thromboxane-a2 and Cardiomyopathies

Topics: Adult; Animals; Antifibrotic Agents; Antihypertensive Agents; Aspirin; Biomarkers; Blood Platelets; Blood Pressure; Cardiomyopathies; Case-Control Studies; Cells, Cultured; Disease Models, Animal; Essential Hypertension; Female; Fibrosis; Humans; Male; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Myocytes, Cardiac; Myofibroblasts; Platelet Aggregation Inhibitors; Receptors, Epoprostenol; Receptors, Thromboxane; Thromboxane A2

Recent studies demonstrated that iron overload could enhance the production of arachidonic acid and prostanoid, suggesting a causal connection between these signals and iron-overload cardiomyopathy. However, information regarding the downstream signaling is limited. Because thromboxane A2 (TXA2) and prostacyclin are the 2 major prostanoids in the cardiovascular system, and TXA2 plays a major role in vascular atherosclerosis and has pro-inflammatory characteristics, we intended to elucidate the role of TXA2 in iron-overload cardiomyopathy.. A 4-week iron loading protocol was instituted for both TXAS gene-deleted (TXAS(-/-)) mice and wild-type (WT) mice, with less severe cardiac fibrosis and preserved normal left ventricular contraction in the TXAS(-/-) mice. Inflammatory profiles, including MCP-1, TNF-α, IL-6, ICAM-1, and myeloperoxidase activity were also lower in the TXAS(-/-) as compared with WT littermates. TXAS supplement to the iron-injured TXAS(-/-) mice re-aggravated cardiac inflammation. Using a TXA2 analog, U46619, for NFAT reporter luciferase activity on cardiomyoctes, and intraperitonal injection of U46619 into nuclear factor of activated T cells (NFAT)-luciferase transgenic mice demonstrated that U46619 increase NFAT expression, and this expression, as well as TNF-α expression, can be blocked by TXA2 receptor antagonist (SQ29548), NFAT-SiRNA, calcineurin inhibitor, or calcium chelator. Finally, intraperitoneal injection of the TNF-α antibody, infliximab, into iron-injured mice decreased TXAS expression and attenuated cardiac fibrosis.. TXA2 mediates iron-overload cardiomyopathy through the TNF-α-associated calcineurin-NFAT signaling pathway. 

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Cardiomyopathies; Cell Line; Cytokines; Infliximab; Intercellular Adhesion Molecule-1; Iron Overload; Mice; Mice, Knockout; NFATC Transcription Factors; Thromboxane A2; Vasoconstrictor Agents

We studied the effects of a thromboxane A2 synthetase inhibitor (RS-5186), a thromboxane A2 antagonist (ONO-3708), a 5-lipoxygenase inhibitor (AA-861) and a peptidoleukotriene antagonist (ONO-1078) on infarct size, polymorphonuclear leukocyte infiltration, gross myocardial hemorrhage and arrhythmias in the canine coronary occlusion (2 hour)-reperfusion model (5 hour). The infarct size and risk area were determined by a double staining technique. Thirty minutes prior to occluding the coronary arteries, dogs were randomly assigned to one of the following five groups: the thromboxane A2 synthetase inhibitor group (n = 11) receiving RS-5186 10 mg/kg i.v., the thromboxane A2 antagonist group (n = 12) receiving continuous intravenous infusion of ONO-3708 1 microgram/kg/min, the lipoxygenase inhibitor group (n = 11) receiving AA-861 3 mg/kg i.v., the peptidoleukotriene antagonist group (n = 11) receiving continuous intravenous infusion of ONO-1078 1 microgram/kg/min and the vehicle control group (n = 15). Except for ONO-3708, all the other drugs reduced the infarct size (RS-5186: 26.3 +/- 2.4% of risk area (mean +/- SEM), AA-861: 21.8 +/- 1.3%, ONO-1078: 22.5 +/- 4.4% vs control: 54.0 +/- 6.4%, p less than 0.01 respectively) as well as reducing the area of gross myocardial hemorrhage (RS-5186: 3.9 +/- 2.6% of infarct size, AA-861: 5.1 +/- 2.4%, ONO-1078: 5.2 +/- 2.5% vs control: 22.3 +/- 3.9%, p less than 0.01 respectively). RS-5186 and AA-861 reduced the intensity of polymorphonuclear leukocyte infiltration into the infarcted area, however, neither ONO-3708 nor ONO-1078 had any significant influence.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Arrhythmias, Cardiac; Benzoquinones; Cardiomyopathies; Chromones; Coronary Disease; Dogs; Hemorrhage; Lipoxygenase Inhibitors; Male; Myocardial Infarction; Myocardium; Neutrophils; Quinones; SRS-A; Thiophenes; Thromboxane A2; Thromboxane-A Synthase

The effects of nicorandil, indomethacin and nicorandil + indomethacin on subendocardial segment shortening (%SS), regional myocardial blood flow and coronary venous thromboxane (TxA2) and prostacyclin (PGI2) levels were compared to those of a saline-treated group in anesthetized dogs subjected to a 15-min coronary artery occlusion and 3 h of reperfusion. During reperfusion, nicorandil markedly improved %SS in the ischemic-reperfused region compared to saline- and indomethacin-treated dogs. Indomethacin did not antagonize the beneficial effects of nicorandil. These results suggest that the beneficial actions of nicorandil in this model are not the result of an increase in PGI2 or decrease in TxA2 synthesis.

Topics: Animals; Blood Pressure; Cardiomyopathies; Coronary Circulation; Cyclooxygenase Inhibitors; Dinoprostone; Dogs; Female; Heart Rate; Hemodynamics; In Vitro Techniques; Indomethacin; Male; Myocardial Reperfusion Injury; Niacinamide; Nicorandil; Prostaglandins; Thromboxane A2; Time Factors; Vasodilator Agents