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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

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

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease affecting approximately 1% of the adult general population. Cardiovascular disease is recognized as the leading cause of death in RA patients, accounting for nearly 40% of their mortality. Patients with RA are at a twofold increased risk for myocardial infarction and stroke, with risk increasing to nearly threefold in patients who have had the disease for 10 years or more. Congestive heart failure appears to be a greater contributor to excess mortality than ischemia. This increased cardiovascular disease risk in RA patients seems to be independent of traditional cardiovascular risk factors. Pathogenic mechanisms include pro-oxidative dyslipidemia, insulin resistance, prothrombotic state, hyperhomocysteinemia, and immune mechanisms such as T-cell activation that subsequently lead to endothelial dysfunction, a decrease in endothelial progenitor cells, and arterial stiffness, which are the congeners of accelerated atherosclerosis observed in RA patients. This paper discusses pathogenic mechanisms, effects of methotrexate, tumor necrosis factor antagonists, steroids, and statins, with a perspective on therapy.
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PMID:Rheumatoid arthritis and cardiovascular disease. 1841 67

Homocysteine (Hcy) is a risk factor for vascular dysfunction. High levels of Hcy may result in vascular injury accelerating atherosclerosis leading to ischemia. After ischemia, endothelial progenitor cells (EPCs) migrate from bone marrow to repair damaged sites either through direct incorporation of EPCs or by repopulating mature endothelial cells. This study looks into the relationship between increased Hcy in patients with cerebrovascular disease (CVD) and EPCs. Some patients with hyperhomocysteinemia were treated with B vitamins to evaluate if the treatment reverses the elevated Hcy and its impact on their EPC levels. EPCs were treated with Hcy to determine the in vitro effects of Hcy. Our clinical findings show that elevated Hcy levels have an inverse relationship with EPC levels and B vitamin intervention can reverse this effect. Our in vitro work shows that Hcy-mediated EPC toxicity is due to apoptosis involving caspase-8, cytochrome c release, and caspase-3 activation. Vitamin B(6), and B(9) significantly impair Hcy-mediated EPC caspase-3 activation in vitro. Our clinical and in vitro data together indicate that increased Hcy results in a decrease in EPC numbers. This decrease in EPC by Hcy may be occurring through increased apoptosis and B vitamins (B(6), B(9)) intervention can attenuate such effects.
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PMID:Homocysteine reduces endothelial progenitor cells in stroke patients through apoptosis. 1876 98

Mesenteric venous thrombosis (MVT), an unusual location of deep venous thrombosis, occurs especially on a predisposing terrain. Recently, hyperhomocysteinemia has been shown to be associated with venous thrombosis, often recurrent and located in an uncommon site. Hyperhomocysteinemia is mainly due to genetic causes (mutations 677C>T and 1298A>C of methylenetetrahydrofolate reductase) and vitamins B deficiencies. MVT may present as acute, subacute or chronic form. The clinical supposition of mesenteric thrombosis is based on the discrepancy between the abdominal pain and the physical examination. The nonspecific character of the pain, mimicking peptic ulceration in some cases, and the possibility of an initial normal clinical examination may delay the diagnosis. The occurrence of the fever, rebound tenderness and guarding suggests progression to bowel infarction. MVT leads to peritonitis in 1/3 to 2/3 of cases. Laboratory blood tests are not helpful in confirming the diagnosis of venous thrombosis. Leukocytosis and metabolic acidosis are considered to be the most specific laboratory findings in patients with mesenteric ischemia. Abdominal computed tomography is the test of choice for the diagnosis. However, most of the cases are diagnosed during laparotomy or autopsy. Anticoagulant therapy administrated early increases the survival rate. Surgery is indicated in cases with bowel infarction or peritonitis.
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PMID:Mesenteric venous thrombosis: clinical and therapeutical approach. 1907 7

Hyperhomocysteinemia has been proposed as an important risk factor for cardiac arrhythmias and ischemia worldwide. However, the cellular mechanism underlying toxic effects of homocysteine on hearts remains conjectural. It is well known that aberrant sodium channels can promote the development of cardiac arrhythmias and ischemic injury. So the present study was to investigate toxic effects of homocysteine on sodium currents recorded in human atrial cells. Human atrial myocytes were acutely enzymatically isolated and the whole-cell patch clamp technique was employed to record sodium currents and membrane potential in human atrial cells in the absence and presence of homocysteine. We found that in human atrial myocytes, sodium currents were significantly increased by pathological concentration of homocysteine with the maximum activation potential shifted toward the positive potential. However, physiological concentration of homocysteine did not have any effects on sodium currents. The time constants for time-dependent activation (tau(act)) and inactivation (tau(inact)) of sodium currents were both markedly shortened by elevated homocysteine levels. The further channel kinetic data showed that elevated homocysteine levels shifted the inactivation curve towards positive potential and accelerated the recovery from inactivation of sodium channel, but did not affect the activation of sodium channel. Additionally, the resting membrane potential of human atrial myocytes was obviously depolarized by elevated homocysteine levels in the current clamp model. Taken together, the data presented in this study first revealed that increased homocysteine levels caused the abnormality of sodium currents in human atrial cells by slowing the inactivation and promote the recovery of sodium channels, which provides a better understanding of hyperhomocysteinemia associated cardiac arrhythmias and ischemia.
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PMID:Homocysteine modulates sodium channel currents in human atrial myocytes. 1911 30

Little attention has been paid to the function of lipoproteins as part of a nonspecific immune defense system that binds and inactivates microbes and their toxins effectively by complex formation. Because of high extra-capillary tissue pressure, aggregates of such complexes may be trapped in vasa vasorum of the major arteries. This complex formation and aggregation may be enhanced by hyperhomocysteinemia, because homocysteine thiolactone reacts with the free amino groups of apo-B to form homocysteinylated low-density lipoprotein (LDL), which is subject to spontaneous precipitation in vitro. Obstruction of the circulation in vasa vasorum, caused by the aggregated complexes, may result in local ischemia in the arterial wall, intramural cell death, bursting of the capillary, and escape of microorganisms into the intima, all of which lead to inflammation and creation of vulnerable plaques. The presence of homocysteinylated LDL and oxidized LDL stimulates production of LDL autoantibodies, which may start a vicious circle by increasing the complex formation and aggregation of lipoproteins. The content of necrotic debris and leukocytes and the higher temperature than its surroundings give the vulnerable plaque some characteristics of a micro-abscess that by rupturing may initiate an occluding thrombosis. This suggested chain of events explains why many of the clinical symptoms and laboratory findings in acute myocardial infarction are similar to those seen in infectious diseases. It explains the presence of microorganisms in atherosclerotic plaques and why bacteriemia and sepsis are often seen in myocardial infarction complicated with cardiogenic shock. It explains the many associations between infections and cardiovascular disease. And it explains why cholesterol accumulates in the arterial wall. Some risk factors may not cause vascular disease directly, but they may impair the immune system, promote microbial growth, or cause hyperhomocysteinemia, leading to vulnerable plaques.
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PMID:Review and Hypothesis: Vulnerable plaque formation from obstruction of Vasa vasorum by homocysteinylated and oxidized lipoprotein aggregates complexed with microbial remnants and LDL autoantibodies. 1920 35

The present study investigated the possible role of Janus kinase-2 (JAK-2) in hyperhomocysteinemia-induced attenuation of the cardioprotective effects of ischemic preconditioning (IPC). Rats were administered L-methionine (1.7 g/kg/day, p.o.) for 4 weeks to produce hyperhomocysteinemia. Isolated Langendorff's perfused normal and hyperhomocysteinemic rat hearts were subjected to global ischemia for 30 min, followed by reperfusion for 120 min. Myocardial infarct size was assessed macroscopically using triphenyltetrazolium chloride staining. Coronary effluent was analyzed for lactate dehydrogenase (LDH) and creatine kinase (CK) release to assess the extent of cardiac injury. The oxidative stress in the heart was assessed by measuring thiobarbituric acid-reactive substances (TBARS), superoxide anion generation and the reduced form of glutathione. Ischemia-reperfusion (I/R) induced oxidative stress by increasing TBARS, superoxide anion generation and decreasing reduced form of glutathione in normal and hyperhomocystenemic rat hearts. Moreover, I/R produced myocardial injury, which was assessed in terms of the increase in myocardial infarct size, LDH and CK release in coronary effluent, and decrease in coronary flow rate in normal and hyperhomocysteinemic rat hearts. The hyperhomocysteinemic rat hearts showed enhanced I/R-induced myocardial injury with a high degree of oxidative stress as compared with normal rat hearts subjected to I/R. Four episodes of IPC (5 min each) afforded cardioprotection against I/R-induced myocardial injury in normal rat hearts as assessed in terms of improvement in coronary flow rate and reduction in myocardial infarct size, levels of LDH, CK, and oxidative stress. On the other hand, IPC-mediated myocardial protection against I/R-injury was abolished in hyperhomocysteinemic rat hearts. Tyrphostin AG490 (5 microM), a selective inhibitor of JAK-2, did not affect the cardioprotective effects of IPC in normal rat hearts, but its administration markedly restored the cardioprotective potential of IPC in hyperhomocysteinemic rat hearts. Administration of diazoxide (30 microM), an ATP-sensitive potassium (K(ATP)) channel opener, also restored the cardioprotective effects of IPC in hyperhomocysteinemic rat hearts. In conclusion, it is suggested that the high degree of oxidative stress produced in hyperhomocysteinemic rat hearts during reperfusion and consequent activation of JAK-2 and closure of K(ATP) channels may be responsible for abolishing the cardioprotective potential of IPC against I/R-induced myocardial injury.
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PMID:Possible role of JAK-2 in attenuated cardioprotective effect of ischemic preconditioning in hyperhomocysteinemic rat hearts. 1942 Aug 83


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