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 multifaceted process of immune cell recruitment to sites of tissue injury is key to the development of an inflammatory response and involved in the pathogenesis of numerous cardiovascular disorders. We recently identified C-type natriuretic peptide (CNP) as an important endothelium-derived mediator that regulates vascular tone and protects against myocardial ischemia/reperfusion injury. Herein, we investigated whether CNP inhibits leukocyte recruitment and platelet aggregation and thereby exerts a potential antiinflammatory influence on the blood vessel wall. We assessed the effects of CNP on leukocyte-endothelial cell interactions in mouse mesenteric postcapillary venules in vivo in animals with high basal leukocyte activation (endothelial nitric oxide synthase knockout mice, eNOS(-/-)) or under acute inflammatory conditions (induced by interleukin-1beta or histamine). CNP suppressed basal leukocyte rolling in eNOS(-/-) mice in a rapid, reversible, and concentration-dependent manner. These effects of CNP were mimicked by the selective natriuretic peptide receptor-C agonist cANF(4-23). CNP also suppressed leukocyte rolling induced by IL-1beta or histamine, inhibited platelet-leukocyte interactions, and prevented thrombin-induced platelet aggregation of human blood. Furthermore, analysis of human umbilical vein endothelial cells, leukocytes, and platelets revealed that CNP selectively attenuates expression of P-selectin. Thus, CNP is a modulator of acute inflammation in the blood vessel wall characterized by leukocyte and platelet activation. These antiinflammatory effects appear to be mediated, at least in part, via suppression of P-selectin expression. These observations suggest that endothelial CNP might maintain an anti-atherogenic influence on the blood vessel wall and represent a target for therapeutic intervention in inflammatory cardiovascular disorders.
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PMID:C-type natriuretic peptide inhibits leukocyte recruitment and platelet-leukocyte interactions via suppression of P-selectin expression. 1617 91

Platelets become activated during myocardial infarction (MI), but the direct contribution of activated platelets to myocardial reperfusion injury in vivo has yet to be reported. We tested the hypothesis that activated platelets contribute importantly to reperfusion injury during MI in mice. After 30 min of ischemia and 60 min of reperfusion, P-selectin knockout mice had a significantly smaller infarct size than that of wild-type mice (P < 0.05). Platelets were detected by P-selectin antibody in the previously ischemic region of wild-type mice as early as 2 min postreperfusion after 45 min, but not 20 min, of ischemia. The appearance of neutrophils in the heart was delayed when compared with platelets. Flow cytometry showed that the number of activated platelets more than doubled after 45 min of ischemia when compared with 20 min of ischemia or sham treatment (P < 0.05). Platelet-rich or platelet-poor plasma was then transfused from either sham-operated or infarcted mice after 45 and 10 min of ischemia-reperfusion to mice undergoing 20 and 60 min of ischemia-reperfusion. Infarct size was increased by threefold and platelet accumulation was remarkably enhanced in mice treated with wild-type, MI-activated platelet-rich plasma but not in mice receiving either platelet-poor plasma from wild types or MI-activated platelet-rich plasma from P-selectin knockout mice. In conclusion, circulating platelets become activated early during reperfusion and their activation depends on the duration of the preceding coronary occlusion and is proportional to the extent of myocardial injury. Activated platelets play an important role in the process of myocardial ischemia-reperfusion injury, and platelet-derived P-selectin is a critical mediator.
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PMID:Activated platelets contribute importantly to myocardial reperfusion injury. 1619 80

Cardiovascular disease is common in asthmatic patients but often is attributed to respiratory drug therapy. With mounting evidence for an inflammatory role in the development of cardiovascular disease, we hypothesized that the inflammation associated with asthma adversely affects the cardiovascular system independent of therapeutic interventions. The hypothesis was tested in a murine model of myocardial ischemia-reperfusion injury. BALB/C mice were sensitized by intraperitoneal injection of ragweed (RW) or normal saline (NS) and challenged by intratracheal instillation of RW or NS. Effective allergic sensitization and challenge were confirmed by hyperresponsiveness to aerosolized methacholine and bronchoalveolar lavage. In vivo myocardial ischemia-reperfusion injury was induced by ligation of the left anterior descending artery for 20 min, followed by reperfusion for 2 h. The infarct size (% risk area) and neutrophil density in the myocardial area at risk were significantly higher in the RW/RW group than in the control groups. The tissue neutrophil count correlated with the infarct size but did not correlate with blood neutrophil counts. Furthermore, in the RW/RW group, circulating granulocytes showed an enhanced expression of CD11b and P-selectin glycoprotein ligand-1, enhanced stimulated release of myeloperoxidase, and enhanced expression of P-selectin in the coronary vasculature. These results indicate that allergic responses in the airways enhance expression of attachment molecules in coronary vasculature and activate circulating neutrophils, resulting in recruitment of highly activated neutrophils to the infarct zone during an acute ischemia-reperfusion event, thereby enhancing tissue destruction.
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PMID:Severity of myocardial injury following ischemia-reperfusion is increased in a mouse model of allergic asthma. 1690 95

The platelet collagen receptor glycoprotein (GP) VI is critical for the formation of arterial thrombosis. GPVI platelet surface expression was examined in patients with stable angina and in patients with acute coronary syndrome (ACS). Surface expression of platelet activation markers such as P-selectin, GPIbalpha, and platelet GPVI was determined by flow cytometry. Patients with ACS showed a significantly enhanced GPVI expression compared with patients with stable angina and healthy controls. The expression of GPVI correlated well with CD62P. Elevated platelet GPVI expression was associated with ACS independent of markers of myocardial necrosis such as troponin and creatine kinase. In ACS, platelet surface GPVI expression was already elevated several hours before troponin and creatine kinase indicated myocardial injury. We conclude that the determination of the platelet-specific thrombotic marker GPVI may help to identify patients at risk before myocardial ischemia is evident.
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PMID:Platelet glycoprotein VI: a novel marker for acute coronary syndrome. 1734 Apr 67

This study compared lipids, the product of lipid peroxidation malondialdehyde (MDA), the acute phase reactant high-sensitive C-reactive protein (hsCRP), endothelin-1 (ET-1), P-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) between healthy controls, subjects with ischemic heart disease (IHD) and type 2 diabetes mellitus (DM) subjects who did not perform coronary artery bypass graft (CABG) surgery as well as type 2 DM subjects who performed CABG. HbA1c, lipids, MDA, hsCRP, ET-1, P-selectin, ICAM-1, and VCAM-1 levels were significantly higher in the diabetic groups than in either healthy controls or IHD subjects. In the diabetic groups, there was a negative association among hsCRP and HDL-C. ET-1, ICAM-1 levels, and TAG were positively correlated, as do the association between P-selectin, VCAM-1, and HbA1c%. Also a positive relation was found among hsCRP levels and ICAM-1, as well as MDA and ET-1. P-selectin and ICAM-1 were significantly positively correlated. This study indicates that increased level of oxidative stress marker, proinflammatory markers, and their downstream effectors adhesion molecules occur in type 2 DM.
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PMID:Evaluation of C-reactive protein, endothelin-1, adhesion molecule(s), and lipids as inflammatory markers in type 2 diabetes mellitus patients. 1749 38

Epidemiological studies have linked levels of particulate matter (PM) in ambient air to cardiovascular mortality and hospitalizations for myocardial infarction (MI) and stroke. Thrombus formation plays a primary role in potentiating acute cardiovascular events, and this study was undertaken to determine whether pulmonary exposure to PM alters hemostasis. PM was collected from the Chapel Hill, NC airshed and was administered to mice by intratracheal instillation at a dose previously shown to exacerbate myocardial ischemia-reperfusion injury. Twenty-four hours after exposure, an increase occurred in the number of circulating platelets and plasma concentrations of fibrinogen and soluble P-selectin. The concentration of tissue factor pathway inhibitor (TFPI) in plasma was decreased, whereas the plasma concentration of plasminogen activator inhibitor (PAI-1) was increased. Consistent with these observations, bleeding time from a tail-tip transection was shortened. These results provide evidence that PM exposure alters hemostasis in otherwise healthy animals and may thereby promote clot formation and impede clot resolution in susceptible individuals. The results also establish definite hemostatic endpoints that can be used to further investigate the effects of dose and particle characteristics on the toxicity of ambient particles.
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PMID:Effect of ambient particulate matter exposure on hemostasis. 1754 51

We demonstrated previously that thrombin stimulation of human coronary artery endothelial cells (HCAEC) results in release of choline lysophospholipids [lysophosphatidylcholine (lysoPtdCho) and lysoplasmenylcholine (lysoPlsCho)]. These amphiphilic metabolites have been implicated in arrhythmogenesis following the onset of myocardial ischemia, but studies examining their direct effects on the vasculature remain limited. We and others have shown that thrombin and lysoPtdCho can increase cell surface adhesion molecules and adherence of circulating inflammatory cells to the endothelium. This study supports our hypothesis that these changes may be mediated, at least in part, by lysoPlsCho, thus implicating this metabolite as an inflammatory mediator in the coronary vasculature and a modulator of the progression of atherosclerosis. Apical stimulation of HCAEC with thrombin resulted in the production and release of choline lysophospholipids from the apical surface of the HCAEC monolayer. Basolateral stimulation had no effect on choline lysophospholipid production or release from either the apical or basolateral surface of the HCAEC monolayer. Incubation of HCAEC with lysoPlsCho or lysoPtdCho resulted in similar increases in HCAEC surface expression of P-selectin and E-selectin. Furthermore, lysoPlsCho increased cell surface expression of P-selectin, E-selectin, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1 with a time course similar to that of thrombin stimulation. Increased presence of cell surface adhesion molecules may contribute to the significant increase in adherence of neutrophils to either thrombin- or lysoPlsCho-stimulated HCAEC. These results demonstrate that the presence of thrombin at sites of vascular injury in the coronary circulation, resulting in increased choline lysophospholipid release from the HCAEC apical surface, has the potential to propagate vascular inflammation by upregulation of adhesion molecules and recruitment of circulating inflammatory cells to the endothelium.
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PMID:Lysoplasmenylcholine increases neutrophil adherence to human coronary artery endothelial cells. 1772 94

Stress may counteract responses to antiplatelet drug treatment. We investigated if adding clopidogrel to aspirin treatment could attenutate stress-induced platelet activation and myocardial ischemia in patients with coronary artery disease (CAD). Thirty-one male patients with documented CAD-treated with aspirin (75-160 mg daily) were randomized to co-treatment with clopidogrel (n = 16) or placebo (n = 15). A symptom-limited exercise test and 48-hour (h) Holter monitoring were performed before and after two weeks of double-blind treatment. Platelet function was assessed by flow cytometry and impedance aggregometry in whole blood. Exercise-induced and ambulatory ischemia was assessed from electrocardiographic (ECG) recordings. Clopidogrel treatment inhibited ADP-induced platelet P-selectin expression by 64% (22-87%), and attenuated the P-selectin response to thrombin (p < 0.001), and platelet aggregation induced by low-dose collagen (p < 0.01). Exercise ( approximately 110W) increased heart rate similarly, and caused approximately 1.8 mm ST-segment depression both before and after treatment. Exercise caused platelet activation, i.e. increased circulating activated single platelets and platelet-platelet aggregates, enhanced the in-vitro responsiveness to ADP or thrombin stimulation, and increased platelet-leukocyte aggregation. Clopidogrel inhibited ADP-induced platelet activation to a similar relative degree at rest and during exercise, but did not attenuate the platelet activating effect of exercise. Addition of clopidogrel to aspirin treatment did not attenuate either ambulatory or exercise-induced ischemia. In conclusion, adding clopidogrel to aspirin treatment inhibited platelet activation by both ADP, thrombin and collagen in vitro, but did not influence the prothrombotic responses to exercise. Intensified antiplatelet treatment did not reduce ECG signs of either exercise-induced or ambulatory myocardial ischemia.
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PMID:Effect of clopidogrel treatment on stress-induced platelet activation and myocardial ischemia in aspirin-treated patients with stable coronary artery disease. 1806 30

Clinical evidence indicates that intensive insulin therapy during critical illness protects the endothelium and contributes to prevention of organ failure and death but the mechanisms involved remain unclear. This study was designed to test the hypothesis that insulin inhibits adherence of polymorphonuclear leukocytes (PMNs) to endothelial cells in myocardial ischemia/reperfusion (MI/R) and to investigate the underlying mechanisms. Anesthetized rabbits were subjected to MI/R (45 min/4 h) and randomly received saline, glucose-insulin-potassium (GIK) or GK respectively (2 mL/kg/h, i.v.). In vitro study was performed on cultured endothelial cells subjected to simulated ischemia/reperfusion. In vivo treatment with GIK but not GK attenuated myocardial injury as evidenced by reduced plasma creatine kinase activity, myocardial apoptosis and infarct size in MI/R rabbits compared with the saline group. Interestingly, GIK but not GK significantly decreased coronary endothelial expression of P-selectin and intercellular adhesion molecule-1 (ICAM-1), inhibited adherence of PMNs to coronary endothelium (107.7+/-7.4 vs. 155.0+/-9.2 PMNs/mm(2) in saline group, n=8, P<0.01), and therefore decreased myocardial PMNs accumulation. In cultured endothelial cells subjected to simulated ischemia/reperfusion, insulin (10(-)(7) M) increased Akt activity and eNOS phosphorylation with subsequent NO production, and concurrently exerted an anti-adhesive effect as manifested by reduced endothelial P-selectin and ICAM-1 surface expression and PMNs adherence (13.7+/-1.3% vs. 22.2+/-1.9% in vehicle, n=9, P<0.01), all of which are abolished by the specific Akt inhibitor. Furthermore, inhibition of insulin-stimulated NO production using either the selective eNOS inhibitor cavtratin or the NOS inhibitor L-NAME blocked the anti-adhesive effect of insulin. These results demonstrate that insulin reduces endothelial P-selectin and ICAM-1 expression, and thus inhibits leukocyte-endothelium adherence in MI/R rabbit hearts. The anti-adhesive property by insulin may be mediated by the Akt-mediated and NO-dependent pathway.
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PMID:Insulin inhibits leukocyte-endothelium adherence via an Akt-NO-dependent mechanism in myocardial ischemia/reperfusion. 1961 3

Over the past fifteen years, numerous observations have linked Helicobacter pylori (H. pylori) infection to ischemic heart disease (IHD). Despite the controversial literature data, it has been postulated that if a role is plausible, it will be in the early events of the acute coronary syndrome. According to this model, we focused on the potential pathogenic mechanisms relating H. pylori to IHD like platelet aggregation and thrombosis. To identify all publications in this field, a MEDLINE search of studies published in English from 1965 to 2009 was conducted. Although very few investigations were found, these showed data of paramount importance. In particular, it has been demonstrated that some strains of H. pylori bind von Willebrand factor and interact with glycoprotein Ib to induce platelet aggregation in humans. In experiments from animal models, such infection promoted the formation of platelet aggregates by both a marked increase in the flux of rolling leukocytes and the appearance of platelet and leukocyte-platelet aggregates in gastric venules. This aggregate formation was abrogated by antibodies against specific adhesion molecules (L- and P-selectin). The future challenge is to gain more knowledge in this field and to translate these information into clinical practice.
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PMID:Potential link between Helicobacter pylori and ischemic heart disease: does the bacterium elicit thrombosis? 2046 11


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