15-hydroxy-11-alpha-9-alpha-(epoxymethano)prosta-5-13-dienoic-acid and Cardiomyopathies

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

Vasomotor responses to various agonists were studied on isolated circular segments of human epicardial coronary arteries from three different age groups; 23-38 years, 40-58 years and 63-86 years. Noradrenaline had no or only weak contractile effect on coronary arteries from younger patients but induced contraction of all artery segments from older patients. The Emax value was significantly (P<0.0001) higher in arteries from the oldest group compared to each of the two younger age groups, whereas the potency was similar in all three groups. Linear regression analysis of noradrenaline-induced contraction in individual patients revealed a significantly positive age-correlation (correlation coefficient 0.67, P<0.0001). Contraction induced by endothelin-1 and relaxation induced by substance P, calcitonin gene-related peptide and vasoactive intestinal peptide on arteries precontracted with U46619 showed no significant differences in maximum responses and potencies between the three age groups, and no significant linear age-correlation. These data demonstrate a large variability in contractile responses to noradrenaline with contractions seen mostly in coronary arteries from older patients. It thus seems that sympathetic activation could contribute to coronary ischaemia in some patients.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adult; Aged; Aged, 80 and over; Aging; Calcitonin Gene-Related Peptide; Cardiomyopathies; Coronary Vessels; Dose-Response Relationship, Drug; Endothelins; Humans; In Vitro Techniques; Middle Aged; Norepinephrine; Substance P; Vasoactive Intestinal Peptide; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Vasomotor System

Vascular responses of human intramyocardial small arteries were examined in vitro to assess the influence of atherosclerosis and risk factors for coronary artery disease on endothelium-dependent relaxation. Recipient hearts were obtained from patients with ischemic (n = 14) and nonischemic (n = 13) cardiomyopathy undergoing heart transplantation. Small intramyocardial coronary arteries (mean internal diameter 313 +/- 11 micrometers) were mounted on a wire myograph for measurement of morphology and isometric tension. Vasodilation was examined after preconstriction with U-46619, a thromboxane A2 analog. Endothelium-dependent relaxation to acetylcholine and bradykinin was impaired in patients with ischemic compared with nonischemic cardiomyopathy (P < 0.01 and P < 0.001, respectively). Endothelium-independent relaxation to sodium nitroprusside was preserved. Incubation with L-arginine (3 mmol/l) did not improve endothelium-dependent relaxation to acetylcholine or bradykinin. With the use of stepwise multivariate analysis, hypercholesterolemia, but no other risk factor for atherosclerosis, was independently associated with impaired endothelium-dependent relaxation to acetylcholine (r = -0.50, P = 0.05) but not to bradykinin. Endothelial dysfunction in intramyocardial small arteries may predispose patients with nonobstructive epicardial atherosclerosis and hypercholesterolemia to myocardial ischemia.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Adult; Arteries; Arteriosclerosis; Bradykinin; Cardiomyopathies; Coronary Circulation; Endothelium, Vascular; Female; Heart; Heart Failure; Heart Transplantation; Humans; Hypercholesterolemia; In Vitro Techniques; Isometric Contraction; Male; Middle Aged; Nitroprusside; Substance P; Vasodilation

This study was designed to assess the effect of the thromboxane receptor antagonist, BM 13.505, in limiting myocardial damage and polymorphonuclear leukocyte accumulation in rats subjected to coronary artery occlusion for 30 min with reperfusion for 24 h (MI/R). Myocardial injury and polymorphonuclear leukocyte infiltration were determined by measuring creatine phosphokinase (CPK) specific activity and myeloperoxidase (MPO) activity, respectively, in the left ventricular free wall (LVFW). Myocardial CPK levels were 8.24 +/- 0.33 U/mg protein in sham MI/R-vehicle-treated animals (n = 18), and were significantly decreased to 6.51 +/- 0.44 U/mg protein in MI/R-vehicle animals (n = 22). Myocardial MPO values were 2.4 +/- 0.5 U/g LVFW in sham MI/R animals, and significantly increased to 10.9 +/- 1.3 U/g LVFW in MI/R-vehicle animals. Administration of BM 13.505 (30 mg/kg, i.p.) 1 min prior to coronary occlusion resulted in CPK values of 7.83 +/- 0.45 U/mg protein and MPO levels of 6.1 +/- 0.9 U/g LVFW (p less than 0.05, compared to the MI/R-vehicle group). The survival rate in the MI/R-BM 13.505 group was 74 and 65% at 2 and 24 h, respectively, and was not different from the MI/R-vehicle group. There were no significant differences in mean arterial blood pressure or heart rate between the MI/R-vehicle and MI/R-BM 13.505 groups, indicating that changes in myocardial oxygen demand do not explain the protective effects. A lower dose did not reduce myocardial injury, indicating that the effects of BM 13.505 were dose dependent.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Cardiomyopathies; Creatine Kinase; Hemodynamics; Male; Myocardial Reperfusion Injury; Myocardium; Neutrophils; Peroxidase; Phenylacetates; Prostaglandin Endoperoxides, Synthetic; Rats; Rats, Inbred Strains; Sulfonamides; Thromboxanes