Download PDF
Thromb Haemost 2018; 118(11): 1982-1996
DOI: 10.1055/s-0038-1672206
Atherosclerosis and Ischaemic Disease
Georg Thieme Verlag KG Stuttgart · New York

Genetic Depletion of Thromboxane A2/Thromboxane-Prostanoid Receptor Signalling Prevents Microvascular Dysfunction in Ischaemia/Reperfusion Injury

Chih-Yao Chiang   *
1   Department of Life Science, National Taiwan Normal University, Taipei, Taiwan
2   Department of Cardiovascular Surgery, Taipei City Hospital RenAi Branch, Taipei, Taiwan
,
Chen-Yen Chien   *
3   Mackay Junior College of Medicine, Nursing and Management, New Taipei City, Taiwan
4   Department of Surgery, Mackay Memorial Hospital and Mackay Medical College, Taipei, Taiwan
,
Wei-Yin Qiou
1   Department of Life Science, National Taiwan Normal University, Taipei, Taiwan
,
Christopher Chang
5   High School Division, Taipei American School, Taipei, Taiwan
,
I-Shing Yu
6   Laboratory of Animal Center, National Taiwan University College of Medicine, Taipei, Taiwan
,
Po-Yuan Chang   **
7   Division of Cardiology, Department of Internal Medicine and Cardiovascular Center, National Taiwan University College of Medicine, Taipei, Taiwan
,
Chiang-Ting Chien   **
1   Department of Life Science, National Taiwan Normal University, Taipei, Taiwan
› Author Affiliations Funding This work was supported by grants MOST-102–2320-B-003–001-MY3 (Chiang-Ting Chien), MOST-106–2314-B-002 -156 -MY2 (Po-Yuan Chang) from the Ministry of Science and Technology, and a research fund from Taipei City Hospital (Chih-Yao Chiang).
Further Information

Publication History

09 February 2018

22 August 2018

Publication Date:
09 October 2018 (online)

    Permissions and Reprints

Abstract

Objective Activation of thromboxane A2 synthase (TXAS)/thromboxane A2 (TXA2)/thromboxane prostanoid (TP) receptor leads to arterial constriction, platelet aggregation and vascular injury. We attempted to characterize the microvascular dysfunction in ischaemia/reperfusion injury using genetically modified TXAS−/−, TP−/− and TXAS−/−TP−/− mice.

Approach and Results The cardiac micro-circulation and electrocardiograms were evaluated from B6, TXAS−/−, TP−/− and TXAS−/−TP−/− mice in response to intravenous saline, endothelin-1, U46619 (a TXA2 agonist) and myocardial ischaemia/reperfusion injury. Cardiac function was investigated with myocardial permeability, the troponin I concentration and the infarct size. Myocardial TXAS, TP, endothelial nitric oxide (NO) synthase (eNOS), nicotinamide adenine dinucleotide phosphate oxidase 4 (NOx4), 4-hydroxynonenal, interleukin (IL)-1β, cell apoptosis, coronary effluent thromboxane B2 (TXB2) and superoxide anions (O2 −) and NO concentrations were measured. Mice mesenteric reactivity in response to various drugs was assessed by wire myography. In vivo fluorescent platelet adhesiveness to the mesenteric arterial endothelium after FeCl3 stimulation was examined. In B6 mice, ischaemia/reperfusion significantly increased levels of ST-segment elevation, myocardial TXAS, TP, NOx4, IL-1β, apoptosis, coronary endothelin-1, TXB2, O2 − release and the infarct size, with concomitant decreases in eNOS, NO concentrations and cardiac micro-circulation. These effects were remarkably depressed in TXAS−/−, TP−/− and TXAS−/−TP−/− mice. Aspirin treatment or depletion of the TXAS, TP or TXAS/TP gene significantly attenuated the exaggerated vascular reactivity by vasoconstrictors and vasodilators and efficiently reduced platelet adhesion to the mesenteric endothelium under FeCl3 stimulation.

Conclusion Inhibiting TXAS/TXA2/TP signalling confers microvascular protection against oxidative injury in both cardiac and mesenteric arteries.

Keywords

aspirin - ischaemia/reperfusion injury - thromboxane A2 - thromboxane A2 synthase - thromboxane prostanoid receptor

* Chih-Yao Chiang and Chen-Yen Chien contributed equally to this study.


** Po-Yuan Chang and Chiang-Ting Chien contributed equally to this study.


Supplementary Material

 

  • References

  • 1 Ammann P, Marschall S, Kraus M. , et al. Characteristics and prognosis of myocardial infarction in patients with normal coronary arteries. Chest 2000; 117 (02) 333-338
    CrossrefPubMedGoogle Scholar
  • 2 Brunner F, du Toit EF, Opie LH. Endothelin release during ischaemia and reperfusion of isolated perfused rat hearts. J Mol Cell Cardiol 1992; 24 (11) 1291-1305
    CrossrefPubMedGoogle Scholar
  • 3 Chien CT, Fan SC, Lin SC. , et al. Glucagon-like peptide-1 receptor agonist activation ameliorates venous thrombosis-induced arteriovenous fistula failure in chronic kidney disease. Thromb Haemost 2014; 112 (05) 1051-1064
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 Li PC, Shaw CF, Kuo TF, Chien CT. Inducible nitric oxide synthase evoked nitric oxide counteracts capsaicin-induced airway smooth muscle contraction, but exacerbates plasma extravasation. Neurosci Lett 2005; 378 (02) 117-122
    CrossrefPubMedGoogle Scholar
  • 5 Angiolillo DJ, Ueno M, Goto S. Basic principles of platelet biology and clinical implications. Circ J 2010; 74 (04) 597-607
    CrossrefPubMedGoogle Scholar
  • 6 Kakouros N, Nazarian SM, Stadler PB, Kickler TS, Rade JJ. Risk factors for nonplatelet thromboxane generation after coronary artery bypass graft surgery. J Am Heart Assoc 2016; 5 (03) e002615
    PubMedGoogle Scholar
  • 7 Siangjong L, Gauthier KM, Pfister SL, Smyth EM, Campbell WB. Endothelial 12(S)-HETE vasorelaxation is mediated by thromboxane receptor inhibition in mouse mesenteric arteries. Am J Physiol Heart Circ Physiol 2013; 304 (03) H382-H392
    CrossrefPubMedGoogle Scholar
  • 8 Zhang M, Song P, Xu J, Zou MH. Activation of NAD(P)H oxidases by thromboxane A2 receptor uncouples endothelial nitric oxide synthase. Arterioscler Thromb Vasc Biol 2011; 31 (01) 125-132
    CrossrefPubMedGoogle Scholar
  • 9 Capra V, Bäck M, Angiolillo DJ, Cattaneo M, Sakariassen KS. Impact of vascular thromboxane prostanoid receptor activation on hemostasis, thrombosis, oxidative stress, and inflammation. J Thromb Haemost 2014; 12 (02) 126-137
    CrossrefPubMedGoogle Scholar
  • 10 Reilly MP, Delanty N, Roy L. , et al. Increased formation of the isoprostanes IPF2alpha-I and 8-epi-prostaglandin F2alpha in acute coronary angioplasty: evidence for oxidant stress during coronary reperfusion in humans. Circulation 1997; 96 (10) 3314-3320
    CrossrefPubMedGoogle Scholar
  • 11 Michel F, Silvestre JS, Waeckel L. , et al. Thromboxane A2/prostaglandin H2 receptor activation mediates angiotensin II-induced postischemic neovascularization. Arterioscler Thromb Vasc Biol 2006; 26 (03) 488-493
    CrossrefPubMedGoogle Scholar
  • 12 Davì G, Patrono C. Platelet activation and atherothrombosis. N Engl J Med 2007; 357 (24) 2482-2494
    CrossrefPubMedGoogle Scholar
  • 13 Saitoh S, Onogi F, Aikawa K. , et al. Multiple endothelial injury in epicardial coronary artery induces downstream microvascular spasm as well as remodeling partly via thromboxane A2. J Am Coll Cardiol 2001; 37 (01) 308-315
    CrossrefPubMedGoogle Scholar
  • 14 Fu LW, Phan A, Longhurst JC. Myocardial ischemia-mediated excitatory reflexes: a new function for thromboxane A2?. Am J Physiol Heart Circ Physiol 2008; 295 (06) H2530-H2540
    CrossrefPubMedGoogle Scholar
  • 15 Chien CY, Chien CT, Wang SS. Progressive thermopreconditioning attenuates rat cardiac ischemia/reperfusion injury by mitochondria-mediated antioxidant and antiapoptotic mechanisms. J Thorac Cardiovasc Surg 2014; 148 (02) 705-713
    CrossrefPubMedGoogle Scholar
  • 16 Xiao CY, Hara A, Yuhki K. , et al. Roles of prostaglandin I(2) and thromboxane A(2) in cardiac ischemia-reperfusion injury: a study using mice lacking their respective receptors. Circulation 2001; 104 (18) 2210-2215
    CrossrefPubMedGoogle Scholar
  • 17 Zaugg CE, Hornstein PS, Zhu P. , et al. Endothelin-1-induced release of thromboxane A2 increases the vasoconstrictor effect of endothelin-1 in postischemic reperfused rat hearts. Circulation 1996; 94 (04) 742-747
    CrossrefPubMedGoogle Scholar
  • 18 Zuccollo A, Shi C, Mastroianni R. , et al. The thromboxane A2 receptor antagonist S18886 prevents enhanced atherogenesis caused by diabetes mellitus. Circulation 2005; 112 (19) 3001-3008
    CrossrefPubMedGoogle Scholar
  • 19 Zhou Y, Mitra S, Varadharaj S, Parinandi N, Zweier JL, Flavahan NA. Increased expression of cyclooxygenase-2 mediates enhanced contraction to endothelin ETA receptor stimulation in endothelial nitric oxide synthase knockout mice. Circ Res 2006; 98 (11) 1439-1445
    CrossrefPubMedGoogle Scholar
  • 20 Fu LW, Guo ZL, Longhurst JC. Undiscovered role of endogenous thromboxane A2 in activation of cardiac sympathetic afferents during ischaemia. J Physiol 2008; 586 (13) 3287-3300
    CrossrefPubMedGoogle Scholar
  • 21 Yu IS, Lin SR, Huang CC. , et al. TXAS-deleted mice exhibit normal thrombopoiesis, defective hemostasis, and resistance to arachidonate-induced death. Blood 2004; 104 (01) 135-142
    CrossrefPubMedGoogle Scholar
  • 22 Patrono C, García Rodríguez LA, Landolfi R, Baigent C. Low-dose aspirin for the prevention of atherothrombosis. N Engl J Med 2005; 353 (22) 2373-2383
    CrossrefPubMedGoogle Scholar
  • 23 Gurbel PA, Kuliopulos A, Tantry US. G-protein-coupled receptors signaling pathways in new antiplatelet drug development. Arterioscler Thromb Vasc Biol 2015; 35 (03) 500-512
    CrossrefPubMedGoogle Scholar
  • 24 Cheng Y, Austin SC, Rocca B. , et al. Role of prostacyclin in the cardiovascular response to thromboxane A2. Science 2002; 296 (5567): 539-541
    CrossrefPubMedGoogle Scholar
  • 25 Zaugg CE, Zhu P, Simper D, Lüscher TF, Allegrini PR, Buser PT. Differential effects of endothelin-1 on normal and postischemic reperfused myocardium. J Cardiovasc Pharmacol 1993; 22 (Suppl. 08) S367-S370
    CrossrefPubMedGoogle Scholar
  • 26 Filep JG, Fournier A, Földes-Filep E. Endothelin-1-induced myocardial ischaemia and oedema in the rat: involvement of the ETA receptor, platelet-activating factor and thromboxane A2. Br J Pharmacol 1994; 112 (03) 963-971
    CrossrefPubMedGoogle Scholar
  • 27 Yang CC, Chen KH, Hsu SP, Chien CT. Augmented renal prostacyclin by intrarenal bicistronic cyclo-oxygenase-1/prostacyclin synthase gene transfer attenuates renal ischemia-reperfusion injury. Transplantation 2013; 96 (12) 1043-1051
    CrossrefPubMedGoogle Scholar
  • 28 Cooke CL, Davidge ST. Endothelial-dependent vasodilation is reduced in mesenteric arteries from superoxide dismutase knockout mice. Cardiovasc Res 2003; 60 (03) 635-642
    CrossrefPubMedGoogle Scholar
  • 29 Thüroff JW, Hort W, Lichti H. Diameter of coronary arteries in 36 species of mammalian from mouse to giraffe. Basic Res Cardiol 1984; 79 (02) 199-206
    CrossrefPubMedGoogle Scholar
  • 30 Basili S, Pignatelli P, Tanzilli G. , et al. Anoxia-reoxygenation enhances platelet thromboxane A2 production via reactive oxygen species-generated NOX2: effect in patients undergoing elective percutaneous coronary intervention. Arterioscler Thromb Vasc Biol 2011; 31 (08) 1766-1771
    CrossrefPubMedGoogle Scholar
  • 31 Wacker MJ, Best SR, Kosloski LM. , et al. Thromboxane A2-induced arrhythmias in the anesthetized rabbit. Am J Physiol Heart Circ Physiol 2006; 290 (04) H1353-H1361
    CrossrefPubMedGoogle Scholar
  • 32 Sakariassen KS, Alberts P, Fontana P, Mann J, Bounameaux H, Sorensen AS. Effect of pharmaceutical interventions targeting thromboxane receptors and thromboxane synthase in cardiovascular and renal diseases. Future Cardiol 2009; 5 (05) 479-493
    CrossrefPubMedGoogle Scholar
  • 33 Sharma R, Randhawa PK, Singh N, Jaggi AS. Possible role of thromboxane A2 in remote hind limb preconditioning-induced cardioprotection. Naunyn Schmiedebergs Arch Pharmacol 2016; 389 (01) 1-9
    PubMedGoogle Scholar
  • 34 Kolh P, Rolin S, Tchana-Sato V. , et al. Evaluation of BM-573, a novel TXA2 synthase inhibitor and receptor antagonist, in a porcine model of myocardial ischemia-reperfusion. Prostaglandins Other Lipid Mediat 2006; 79 (1-2): 53-73
    CrossrefPubMedGoogle Scholar
  • 35 Fontana P, Zufferey A, Daali Y, Reny JL. Antiplatelet therapy: targeting the TxA2 pathway. J Cardiovasc Transl Res 2014; 7 (01) 29-38
    CrossrefPubMedGoogle Scholar
  • 36 Kusama Y, Kodani E, Nakagomi A. , et al. Variant angina and coronary artery spasm: the clinical spectrum, pathophysiology, and management. J Nippon Med Sch 2011; 78 (01) 4-12
    CrossrefPubMedGoogle Scholar
  • 37 Yasue H, Nakagawa H, Itoh T, Harada E, Mizuno Y. Coronary artery spasm--clinical features, diagnosis, pathogenesis, and treatment. J Cardiol 2008; 51 (01) 2-17
    CrossrefPubMedGoogle Scholar
  • 38 Sun H, Mohri M, Shimokawa H, Usui M, Urakami L, Takeshita A. Coronary microvascular spasm causes myocardial ischemia in patients with vasospastic angina. J Am Coll Cardiol 2002; 39 (05) 847-851
    CrossrefPubMedGoogle Scholar
  • 39 Ong P, Athanasiadis A, Borgulya G, Mahrholdt H, Kaski JC, Sechtem U. High prevalence of a pathological response to acetylcholine testing in patients with stable angina pectoris and unobstructed coronary arteries. The ACOVA Study (Abnormal COronary VAsomotion in patients with stable angina and unobstructed coronary arteries). J Am Coll Cardiol 2012; 59 (07) 655-662
    CrossrefPubMedGoogle Scholar
  • 40 Sueda S, Kohno H, Inoue K. , et al. Intracoronary administration of a thromboxane A2 synthase inhibitor relieves acetylcholine-induced coronary spasm. Circ J 2002; 66 (09) 826-830
    CrossrefPubMedGoogle Scholar
  • 41 del Campo M, Sagredo A, del Campo L, Villalobo A, Ferrer M. Time-dependent effect of orchidectomy on vascular nitric oxide and thromboxane A2 release. Functional implications to control cell proliferation through activation of the epidermal growth factor receptor. PLoS One 2014; 9 (07) e102523
    CrossrefPubMedGoogle Scholar
  • 42 Järvinen O, Laurikka J, Sisto T, Salenius JP, Tarkka MR. Atherosclerosis of the visceral arteries. Vasa 1995; 24 (01) 9-14
    PubMedGoogle Scholar
  • 43 Arshad M, Vijay V, Floyd BC. , et al. Thromboxane receptor stimulation suppresses guanylate cyclase-mediated relaxation of radial arteries. Ann Thorac Surg 2006; 81 (06) 2147-2154
    CrossrefPubMedGoogle Scholar
  • 44 Minarchick VC, Stapleton PA, Porter DW. , et al. Pulmonary cerium dioxide nanoparticle exposure differentially impairs coronary and mesenteric arteriolar reactivity. Cardiovasc Toxicol 2013; 13 (04) 323-337
    CrossrefPubMedGoogle Scholar
  • 45 Dzeshka MS, Shantsila A, Lip GY. Effects of aspirin on endothelial function and hypertension. Curr Hypertens Rep 2016; 18 (11) 83
    CrossrefPubMedGoogle Scholar
  • 46 Chang PY, Chen YJ, Chang FH. , et al. Aspirin protects human coronary artery endothelial cells against atherogenic electronegative LDL via an epigenetic mechanism: a novel cytoprotective role of aspirin in acute myocardial infarction. Cardiovasc Res 2013; 99 (01) 137-145
    CrossrefPubMedGoogle Scholar