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)

Ischemia followed by reperfusion is a major cause for renal injury in both native kidney and renal allografts. Hyperhomocysteinemia, a condition of elevated plasma homocysteine (Hcy) level, is associated with cardiovascular diseases. Recent evidence suggests that Hcy, at higher levels, may be harmful to other organs such as the kidney. In this study, we investigated the role of Hcy in ischemia-reperfusion-induced renal injury. The left kidney of a Sprague-Dawley rat was subjected to either 30-min or 1-h ischemia followed by 1- or 24-h reperfusion. Ischemia-reperfusion caused a significant increase in peroxynitrite formation and lipid peroxidation in kidneys, which reflected oxidative stress. The number of apoptotic cells in those kidneys was also markedly increased. Hcy levels were elevated 2.9- and 1.5-fold in kidneys subjected to ischemia alone or ischemia-reperfusion, respectively. Further investigation revealed that elevation of Hcy level in the kidney upon ischemia-reperfusion was due to reduced activity of cystathionine-beta-synthase, a key enzyme in Hcy metabolism. Administration of anti-Hcy antibodies into the kidney not only abolished ischemia-reperfusion-induced oxidative stress and cell death in the kidneys but also restored renal function after 1 h of reperfusion. However, such a protective effect was not sustained after 24 h of reperfusion. In conclusion, ischemia-reperfusion impairs Hcy metabolism in the kidney. Hcy, at elevated levels, is capable of inducing oxidative stress and renal injury. Neutralization of Hcy with antibodies offers transient functional benefit against ischemia-reperfusion-induced oxidative stress and renal injury. These results suggest that Hcy may play a detrimental role in the kidney during ischemia-reperfusion.
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PMID:Detrimental role of homocysteine in renal ischemia-reperfusion injury. 1726 13

Cardiovascular disease is the leading cause of death among men and women in the United States. Silent myocardial ischemia, defined as documentation of ischemia in the absence of angina or anginal equivalents, affects up to 4 million Americans and carries a poor prognosis. The assessment of the presence of subclinical coronary atherosclerosis affords an opportunity to identify patients who may be at risk for coronary artery disease over the long term. In addition to traditional risk factors (such as lipid parameters, diabetes, hypertension, smoking, and age), a variety of novel factors (such as lipoprotein[a], homocysteine, and C-reactive protein) may enhance assessment of risk in specific populations. Risk modification should be aimed at achieving recommended levels of lipids and blood pressure, reducing obesity, facilitating optimal management of diabetes and the metabolic syndrome, and encouraging smoking cessation and physical activity. Clinicians should be knowledgeable regarding the application of national guidelines for the reduction of cardiovascular risk so as to maximize the prospects for both the primary and secondary prevention of coronary artery disease and associated adverse outcomes.
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PMID:Cardiovascular disease: strategies for risk assessment and modification. 1729 47

Our previous study found that hyperhomocysteinemia was strongly associated with central retinal vein occlusion (CRVO) in the Chinese population. The aim of this study is to determine whether MTHFR C677T mutation is an independent risk factor for CRVO in the Chinese population. A matched case-control study was conducted between July 2004 and May 2005. The study cohort consisted of 64 individuals that had been diagnosed with CRVO and 64 healthy controls (matched for age, gender, hypertension, smoking, and drinking habits). None of the cases or controls had a history of diabetes, glaucoma, medication or any other vascular events that might influence plasma homocysteine levels. A cross-sectional analysis among the 64 cases was performed to compare the prevalence of MTHFR C677T mutation among subjects with and without ischemia and subjects aged above 45 and below 45 years. MTHFR C677T mutation was determined by the template-directed dye-terminator incorporation with fluorescence polarization (TDI-FP) method. The result showed that the prevalence of the MTHFR 677 TT genotype did not significantly differ between patients and controls. However, 10 (34.5%) MTHFR C677 TT genotype was found in the ischemic group but only 4 (14.3%) in the nonischemic group (p=0.026). And we found that 6 MTHFR C677 TT genotype patients who have hyperhomocysteinemia in the ischemic group but only 2 in the nonischemic group (p=0.016). It suggests that MTHFR C677T mutation is associated with hyperhomocysteinemia in the ischemic CRVO in the Chinese population. It may contribute to hyperhomocysteinemia and associate with the development of CRVO.
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PMID:MTHFR C677T mutation in central retinal vein occlusion: a case-control study in Chinese population. 1771 79

Abnormal increases of antiphospholipid antibody and plasma homocysteine levels are recently emerging as nonlipidic risk factors for cerebral atherogenesis and thrombosis. Both antiphospholipid antibody and homocysteine share many similar bioeffects in hemostasis, but their interaction is still inconsistent. In this study, we examined the relation between the plasma homocysteine level and lupus anticoagulant, anticardiolipin antibody, and anti-beta2-glycoprotein I antibody in patients with noncardiac cerebral ischemia. Systemic lupus erythrematosus patients were excluded. The results showed a higher frequency of moderate hyperhomocysteinemia in patients with an abnormal increase of lupus anticoagulant only. Neither the serum folate and cobalamin levels nor methylenetetrahydrofolate reductase allele mutation contributes to this result. Accordingly, homocysteine interacts with lupus anticoagulant to promote cerebral atherosclerosis and ischemia. The role of vasculopathic or prothrombotic autoantibody generation in response to specific pathological change such as hyperhomocysteinemia warrants further investigation.
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PMID:Hyperhomocysteinemia relates to the subtype of antiphospholipid antibodies in non-SLE patients. 1791 Nov 91

Endoplasmic reticulum stress, initiated by protein overload or malfolding, activates a complex network of interacting and parallel responses that dampen the stress. However, when the protective response is insufficient, a set of responses leads to apoptosis. Coupled with the latter are promotion of lipid synthesis and proinflammatory responses. Evidence has been mounting for an important role of the endoplasmic reticulum (ER) stress response in the pathogenesis of chronic viral hepatitis, insulin resistance and nonalcoholic fatty liver disease, ischemia-reperfusion injury, genetic disorders of protein malfolding, and alcoholic liver disease. In the latter, a key candidate for inducing ER stress is hyperhomocysteinemia. Betaine treatment promotes removal of homocysteine and prevents ER stress, fatty liver, and apoptosis in a mouse model of alcohol-induced liver disease. With increasing interest in the potential role of ER stress in liver disease, greater understanding of pathophysiology, prevention, and treatment of liver disease is anticipated.
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PMID:Endoplasmic reticulum stress and liver injury. 1797 73

The mechanism of thrombogenicity in hyperhomocysteinemia remains controversial. The authors investigated the association between elevated plasma homocysteine levels, platelet function, and blood coagulation. Blood was collected from healthy subjects and patients with critical limb ischemia. Basal platelet counts and platelet aggregation as well as flow cytometry were performed to assess spontaneous- and agonist-induced platelet aggregation as well as P-selectin and Glycoprotein IIb/IIIa expression at different homocysteine concentrations. Thromboelastography was performed, and platelet shape change was assessed, using a channelyzer, by measuring median platelet volume. Lactate dehydrogenase was measured, to indirectly assess red blood cell membrane integrity, after homocysteine exposure. The study results suggest that platelet activation and hypercoagulability occur after exposure to homocysteine, especially in patients with critical limb ischemia. Homocysteine concentrations of approximately 50 micromol/L appear to be the level at which these changes occur in vitro, and this effect on platelets appears to be indirect.
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PMID:Homocysteine activates platelets in vitro. 1816 May 93

The treatment of coronary artery disease (CAD) is clinically measured by monitoring changes in venous lipids and inflammatory markers. There is currently no established quantified relationship between coronary flow reserve and markers of inflammatory CAD. A total of 120 men and women underwent quantified measurement of coronary blood flow using SPECT imaging at baseline and 1 year later. They had fasting venous blood work obtained at baseline and 1 year later. These markers of lipids and inflammation included, total cholesterol, low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, lipoprotein-a, homocysteine, fibrinogen, C-reactive protein, and interleukin-6. Regression analysis reveals no general statistical relationship between these markers and coronary blood flow as measured by myocardial perfusion imaging. However, when changes in indices are considered and changes in risk factors are compared with changes in ischemia, blood factor based estimates yield an adjusted R2 = 0.31, R = 0.57, P < .0001. Initial levels of coronary ischemia cannot be diagnostically inferred from baseline values in lipid and inflammatory markers of coronary artery disease. When change in coronary blood flow is quantified using SPECT imaging, 6 independent underlying blood factors provided statistically useful information in identifying changes in coronary blood flow. Although the relationship of changes is statistically significant ( P < .0001), quantification of coronary blood flow by SPECT imaging provides physiologic status information, which cannot be inferred from fasting markers of lipids and inflammation status.
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PMID:What is the relationship between myocardial perfusion imaging and coronary artery disease risk factors and markers of inflammation? 1831 18

Folic acid deficiency increases stroke risk. In the present study, we examined whether folic acid deficiency enhances neuronal damage and gliosis via oxidative stress in the gerbil hippocampus after transient forebrain ischemia. Animals were exposed to a folic acid-deficient diet (FAD) for 3 months and then subjected to occlusion of both common carotid arteries for 5 min. Exposure to an FAD increased plasma homocysteine levels by five- to eightfold compared with those of animals fed with a control diet (CD). In CD-treated animals, most neurons were dead in the hippocampal CA1 region 4 days after ischemia/reperfusion, whereas, in FAD-treated animals, this occurred 3 days after ischemia/reperfusion. Immunostaining for 8-hydroxy-2'-deoxyguanosine (8-OHdG) was performed to examine DNA damage in CA1 neurons in both groups after ischemia, and it was found that 8-OHdG immunoreactivity in both FAD and CD groups peaked at 12 hr after reperfusion, although the immunoreactivity in the FAD group was much greater than that in the CD group. Platelet endothelial cell adhesion molecule-1 (PECAM-1; a final mediator of neutrophil transendothelial migration) immunoreactivity in both groups increased with time after ischemia/reperfusion: Its immunoreactivity in the FAD group was much higher than that in the CD group 3 days after ischemia/reperfusion. In addition, reactive gliosis in the ischemic CA1 region increased with time after ischemia in both groups, but astrocytosis and microgliosis in the FAD group were more severe than in the CD group at all times after ischemia. Our results suggest that folic acid deficiency enhances neuronal damage induced by ischemia.
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PMID:Folic acid deficiency increases delayed neuronal death, DNA damage, platelet endothelial cell adhesion molecule-1 immunoreactivity, and gliosis in the hippocampus after transient cerebral ischemia. 1833 23

Accumulation of unfolded or malfolded proteins induces endoplasmic reticulum (ER) stress which elicits a complex network of interacting and parallel responses that dampen the stress. The ER stress response in the liver is controlled by intrinsic feedback effectors and is initially protective. However, delayed or insufficient responses or interplay with mitochondrial dysfunction may turn physiological mechanisms into pathological consequences including apoptosis, fat accumulation and inflammation all of which have an important role in the pathogenesis of liver disorders such as genetic mutations, viral hepatitis, insulin resistance, ischemia/reperfusion injury, and alcoholic and non-alcoholic steatosis. In both alcohol and non-alcohol-induced ER stress, a common candidate is hyperhomocysteinemia. Betaine supplementation and/or expression of betaine-homocysteine methyltransferase (BHMT) promote removal of homocysteine and alleviate ER stress, fatty accumulation and apoptosis in cultured hepatocytes and mouse models. The rapidity and magnitude of homocysteine-induced activation of each of the main ER resident transmembrane sensors including inositol requiring enzyme 1 (IRE-l alpha), activating transcription factor 6 (ATF-6) and RNA-activated protein kinase (PKR)-like ER kinase (PERK) appear different in different experimental models. Dissection and differentiation of ER stress signaling may reveal clues on the specific importance of the ER stress response in contributing to liver injury and thus provide better strategies on prevention and treatment of liver disease.
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PMID:Dissection of endoplasmic reticulum stress signaling in alcoholic and non-alcoholic liver injury. 1833 57

Chronic volume/pressure overload-induced heart failure augments oxidative stress and activates matrix metalloproteinase which causes endocardial endothelial-myocyte (EM) uncoupling eventually leading to decline in myocardial systolic and diastolic function. The elevated levels of homocysteine (Hcy), hyperhomocysteinemia (HHcy), are associated with decline in cardiac performance. Hcy impairs the EM functions associated with the induction of ventricular hypertrophy leading to cardiac stiffness and diastolic heart failure. Hcy-induced neurological defects are mediated by the NMDA-R (N-methyl-D-aspartate (NMDA) receptor) activation. NMDA-R is expressed in the heart. However, the role of NMDA-R on cardiac function during HHcy is still in its infancy. The blockade of NMDA-R attenuates NMDA-agonist-induced increase in the heart rate. Hcy increases intracellular calcium and activates calpain and calpain-associated mitochondrial (mt) abnormalities have been identified in HHcy. Mitochondrial permeabilization and uncoupling in the pathological setting is fueled by redox stress and calcium mishandling. Recently the role of cyclophilin D, a component of the mitochondrial membrane permeability transition pore, has been identified in cardiac-ischemia. Mechanisms underlying the potentiation between NMDA-R activation and mitochondrial defects leading to cardiac dysfunction during HHcy remain to be elucidated. This review addresses the mitochondrial mechanism by which Hcy contributes to the decline in mechano-electrical function and arrhythmogenesis via agonizing NMDA-R. The putative role of mitochondrial MMP activation, protease stress and mitochondrial permeability transition in cardiac conduction during HHcy is discussed. The review suggests that Hcy increases calcium overload and oxidative stress in the mitochondria and amplifies the activation of mtMMP, causing the opening of mitochondrial permeability transition pore leading to mechano-electrical dysfunction.
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PMID:Mitochondrial MMP activation, dysfunction and arrhythmogenesis in hyperhomocysteinemia. 1839 9


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