LDL receptor-related protein (LRP) and by the LRP antagonist, receptor-associated protein (RAP), suggesting a receptor-mediated process. Together these studies demonstrate that tPA is both necessary and sufficient to directly increase vascular permeability in the early stages of BBB opening, and suggest that this occurs through a receptor-mediated cell signaling event and not through generalized degradation of the vascular basement membrane.
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PMID:Tissue-type plasminogen activator induces opening of the blood-brain barrier via the LDL receptor-related protein. 1461 49

We have previously shown that atherosclerotic apolipoprotein E-deficient (apoE(-/-)) x LDL receptor-deficient (LDLR(-/-)) mice develop myocardial infarction when exposed to hypoxic stress. This study was performed to assess the role of thrombin and thrombosis in this process. ApoE(-/-) x LDLR(-/-) mice were fed a cholesterol-rich diet for 8 mo and were then subjected to hypoxic stress while receiving isoflurane anesthesia. One group received a bolus dose (5.6 micromol/kg) of the thrombin inhibitor melagatran, and control animals received PBS 10 min before the hypoxic stress. The mice were exposed to 10 min of hypoxia followed by normoxia. Ten minutes after the stress, Alzet pumps delivering melagatran (20 nmol x kg x (-1)min(-1)) or PBS were implanted, and the mice were allowed to recover for 48 h. The cardiac response was analyzed by histology, immunohistochemistry, and serum troponin T assay. All animals showed reversible ECG changes as a sign of ischemia during hypoxic stress, and 50% developed infarctions afterward as judged by troponin T levels. The group that received thrombin inhibitor had significantly lower troponin T and smaller myocardial infarctions than the PBS-treated group. These data show that thrombin generation is an important pathogenetic factor and suggest that coronary thrombosis is involved in myocardial infarction in atherosclerotic mice. Exposure of atherosclerotic mice to hypoxia leads to myocardial infarction through a two-phase pathway in which acute transient ischemia is followed by thrombin-dependent, irreversible, myocardial ischemia and myocardial cell death.
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PMID:Thrombin inhibitor reduces myocardial infarction in apoE-/- x LDLR-/- mice. 1503 Nov 24

Low-density lipoprotein (LDL) receptor is involved in cholesterol metabolism of CNS as a receptor of apolipoprotein E (ApoE), which plays an important role in regenerative process after brain ischemia. Temporal and spatial changes of LDL receptor were investigated after 90 min of transient middle cerebral artery occlusion (MCAO) in relation to those of microtubule-associated protein 2 (MAP2) and ApoE. In the ischemic core, LDL receptor became positive at 1 d after transient MCAO, which was not double positive for MAP2 or ApoE, and disappeared in 7 and 56 d. In the peri-ischemic area, LDL receptor became observed at 7 d, which peaked at 21 d, most of which were double positive for MAP2. The number of LDL receptor and ApoE double-positive cells increased at 7 d and decreased at 21 d with the shift of LDL receptor immunoreactivity from cytoplasm at 7 d to dendrites at 21 d in the peri-ischemic area. These results suggest that LDL receptor, interacting with ApoE, is profoundly involved in lipid transport of CNS for tissue repair in the peri-ischemic area after brain ischemia.
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PMID:Up-regulation of low-density lipoprotein receptor expression in the ischemic core and the peri-ischemic area after transient MCA occlusion in rats. 1583 15


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