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

Chronic infection and inflammation have recently been implicated as important etiologic agents for atherosclerosis in general and, in particular, ischemic heart disease. Several agents have been suggested as possible candidates for the chronic inflammation including cytomegalovirus, Helicobacter pylori and Chlamydia pneumoniae. We hypothesized that a vascular infection with C. pneumoniae may induce a chronic inflammatory reaction in the host vascular tissue and activated inflammatory cells may express inflammatory mediators such as cyclooxygenase-2 (COX-2) and matrix metalloproteinases (MMPs). At first, we evaluated the relationship between C. pneumoniae infection and atherosclerosis indirectly by serologic study, and then, to confirm our hypothesis, we performed an immunohistochemical study of atherosclerotic plaques. The seropositive rate of anti-Chlamydia pneumoniae IgG was higher in the disease group (Group I, 59.8%, n = 254) than in the negative control group (Group III, 47.4%, n = 97) (p = 0.041), but the anti-Chlamydia pneumoniae IgA was not different in seropositivity between the two groups (Group I, 64.6%; Group III, 57.7%). The simultaneous seropositive rates of both IgG and IgA were 56.7% in Group I and 43.3% in Group III (p = 0.033). In subgroups without the conventional risk factors of atherosclerosis, these findings were more prominent. Furthermore, we performed immunohistochemical staining on the atherosclerotic aortic tissues obtained from patients that were seropositive to C. pneumoniae (n = 5), by using antibodies to C. pneumoniae, COX-2, and MMP-9. The immunoreactivity for COX-2 and MMP-9 increased in the atherosclerotic plaques itself, predominantly in the surrounding area of immunoreactive C. pneumoniae. These findings support our hypothesis and C. pneumoniae may participate in a pathogenetic mechanism for atherogenesis or progression of atherosclerosis. The present study may open a promising perspective concerning future therapeutic trials of chronic inflammation related atherogenesis under pathophysiological conditions.
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PMID:Serologic and histopathologic study of Chlamydia pneumoniae infection in atherosclerosis: a possible pathogenetic mechanism of atherosclerosis induced by Chlamydia pneumoniae. 1095 85

The Janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathway is a stress-responsive mechanism that transduces signals from the cell surface to the nucleus, thereby modulating gene expression. Recent studies have demonstrated that myocardial ischemia and reperfusion induce rapid activation of this pathway. Although the functional consequences of this event remain to be elucidated, there is emerging evidence that JAK-STAT signaling plays an important role in the development of the cardioprotected phenotype associated with ischemic preconditioning. Specifically, brief episodes of myocardial ischemia/reperfusion activate JAK1 and JAK2, followed by recruitment of STAT1 and STAT3, resulting in transcriptional upregulation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), which then mediate the infarct-sparing effects of the late phase of preconditioning. The present review focuses on this novel cardioprotective role of JAK-STAT signaling and on its potential exploitation for developing therapeutic strategies aimed at limiting ischemia/reperfusion injury.
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PMID:Role of the JAK-STAT pathway in protection against myocardial ischemia/reperfusion injury. 1258 43

Although the inducible isoform of NO synthase (iNOS) mediates late preconditioning (PC), it is unknown whether iNOS gene transfer can replicate the cardioprotective effects of late PC, and the role of this protein in myocardial ischemia is controversial. Thus, the cDNA for human iNOS was cloned behind the Rous sarcoma virus (RSV) promoter to create adenovirus (Ad) 5/iNOS lacking E1, E2a, and E3 regions. Intramyocardial injection of Ad5/iNOS in mice increased local iNOS protein expression and activity and markedly reduced infarct size. The infarct-sparing effects of Ad5/iNOS were at least as powerful as those of ischemic PC. The increased iNOS expression was associated with increased cyclooxygenase-2 (COX-2) protein expression and prostanoid levels. Pretreatment with the COX-2-selective inhibitor NS-398 completely abrogated the infarct-sparing actions of Ad5/iNOS, demonstrating that COX-2 is an obligatory downstream effector of iNOS-dependent cardioprotection. We conclude that gene transfer of iNOS (an enzyme commonly thought to be detrimental) affords powerful cardioprotection the magnitude of which is equivalent to that of late PC. This is the first report that upregulation of iNOS, in itself, is sufficient to reduce infarct size. The results provide proof-of-principle for gene therapy against ischemia/reperfusion injury, which increases local myocardial NO synthase levels without the need for continuous intravenous infusion of NO donors and without altering systemic hemodynamics. The data also reveal the existence of a close coupling between iNOS and COX-2, whereby induction of the former enzyme leads to secondary induction of the latter, which in turn mediates the cytoprotective effects of iNOS. We propose that iNOS and COX-2 form a stress-responsive functional module that mitigates ischemia/reperfusion injury.
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PMID:Gene therapy with inducible nitric oxide synthase protects against myocardial infarction via a cyclooxygenase-2-dependent mechanism. 1270 42

The purpose of the study was to examine the clinical features of the course of coronary heart disease (CHD) in patients with rheumatoid arthritis (RA) and to evaluate the effects of the selective cyclooxygenase-2 (COG-2) inhibitor movalis (meloxicam) in two dosage forms (as injections and tablets) on the course of CHD in this group of patients. The developed questionnaire was used to make a comparative screening survey of 304 patients with RA and 152 patients with osteoarthrosis (OA), who were aged above 40 years. A comprehensive examination of the cardiovascular system was performed in 52 patients with RA concurrent with CHD and 25 patients with OA concurrent with CHD. Angina pectoris on exertion was detected in 37% of the patients with PA and in 35% of the patients with OA. Most (52%) patients with RA and CHD reported rare anginal attacks (once a month) whereas 24-day ECG monitoring revealed myocardial ischemia in 71% of the patients with RA concurrent with CHD; only silent ischemic episodes were recorded in 70% of them. The incidence of silent myocardial ischemia was higher in patients with RA concurrent with CHD than that in those with OA concurrent with CHD (p < 0.03). Examination of the incidence of anginal attacks showed that there was a tendency of the incidence of pains to decrease in patients with RA concurrent with CHD who took selective COG-2 inhibitors. Patients with RA concurrent with CHD who received movalis had atendency of arrhythmia to occur more rarely and of the duration of myocardial ischemia to reduce as compared with those who took nonselective COG-2 inhibitors.
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PMID:[Use of meloxicam (movalis) in patients with rheumatic diseases with concomitant coronary heart disease]. 1573 22

We investigated whether endogenous ligands of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) protect the heart against ischemia-reperfusion (I/R) injury. The selective PPAR-gamma antagonist GW9662 (2-chloro-5-nitrobenzanilide) was used in rat models of 1) regional myocardial I/R, 2) ischemic preconditioning, and 3) delayed cardioprotection by endotoxin. We also investigated the effects of the selective cyclooxygenase-2 inhibitor, parecoxib, on ischemic preconditioning and delayed cardioprotective effects of endotoxin. Male Wistar rats were anesthetized with sodium thiopentone. Animals were subjected to either 15 or 25 min of regional myocardial I/R and pretreated with the PPAR-gamma agonist ciglitazone (0.3 mg/kg), the PPAR-gamma antagonist GW9662 (1 mg/kg), or GW9662 and ciglitazone. Animals were also subjected to either 1) ischemic preconditioning alone, ischemic preconditioning, and pretreated with either GW9662 or parecoxib (20 mg/kg) or 2) lipopolysaccharide (LPS) (1 mg/kg) alone, LPS, and pretreated with ciglitazone, GW9662, or parecoxib (20 mg/kg). Myocardial infarct size was determined by p-nitroblue tetrazolium staining. The PPAR-gamma antagonist GW9662 (1 mg/kg) abolished the cardioprotection afforded by the potent PPAR-gamma agonist ciglitazone (0.3 mg/kg). Neither GW9662 nor parecoxib affected the cardioprotective effects of ischemic preconditioning. Pretreatment with ciglitazone did not provide additional cardioprotection to LPS-treated animals. Both GW9662 and parecoxib abolished the delayed cardioprotective effects of endotoxin. Thus, we propose that 1) endogenous ligands of PPAR-gamma are being generated by myocardial ischemia in sufficient amounts to attenuate myocardial I/R injury, and 2) that cyclooxygenase-2 metabolites contribute to (or even account for) the cardioprotective effects of endotoxin (second window of protection) by acting as endogenous PPAR-gamma ligands.
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PMID:The cardioprotective effects of preconditioning with endotoxin, but not ischemia, are abolished by a peroxisome proliferator-activated receptor-gamma antagonist. 1573 1

Cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) have been shown to be mediators of cardioprotection induced by ischemic preconditioning and opioids. However, it is not known whether COX-2 is involved in morphine-induced cardioprotection accompanied with iNOS. Therefore, we investigated the role of COX-2 in morphine-induced cardioprotection and the effect of iNOS on COX-2. Myocardial ischemia was induced by a 45-min coronary artery occlusion in mice. Infarct size (IS) as a percentage of the area at risk (AAR) was determined by triphenyltetrazolium chloride staining. The COX-2-selective inhibitor NS-398 was used to investigate the role of COX-2. Expression of COX-2 was assessed by Western blotting, and the myocardial prostaglandin (PG)E2 and 6-keto-PGF(1alpha) contents were measured using enzyme immunoassays. The iNOS-selective inhibitor SMT and iNOS gene-knockout mice were used to investigate the effect of iNOS on COX-2. IS/AAR was reduced significantly 1 and 24 h after morphine preconditioning. The infarct-sparing effect 24 h after morphine administration, but not the cardioprotection 1 h later, was completely abolished by NS-398. Marked enhancement of myocardial COX-2 expression was measured 24 h after morphine preconditioning associated with up-regulation of myocardial contents of PGE2 and 6-keto-PGF(1alpha). Neither the level of COX-2 nor the contents of PGE2 and 6-keto-PGF(1alpha) were enhanced 1 h later. Administration of SMT and targeted abrogation of iNOS gene blocked the enhancement of myocardial PGE2 and 6-keto-PGF(1alpha) 24 h after morphine administration but did not inhibit the up-regulation of COX-2 expression. We concluded that COX-2 mediates morphine-induced delayed cardioprotection via an iNOS-dependent pathway.
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PMID:COX-2 mediates morphine-induced delayed cardioprotection via an iNOS-dependent mechanism. 1632 9

Experiments were conducted in the anesthetized rabbit to investigate mechanisms for arrhythmias that occur after left atrial injection of the thromboxane A(2) (TxA(2)) mimetic U-46619. Arrhythmias were primarily of ventricular origin, dose dependent in frequency, and TxA(2) receptor mediated. The response was receptor specific since arrhythmias were absent after pretreatment with a specific TxA(2) receptor antagonist (SQ-29548) and did not occur in response to another prostaglandin, PGF(2alpha). Alterations in coronary blood flow were unlikely the cause of these arrhythmias because coronary blood flow (as measured with fluorescent microspheres) was unchanged after U-46619, and there were no observable changes in the ECG-ST segment. In addition, arrhythmias did not occur after administration of another vasoconstrictor (phenylephrine). The potential involvement of autonomic cardiac efferent nerves in these arrhythmias was also investigated because TxA(2) has been shown to stimulate peripheral nerves. Pretreatment of animals with the beta-adrenergic receptor antagonist propranolol did not reduce the frequency of these arrhythmias. Pretreatment with atropine or bilateral vagotomy resulted in an increased frequency of arrhythmias, suggesting that parasympathetic nerves may actually inhibit the arrhythmogenic activity of TxA(2). These experiments demonstrate that left atrial injection of U-46619 elicits arrhythmias via a mechanism independent of a significant reduction in coronary blood flow or activation of the autonomic nervous system. It is possible that TxA(2) may have a direct effect on the electrical activity of the heart in vivo, which provides significant implications for cardiac events where TxA(2) is increased, e.g., after myocardial ischemia or administration of cyclooxygenase-2 inhibitors.
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PMID:Thromboxane A2-induced arrhythmias in the anesthetized rabbit. 1633 32

Selective cyclooxygenase-2 inhibitors have been marketed as alternatives of conventional, non-steroidal anti-inflammatory drugs with the purpose of reducing/eliminating the risk of ulcer complications. Unexpectedly, randomized-controlled trials revealed that long-term use of coxibs, such as rofecoxib, significantly increased the risk of myocardial infarction and stroke, while the use of valdecoxib was associated with potentially life-threatening skin reactions. Subsequently, rofecoxib and valdecoxib were withdrawn from the market. Although more strict precautions for other coxibs, such as celecoxib, etoricoxib, lumiracoxib and parecoxib, may be accepted/recommended by regulatory agencies, a critical review of published data suggests that their use may not be justified - even in high-risk patients - taking benefits, costs and risks into consideration. Clinicians should, therefore, never prescribe coxibs to patients with cardiovascular risk factors, and should only reluctantly prescribe coxibs to patients with a history of ulcer disease or dyspepsia to overcome persistent pain due to, e.g. rheumatoid arthritis or osteoarthritis. Instead, they should consider using conventional non-steroidal anti-inflammatory drugs in combination with a proton pump inhibitor or a prostaglandin analogue, especially for patients with increased cardiovascular risks, i.e. established ischaemic heart disease, cerebrovascular disease and/or peripheral arterial disease, or alternatively acetaminophen. An evidence-based algorithm for treatment of a chronic arthritis patient with one or more gastrointestinal risk factors is presented.
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PMID:Systematic review: coxibs, non-steroidal anti-inflammatory drugs or no cyclooxygenase inhibitors in gastroenterological high-risk patients? 1639 77

We assessed 1) whether pretreatment before ischemia with pioglitazone (Pio) limits infarct size (IS) and whether this protective effect is due to nitric oxide synthase (NOS) and/or prostaglandin production, as has been shown for atorvastatin (ATV); and 2) whether Pio and ATV have synergistic effects on myocardial protection. Sprague-Dawley rats received oral ATV (10 mg.kg-1.day-1), Pio (10 mg.kg-1.day-1), their combination (Pio+ATV), or water alone for 3 days. Additional rats received Pio (10 mg.kg-1.day-1) for 3 days and intravenous SC-58125 [a cyclooxygenase-2 (COX-2) inhibitor] or SC-560 (a COX-1 inhibitor) 15 min before ischemia. Rats underwent 30 min of myocardial ischemia and 4 h of reperfusion, or hearts were harvested for analysis. IS in the Pio and in the ATV groups was significantly smaller than in the sham-treated group. IS in the Pio+ATV group was smaller than in all other groups (P<0.001 vs. each group). The protective effect of Pio was abrogated by SC-58125 but not by SC-560. Pio, ATV, and Pio + ATV increased the expression and activity of cytosolic phospholipase A2 (cPLA2) and COX-2. ATV increased phosphorylated-Akt, phosphorylated-endothelial NOS (P-eNOS), inducible NOS, and COX-2 levels. In contrast, Pio caused an insignificant increase in myocardial levels of phosphorylated-Akt but did not change P-eNOS and iNOS expression. In conclusion, the IS-limiting effects of Pio and ATV involve COX-2. However, the upstream steps differ. ATV induced eNOS phosphorylation and iNOS, cPLA2, and COX-2 expression, whereas Pio induced mainly the expression and activity of cPLA2. The effects of Pio and ATV were additive.
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PMID:Myocardial protection by pioglitazone, atorvastatin, and their combination: mechanisms and possible interactions. 1660 98

In this study, the cardioprotective effects of nitric oxide (NO)-aspirin, the nitroderivative of aspirin, were compared with those of aspirin in an anesthetized rat model of myocardial ischemia-reperfusion. Rats were given aspirin or NO-aspirin orally for 7 consecutive days preceding 25 min of myocardial ischemia followed by 48 h of reperfusion (MI/R). Treatment groups included vehicle (Tween 80), aspirin (30 mg.kg(-1).day(-1)), and NO-aspirin (56 mg.kg(-1).day(-1)). NO-aspirin, compared with aspirin, displayed remarkable cardioprotection in rats subjected to MI/R as determined by the mortality rate and infarct size. Mortality rates for vehicle (n = 23), aspirin (n = 22), and NO-aspirin groups (n = 22) were 34.8, 27.3, and 18.2%, respectively. Infarct size of the vehicle group was 44.5 +/- 2.7% of the left ventricle (LV). In contrast, infarct size of the LV decreased in the aspirin- and NO-aspirin-pretreated groups, 36.7 +/- 1.8 and 22.9 +/- 4.3%, respectively (both P < 0.05 compared with vehicle group; P < 0.05, NO-aspirin vs. aspirin ). Moreover, NO-aspirin also improved ischemia-reperfusion-induced myocardial contractile dysfunction on postischemic LV developed pressure. In addition, NO-aspirin downregulated inducible NO synthase (iNOS; 0.37-fold, P < 0.01) and cyclooxygenase-2 (COX-2; 0.61-fold, P < 0.05) gene expression compared with the vehicle group after 48 h of reperfusion. Treatment with N(G)-nitro-L-arginine methyl ester (L-NAME; 20 mg/kg), a nonselective NOS inhibitor, aggravated myocardial damage in terms of mortality and infarct size but attenuated effects when coadministered with NO-aspirin. L-NAME administration did not alter the increase in iNOS and COX-2 expression but did reverse the NO-aspirin-induced inhibition of expression of the two genes. The beneficial effects of NO-aspirin appeared to be derived largely from the NO moiety, which attenuated myocardial injury to limit infarct size and better recovery of LV function following ischemia and reperfusion.
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PMID:Cardioprotective effects of nitric oxide-aspirin in myocardial ischemia-reperfused rats. 1752 56


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