Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0151744 (myocardial ischemia)
 31,282 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The transient receptor potential vanilloid (TRPV1) channels expressed in sensory afferent fibers innervating the heart may be activated by protons or endovanilloids released during myocardial ischemia (MI), leading to angina. Although our previous in vitro data indicate that TRPV1 activation may preserve cardiac function after ischemia-reperfusion injury, the underlying mechanisms are largely unknown. To test the hypothesis that TRPV1 modulates inflammatory and early remodeling processes to prevent cardiac functional deterioration after myocardial infarction, TRPV1-null mutant (TRPV1(-/-)) and wild-type (WT) mice were subjected to left anterior descending coronary ligation or sham operation. The infarct size was greater in TRPV1(-/-) than in WT mice (P<0.001) 3 days after MI, and the mortality rate was higher in TRPV1(-/-) than in WT mice (P<0.05) 7 days after MI. The levels of plasma cardiac troponin I; cytokines, including tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6; chemokines, including monocyte chemoattractant protein-1 and macrophage inflammatory protein-2; and infiltration of inflammatory cells, including neutrophils, macrophages, and myofibroblasts; as well as collagen contents, were greater in TRPV1(-/-) than in WT mice (P<0.05) in the infarct area on days 3 and 7 after MI. Changes in left ventricular geometry led to increased end-systolic and -diastolic diameters and reduced contractile function in TRPV1(-/-) compared with WT mice. These data show that TRPV1 gene deletion results in excessive inflammation, disproportional left ventricular remodeling, and deteriorated cardiac function after MI, indicating that TRPV1 may prevent infarct expansion and cardiac injury by inhibiting inflammation and abnormal tissue remodeling.
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PMID:Transient receptor potential vanilloid gene deletion exacerbates inflammation and atypical cardiac remodeling after myocardial infarction. 1911 47

Toll-like receptor 4 (TLR4) activation has been implicated in the pathogenesis of myocardial ischemia/reperfusion (I/R) injury. The activated TLR4 is capable of activating a variety of proinflammatory mediators, such as tumor necrosis factor-a (TNF-a) and interleukin-6 (IL-6). Valsartan as a kind of Angiotensin II type 1 receptor blockers is gradually used for the treatment of ischemic heart disease depending on its anti-inflammation function. Therefore, we hypothesized that valsartan protects against myocardial I/R injury by suppressing TLR4 activation. We constructed the rat model of myocardial I/R injury. The rats were pretreated with valsartan for 2 weeks, and then subjected to 30 min ischemia and 2 h reperfusion. TLR4 and Nuclear factor kappa-B (NF-kappaB) levels were detected by quantitative real-time PCR and western blot. In order to evaluate myocardial damage, the myocardial infarct size, histopathologic changes, and the release of myocardial enzymes, proinflammation cytokines and Angiotensin II were analyzed by triphenyl tetrazolium chloride (TTC) staining, light microscopy, and enzyme-linked immunosorbent assay (ELISA), respectively. Valsartan preconditioning inhibited TLR4 and NF-kappaB expressions concomitant with an improvement in myocardial injury, such as smaller infarct size, fewer release of myocardial enzymes, and proinflammation mediators. These findings suggest that valsartan plays a pivotal role in the protective effects on myocardial I/R injury. This protection mechanism is possibly due to its anti-inflammation function via TLR4/NF-kappaB signaling pathway.
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PMID:Valsartan preconditioning protects against myocardial ischemia-reperfusion injury through TLR4/NF-kappaB signaling pathway. 1937 Mar 15

Knowledge about the physiologic and pathophysiologic roles of tumor necrosis factor-alpha (TNF-alpha) in acute myocardial ischemia/infarction is still very limited. Evidence implies that TNF-alpha is involved in neural activity including nociception in peripheral and central nervous system. Current study was designed to examine the association of change in TNF-alpha and its mRNA in upper thoracic dorsal root ganglia and spinal cord (T1-T5) during acute myocardial ischemia/infarction induced by coronary artery occlusion (CAO) in rats. The experiment was performed using immunohistochemistry, enzyme immunoassay, in situ hybridization and real time reverse transcription-polymerase chain reaction techniques. At 0.5h, 1h, 3h and 6h of acute myocardial ischemia/infarction, TNF-alpha was mainly up-regulated in a sub-population of small and medium neurons and satellite cells in the dorsal root ganglia (DRG) and spinal neurons, mainly in laminae I, II and V, VI of the spinal dorsal horn of upper thoracic segments. The up-regulation of TNF-alpha mRNA was observed at 30min of CAO, which was statistically significant, compared with the control and the sham surgery groups (P<0.01). The TNF-alpha mRNA was located in the satellite cells and afferent neurons of the DRG and spinal neurons, located mainly in laminae II-VI. The findings indicate an association of up-regulation of TNF-alpha in DRG and spinal cord with acute myocardial ischemia/infarction, suggesting that TNF-alpha may be associated with the nociception initiated by acute myocardial ischemia/infarction, while the pathophysiological role needs to be studied.
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PMID:Up-regulation of TNF-alpha in neurons of dorsal root ganglia and spinal cord during coronary artery occlusion in rats. 1939 8

We examined our hypothesis that (S)-1-(alpha-naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (CKD712) inhibits apoptosis in myocardial ischemia and reperfusion (I/R) injury in vivo via activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and by reducing inflammation during I/R. To do this, we induced a 30-min period of ischemia by occlusion of the left anterior descending coronary artery of the rat followed by a 2-h (for phosphorylation of Akt), 6-h (for biochemical analysis), or 24-h (for functional analysis) period of reperfusion to determine the effect of CKD712 treatment. Pretreatment with CKD712 significantly improved myocardial function as evidenced by an increase in the +/-dP/dt and a decrease in the infarct size, which were antagonized by a PI3K inhibitor, wortmannin (WT). Interestingly, CKD712 increased the phosphorylation of Akt and cAMP-response element-binding protein and increased the expression of the Bcl-2 gene, but it reduced the expression of the Bax gene. CKD712 decreased not only the expression but also the activity of the caspase-3 protein in the myocardium after reperfusion. Thus, all of the antiapoptotic effects of CKD712 were significantly inhibited by WT. Furthermore, the antiapoptotic effects of CKD712 and its inhibition by WT in myocardium after reperfusion were confirmed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining. Finally, CKD712 was found to reduce the serum levels of the high-mobility group box 1 protein, tumor necrosis factor-alpha, and the cardiac troponin I protein in addition to tissue levels of malondialdehyde and myeloperoxidase activity in I/R hearts. Taken together, both the activation of PI3K/Akt and its anti-inflammatory action prevent apoptosis in myocardial I/R injury by CKD712.
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PMID:(S)-1-(alpha-naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (CKD712) reduces rat myocardial apoptosis against ischemia and reperfusion injury by activation of phosphatidylinositol 3-kinase/Akt signaling and anti-inflammatory action in vivo. 1945 86

Flaxseed and its components may improve cardiovascular health because of their numerous attributes. Flaxseed contains 35% of its mass as oil, of which 55% is alpha-linolenic acid (ALA). Flax meal, which is devoid of oil, contains the lignan secoisolariciresinol diglucoside (SDG). Flaxseed, flaxseed with very low ALA, flaxseed oil, flax lignan complex (FLC), and SDG reduce the development of hypercholesterolemic atherosclerosis by 46%, 69%, 0%, 73%, and 34%, respectively, in the rabbit model. FLC and SDG slow the progression of atherosclerosis but have no effect in regression of atherosclerosis. Suppression of atherosclerosis by flaxseed is the result of its lignan content and not the result of ALA content. Suppression of atherosclerosis is associated with lowering of serum lipids and antioxidant activity. Effects of flaxseed on serum lipids in experimental animals are variable from no change to slight reduction. Flaxseed oil does not affect serum lipids, except for a slight reduction in serum triglycerides. Lignan in general reduces serum total cholesterol and low-density lipoprotein cholesterol and raises serum high-density lipoprotein cholesterol. SDG and its metabolites have antioxidant activity. Flaxseed and flaxseed oil do not have antioxidant activity except they suppress oxygen radical production by white blood cells. Flaxseed oil/ALA has variable effects on inflammatory mediators/markers (interleukin [IL]-1beta, IL-2, IL-4, IL-6, IL-10, tumor necrosis factor-alpha, interferon-gamma, C-reactive protein, and serum amyloid A). Doses of ALA less than 14 g/d do not affect inflammatory mediators/markers, but 14 g/d or greater reduce inflammatory mediators/markers. Flaxseed oil decreases soluble vascular cell adhesion molecule-1 but has no effect on soluble intracellular adhesion molecule-1, soluble E-selectin, and monocyte colony-stimulating factor. Flaxseed has variable effects on IL-6, high-sensitivity C-reactive protein, and soluble vascular cell adhesion molecule-1. FLC reduces plasma levels of C-reactive protein but has no effects on IL-6, tumor necrosis factor-alpha, soluble intracellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, or monocyte chemoattractant protein. Flaxseed has a very small hypotensive effect, but flaxseed oil does not lower blood pressure. However, SDG is a very potent hypotensive agent. Flaxseed oil decreases platelet aggregation and increases platelet activating inhibitor-1 and bleeding time. Flaxseed and FLC have no effect on the hemopoietic system. SDG is a potent angiogenic and antiapoptotic agent that may have a role in cardioprotection in ischemic heart disease. In conclusion, flaxseed, FLC, and SDG, but not flaxseed oil, suppress atherosclerosis, and FLC and SDG slow progression of atherosclerosis but have no effect on regression. Flaxseed oil suppresses oxygen radical production by white blood cells, prolongs bleeding time, and in higher doses suppresses serum levels of inflammatory mediators and does not lower serum lipids.
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PMID:Flaxseed and cardiovascular health. 1956 81

This study was designed to determine the role of tumor necrosis factor-alpha (TNFalpha) in apoptosis observed in the myocardium and limbic system after myocardial ischemia. PEG sTNFRI, a recombinant, human, soluble p55 Type 1 TNF receptor (3 mg/kg) or vehicle (saline) was administered s.c. to male Sprague-Dawley rats on days 5, 3 and 1 before myocardial ischemia. The animals were then subjected, under anesthesia, to left anterior descending coronary artery occlusion for 40 min, followed by 15-min or 72-h reperfusion. Caspase-3 and -8 activities as well as terminal dUTP nick-end labelling-positive cells were examined in the myocardium (subendocardial and subepicardial regions), lateral (LA) and medial amygdala (MA) and hippocampus (CA1, CA3, dentate gyrus (DG)). After 15 min of reperfusion, the subendocardial and CA1 regions presented an increase in caspase-3 activity, whereas caspase-8 activity appeared to be augmented in the DG. PEG sTNFRI inhibited caspase-8 activation in the DG. After 72 h of reperfusion, plasma TNFalpha levels were reduced in the treated groups. The DG, CA1, CA3 and MA showed an increment of caspase-8 activity, which was reversed by PEG sTNFRI, except in the MA. Furthermore, caspase-3 activity was increased in the CA1, DG, LA and MA. These results indicate that TNFalpha contributes to apoptosis via activation of the extrinsic pathway in the limbic system after myocardial infarction, which is not the case in the myocardium.
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PMID:Tumor necrosis factor-alpha participates in apoptosis in the limbic system after myocardial infarction. 1972 97

One hundred and eighty-four patients aged 60-95 years who had ischemic heart disease (IHD) were examined. The serum levels of total cholesterol, triglycerides, high-density lipoproteins, low-density lipoproteins, apoA- and apoB-lipoproteins, calcium, phosphorus, alkaline phosphatase, etc. were measured on a Vitalab Flexor E. biochemical analyzer. The content of cytokines was determined by solid-phase immunoassay using the Protein contour test systems (State Research Institute of Particularly Pure Biologicals, Saint-Petersburg) on a Stat Fax photometer. There were pronounced changes in the cytokine spectrum in elderly and senile persons despite the fact that they had an adequate lipid spectrum. The increased levels of interleukin (IL)-1 beta and IL-6 suggest that there is an inflammatory reaction whereas those of tumor necrosis factor-alpha may be indicative of the body's autoimmune readiness. There was a high direct correlation of the content of apolipoproteins Apo-B1 and IL-6, as well as LP alpha and IL-6; ApoB1/Apo-A1 and IL-6. A high inverse correlation was found in the content of Apo-B1 and IL-6, which is a poor predictor in old age group patients. There was a mean correlation in the levels of apolipoproteins (B1 and B alpha) and the cytokines IL-1 beta, IL-4, IFN-gamma, TNF-alpha, and IFN-alpha; and there was a mean inverse correlation between the concentrations of apolipoproteins A1 and these cytokines.
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PMID:[Plasma lipids and interleukins in geriatric patients with ischemic heart disease]. 1982 89

We previously found that myocardial ischemia/reperfusion (I/R) initiates expression of tumor necrosis factor-alpha (TNF) leading to coronary endothelial dysfunction. However, it is not clear whether there is a direct relationship between levels of TNF expression and endothelial dysfunction in reperfusion injury. We studied levels of TNF expression by using different transgenic animals expressing varying amounts of TNF in I/R. We crossed TNF overexpression (TNF(++/++)) with TNF knockout (TNF(-/-)) mice; thus we have a heterozygote population of mice with the expression of TNF "in between" the TNF(-/-) and TNF(++/++) mice. Mouse hearts were subjected to 30 min of global ischemia followed by 90 min of reperfusion and their vasoactivity before and after I/R was examined in wild type (WT), TNF(-/-), TNF(++/++) and TNF heterozygote (TNF(-/++), cross between TNF(-/-) and TNF(++/++)) mice. In heterozygote TNF(-/++) mice with intermediate cardiac-specific expression of TNF, acetylcholine-induced or flow-induced endothelial-dependent vasodilation following I/R was between TNF(++/++) and TNF(-/-) following I/R. Neutralizing antibodies to TNF administered immediately before the onset of reperfusion-preserved endothelial-dependent dilation following I/R in WT, TNF(-/++) and TNF(++/++) mice. In WT, TNF(-/++) and TNF(++/++) mice, I/R-induced endothelial dysfunction was progressively lessened by administration of free-radical scavenger TEMPOL immediately before initiating reperfusion. During I/R, production of superoxide (O(2) (.-)) was greatest in TNF(++/++) mice as compared to WT, TNF(-/++) and TNF(-/-) mice. Following I/R, arginase mRNA expression was elevated in the WT, substantially elevated in the TNF(-/++) and TNF(++/++) mice and not affected in the TNF(-/-) mice. These results suggest that the level of TNF expression determines arginase expression in endothelial cells during myocardial I/R, which is one of the mechanisms by which TNF compromises coronary endothelial function in reperfusion injury.
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PMID:Direct relationship between levels of TNF-alpha expression and endothelial dysfunction in reperfusion injury. 2009 14

Vagal nerve stimulation (VS) has been reported to improve the survival after both acute and chronic myocardial infarction through the release of neurotransmitter ACh. However, the precise mechanism behind its beneficial effect is still unknown. In this study, we demonstrate the upregulation of tumor necrosis factor-alpha (TNF-alpha) and its cell survival TNF receptor-2 (TNFR2) as the mechanism behind VS induced myocardial protection. We investigated the effects of efferent VS on myocardial ischemic injury with in vivo and in vitro mouse models. In in vivo hearts VS significantly increased the expression of TNF-alpha both at the messenger and protein level after 3-hours of myocardial ischemia. In the in vitro studies ACh treatment before hypoxia, induced a significant upregulation of TNF-alpha compared to the untreated cardiomyocytes. Immunofluorescence analysis confirmed the synthesis of TNF-alpha by cardiomyocytes both in vivo and in vitro. VS also significantly reduced the myocardial infarct size (23.9+/-5.7% vs. 56+/-1.9%) and activated the cell survival Akt cascade system. Further, ACh upregulated the cell survival TNFR2 expression, while downregulating the cell destructive TNF receptor 1 (TNFR1) expression. These results were confirmed using the TNF receptors deficient mice, where the VS mediated protection was lost both in vivo and in vitro in TNFR2 (TNFR2(-/-)) and TNF receptors double knock out (TNFR1(-/-)2(-/-)) mice. VS and ACh protects the heart against acute ischemia or hypoxic injury by differentially regulating the TNF receptor subtypes.
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PMID:Differential regulation of TNF receptors by vagal nerve stimulation protects heart against acute ischemic injury. 2030 76

Recently we reported that an efferent vagal fibre-mediated cholinergic protective pathway, activated by melanocortins acting at brain melanocortin MC(3) receptors, is operative in a condition of short-term myocardial ischemia/reperfusion associated with a high incidence of severe arrhythmias and death. Here we investigated melanocortin effects, and the role of the vagus nerve-mediated cholinergic protective pathway, in a rat model of prolonged myocardial ischemia/reperfusion associated with marked inflammatory and apoptotic reactions, and a large infarct size. Ischemia was produced in rats by ligature of the left anterior descending coronary artery for 30 min. At the end of the 2-h reperfusion, western blot analysis of the inflammatory and apoptotic markers tumor necrosis factor-alpha (TNF-alpha), c-jun N-terminal kinases (JNK) and caspase-3, as well as of the anti-apoptotic extracellular signal-regulated kinases (ERK 1/2), was performed in the left ventricle. In saline-treated ischemic rats there was an increase in TNF-alpha levels and in the activity of JNK and caspase-3 accompanied, despite an appreciable ERK 1/2 activation, by a large infarct size. Intravenous treatment, during coronary artery occlusion, with the melanocortin analog [Nle(4), D-Phe(7)]alpha-melanocyte-stimulating hormone (NDP-alpha-MSH) produced a reduction in TNF-alpha levels and in the activity of JNK and caspase-3, associated with marked activation of the pro-survival kinases ERK 1/2, and consequent attenuation of infarct size. Bilateral cervical vagotomy blunted the protective effects of NDP-alpha-MSH. These results indicate that melanocortins modulate the inflammatory and apoptotic cascades triggered by prolonged myocardial ischemia/reperfusion, and reduce infarct size, seemingly by activation of the vagus nerve-mediated cholinergic protective pathway.
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PMID:Melanocortins counteract inflammatory and apoptotic responses to prolonged myocardial ischemia/reperfusion through a vagus nerve-mediated mechanism. 2038 18


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