VI. RESULTS
3. E FFECT OF CONTRACTION AND RELAXATION IN MESENTERIC ARTERIES
B6+aspirin (ASP), TXAS-/-TP+/+ and TXAS-/-TP-/-mice under NE, ACh, U46619 and ET-1. MAs from TXAS-/-TP+/+ and TXAS-/-TP
-/- mice had significantly reduced contraction to NE, comparing
27
with B6 (P<0.05) in Figure 14-a. ASP havd no impact on contraction to NE. MAs from B6+ASP, TXAS-/-TP+/+ and TXAS -/-TP-/-mice havd significantly sensitive relaxation to ACh (10-8~10
-7M, P<0.05), comparing with B6. In addition, MAs from B6+ASP, TXAS-/-TP+/+ and TXAS-/-TP-/- mice maintain higher tension, comparing with B6 under high concentration of ACh in Figure
14-b. MAs from B6+ASP and TXAS
-/-TP-/-mice had significantly reduced contraction to U46619, comparing with B6 and TXAS -/-TP+/+ (P<0.05) in Figure 14-c. Although MAs from TXAS-/-TP+/+mice show lower contraction to U46619 than B6, it had no significance. MAs from B6+ASP and TXAS-/-TP-/- mice havd significantly reduced contraction to ET-1, comparing with B6 and TXAS-/-TP+/+ (P<0.05) in Figure 14-d. Although MAs from TXAS-/-TP+/+mice showed lower contraction to ET-1 than B6, it had no significance.
4. Cardiac microcirculation and ECG under myocardial ischemia reperfusion injury among three genotype mice
The cardiac microcirculation of myocardial I/R injury among three genotype mice was determined and shown in Figure a of
15~17. All genotype mice suffered from ischemia operation
express decreasing of blood flow (black hollow square) which LAD was ligated. When origin of reperfusion, cardiac microcirculation of all genotype mice was recovery. Figure b of15~17 showed that S-T segment elevation appear in all genotype
mice under ischemia and it didn’t recover under reperfusion.28
5. Hematoxylin and eosin (H&E) stain
In order to examine the tissue abnormality, the histological heart sections were stained with H&E. The histological stain of heart was shown in Figure 18-a. I/R injury increased the intracellular split (edema), red blood cell extravasation, loss of cross striations in three genotype mice. According to Figure 18-b, there were the differences of degree of split formation could be compared among three genotype mice. All genotype mice showed significantly higher ratio of split formation than their control group (P<0.05).
The significantly higher ratio of split formation in B6 I/R treated group was shown than TXAS-/-TP+/+ and TXAS-/-TP-/- I/R treated group (P<0.05). But it had no significance between TXAS-/-TP+/+
and TXAS-/-TP-/- I/R treated group.
6. Terminal deoxynucleotide transferase dUTP Nick End Labeling stain
We used TUNEL stain to quantify the apoptotic cells formation and the DNA fragmentation occurred in the nucleus appeared brown color, which was shown in Figure 19-a. There are the differences of degree of apoptotic cell could be compared among three genotype mice in Figure 19-b. All genotype mice showed significantly higher ratio of apoptotic cell than their control group (P<0.05). The significantly higher ratio of apoptotic cell in B6 I/R treated group was shown than TXAS-/-TP+/+ and TXAS-/-TP-/- I/R treated group (P<0.05). But it had no significance between TXAS
-/-TP+/+ and TXAS-/-TP-/- I/R treated group.
29
7. Immunohistochemistry analysis
To further confirm the possible pathophysiologic mechanisms of myocardial I/R injury, several IHC stains were performed. Tissue sections were stained to determine the degree of oxidative stress, inflammatory cytokines and autophagy in response to I/R injury.
As shown in Figure 20-a, Beclin-1 is a marker for autophagy.
There are significant differences of Beclin-1 expression could be compared among three genotype mice in Figure 20-b. All genotype mice showed significantly higher ratio of Beclin-1 than their control group (P < 0.05). The significantly higher ratio of Beclin-1 in B6 I/R treated group was shown than TXAS-/-TP+/+ and TXAS-/-TP-/- I/R treated group (P<0.05). But it had no significance between TXAS-/-TP+/+ and TXAS-/-TP-/- I/R treated group. (P<0.05). The significantly higher ratio of IL-1β in B6 I/R treated group was shown than TXAS-/-TP+/+ and TXAS-/-TP-/- I/R treated group (P<0.05). But it had no significance between TXAS-/-TP+/+
and TXAS-/-TP-/- I/R treated group.
Oxidative injury represented by 4-HNE, it is a product of lipid peroxidation—is shown in Figure 22-a. There are the differences
30
of degree of 4-HNE could be compared among three genotype mice in Figure 22-b. All genotype mice showed significantly higher ratio of 4-HNE than their control group (P<0.05). The significantly higher ratio of 4-HNE in B6 I/R treated group was shown than TXAS-/-TP+/+ and TXAS-/-TP-/- I/R treated group (P<0.05). But it had no significance between TXAS-/-TP+/+ and TXAS-/-TP-/- I/R treated group.
8. Plasma level of troponin I measurement.
Troponin I level is an indirect marker to evaluate the infraction size. Troponin I concentration was determined in three genotype mice under myocardial I/R injury in Figure 23. The Troponin I level were significantly elevated in all I/R mice compared with their sham control group (B6, P < 0.001; TXAS -/-TP+/+ and TXAS-/-TP-/-, P < 0.05). I/R treated B6 had significantly higher troponin I concentration than IR treated TXAS-/-TP+/+ and TXAS-/-TP-/- mice (P < 0.01). However, there is no significance in troponin I level between IR treated TXAS-/-TP+/+ and TXAS-/-TP-/- mice.
31
VII. Discussion
1. Previous studies of TXAS-TXA
2-TP signaling and ET-1 in cardiovascular diseases.
TXAS-TXA2-TP signaling paly important bioactivities.
TXAS-/-TP+/+ mice cannot biosynthesize TXA2 because there is no TXAS gene expression. There are no TXAS and TP gene expression in TXAS-/-TP-/- mice, it is not only TXA2 cannot be produced but also TP receptor cannot be presented. Especially, it is not only one ligand can trigger TP receptor to reach
downstream respond. Precious studies about TXAS-TXA2-TP signaling usually focused on thrombotic heart diseases such as anti-atherosclerosis, anti-platelet aggregation. less studies in acute myocardial infarction. In addition, ET-1 is the strongest known vascular contraction factor (Yanagisawa, et al., 1988).
Several cardiovascular pathologies are associated with increasing level of circulating ET-1, such as congestive heart failure,
pulmonary hypertension, coronary artery disease, ischemic heart disease and acute myocardial infarction (McMurray, et al., 1992;
Giaid, et al., 1993). There has been an elevation in the
concentration of ET-1 in the plasma of patients with myocardial infarction and Setianto and their team have reported currently that the increasing level of plasma ET-1 in S-T segment elevation acute myocardial infarction (STEMI). However, report of the relation between TXAS-TXA2-TP signaling and ET-1 is rare.
32
Our experiments showed the change of heart microcirculation through TXAS-TXA2-TP signaling first time.
2. Impact of ECG and cardiac microcirculation through TXAS-TXA
2-TP signaling and ET-1.
An extreme reduction of cardiac microcirculation was
observed when U46619 was injected intravenously into B6 and TXAS-/-TP+/+ mice but TXAS-/-TP-/- mice. As a powerful
vasocontraction factor, a strong contractile response was
generated via TXAS-TXA2-TP signaling (Shen, et al., 1998). In the experiment of intravenous injection different dose of ET-1 (low, middle, high). Our data showed that reduction of cardiac microcirculation in middle and high dose of ET-1 in B6 mice but TXAS-/-TP+/+ and TXAS-/-TP-/- mice. As the strongest
vasocontraction factor, most of the myocardium and vessels have ETA receptor induced a contractile response. Wang and their team has reported that over activation of TXAS-TXA2-TP
signaling lead to upregulation of ETA receptor with CKD mice.
The reason of the poor respond to ET-1 in TXAS-/-TP+/+ and TXAS-/-TP-/- mice, we speculated that decrease the expression of ETA receptor via inhibition of TXAS-TXA2-TP signaling. We also observed that bradycardia or arrhythmia appear when
U46619 was injected into B6 and TXAS-/-TP+/+ mice but TXAS -/-TP-/- mice. S-T segment elevation had been reported in rats with intracoronary injection of U46619, while the study didn’t
33
indicate that U46619 result in bradycardia or arrhythmia
(Yamamoto, et al., 1993). Dosage of U46619 (10ug/kg in rat vs 2mg/kg in mice) and location (coronary artery vs jugular vein)
are different from our research. In addition to respond caused by U46619, intravenous injection of ET-1 (high dose) has a similar phenomenon.3. Pharmacological respond in resistance artery through TXAS-TXA
2-TP signaling and ET-1.
Due to intravenous injection take the drug to the whole body, so we cannot ensure those respond from coronary arteries or myocardium. Moreover, we perform contraction effect to NE, U46619 and ET-1, relaxation effect to ACh via MAs. There are two reasons why we choose the MA to simulate the coronary artery (CA). One of two is MA and CA belong to resistance artery and the diameter of the MA we used is equal to the
diameter of the CA (about 200 um). Another reason is that right gastroepiploic artery (GEA) has been used to complete clinical coronary artery bypass graft. The GEA graft is a safe and effective arterial conduit for coronary artery bypass grafting (Suma, et al., 2013). According to this, the arteries of the digestive system can be used as a CA. Reduction of vessels
tension to NE in TXAS-/-TP+/+ and TXAS-/-TP-/- mice indicate that inhibition of TXAS-TXA2-TP signaling maybe decrease
sympathetic activity via decreasing adrenergic receptors (α1 receptor). Relaxation of vessels tension to low concentration
34
ACh (10-9~10-7M) in B6+ASP, TXAS-/-TP+/+ and TXAS-/-TP-/- mice are more sensitive than B6 mice. The strongest relaxation of vessels tension to high concentration ACh (10-5~10-3M) was reached in B6 mice.B6 mice presents a wide range of vessels tone than those who inhibition of TXAS-TXA2-TP signaling mice. This result we explain in the face of sudden changes in blood pressure such as septic shock still possessing a better
function to maintain homeostasis in individuals with inhibition of TXAS-TXA2-TP signaling. Reduction of contraction of vessels tension to U46619 in B6+ASPand TXAS-/-TP-/- mice compared with B6 and TXAS-/-TP+/+ mice. Although vessels tension in TXAS-/-TP+/+ mice lower than B6, there is no significance between them. The data can be associated with the data of heart microcirculation. Reduction of contraction of vessels tension to ET-1 in B6+ASPand TXAS-/-TP-/- mice than B6 and TXAS -/-TP+/+ mice. And when the concentration of ET-1 is 10-8M, vessels in TXAS-/-TP+/+ mice significantly present lower tension than B6. This result indicates that vessels contraction are induced via Et-1 are decreased through inhibition of TXAS-TXA2-TP
signaling. According to this data, we confirm our hypothesis that TXAS-TXA2-TP signaling is upstream of ET-1 in cardiovascular function.
4. Inhibition of TXAS-TXA
2-TP signaling attenuate injury evoked
by myocardial ischemia reperfusion through apoptosis, oxidative
35
stress, inflammation and pyroptosis.
For many years, it was thought that myocardial reperfusion is only beneficial and that there was no cell death related to it (Braunwald, et al., 1985; Kloner, et al.,1993). Later when
cardiomyocytes death was seen in the reperfusion myocardium it was postulated that they are the already irreversibly damaged cardiomyocytes that were fated to die during ischemia (Gottlieb,
et al., 1994). The concept of ‘reperfusion injury was presentedwhen it was shown that reperfusion induced death in
cardiomyocytes that were viable during ischemia.
The burst production of reactive oxygen species (ROS) during I/R stage might impair the function and structure of the tissue or organ by triggering several abnormal signal transductions to induce several types of cell death such as apoptosis, autophagy, pyroptosis, and necrosis (Chien CT, et al., 2012). Prostanoid, including prostaglandins (PGs) and thromboxane, are generated from AA by the enzyme cyclooxygenases (COXs). The role of
PGs and its mechanism in apoptotic impairment with myocardial I/R injury had been reported (Qiu, Hong, et al., 2012). However, less studies discuss the role of TXA
2with myocardial I/R injury (Mullane, et al., 1988; Nichols, et al., 1989). We perform
myocardial I/R model in three genotype mice to clarify whether suppress TXAS-TXA
2-TP signaling could reduce I/R injury in mouse heart. We cannot find any difference on heartmicrocirculation in this model among three genotype mice.
36
Theoretically, the level of thrombosis and vasocontraction are decline via inhibition of TXAS-TXA2-TP signaling. But in this model, LAD was ligated physically so the situation in ischemia should be similar no matter what kind of animal. Therefore, we must to discuss the role of inhibiting TXA2-TP- signaling in myocardial I/R injury from other aspects such as HE stain, IHC stain, TUNEL and plasma troponin I.
Represent views of heart section in B6 mice showing I/R treated heart with higher levels of intracellular split (edema), red blood cell extravasation and loss of cross striations. According to histological evidences, I/R injury on cardiomyocytes were
attenuated through the inhibition of TXA2-TP- signaling. The increasing level of plasma IL-6 and neutrophil polymorphs infiltration was observed by HE stain had been reported on acute myocardial infarction (Hashmi, et al., 2015). But we didn’t find neutrophil polymorphs infiltration on our HE stain. Experimental studies provide strong but somewhat conflicting evidence that neutrophils are involved in the myocardial response leading to lethal injury upon reperfusion. Some anti-neutrophil
interventions successfully reducing lethal reperfusion injury reported by some laboratories have not been reproduced by other laboratories using different or even similar animal models
(Vinten-Johansen, et al., 2004). Although neutrophil polymorphs infiltration didn’t find in our HE stain data, IL-1β present in our IHC stain showed lower level through blocking TXA2-TP-
37
signaling. IL-1β is one of inflammation and pyroptosis markers.
Pyroptosis is characterized by rapid plasma membrane rupture and release of proinflammatory intracellular contents, which is morphologically and mechanistically distinct from other forms of cell death (Yang, et al., 2014). Recently, a review demonstrated the main role of pyroptosis in I/R injury (Bell, et al., 2016). IL-1β played a pivotal role in inflammation in myocardial I/R injury and vascular endothelial dysfunction (Nowak, et al., 2016). IL-1β was upregulated of pro- IL-1β through NF-κB mediated
transcriptional activation and it activated TXAS and TP receptors through an auto-activation mechanism (Huang, et al., 2013).
TUNEL stain show higher anti-apoptotic activity through the inhibition of TXA2-TP- signaling. It was shown by Lieberthal that the severity and duration of ATP depletion determines the mechanism of death: cells with an intracellular ATP
concentration below a certain threshold become necrotic, whereas an ATP value above that threshold induces apoptosis (Shiraish, et al., 2001). As ischemia is associated with more ATP depletion, whereas reperfusion may replenish the ATP stores, the main mechanism of cell death is caspase activated apoptosis in ischemia reperfusion model.
We also demonstrated that oxidative stress was attenuated in myocardial I/R injury via 4-HNE through inhibition of TXA2 -TP- signaling. Main impairment of reperfusion result from oxidative stress had been discussed a long time. Various studies
38
have demonstrated that generation of ROS in I/R injury induced injury or oxygen-derived free radicals can lead to programmed cell death (Zweier, et al., 1988; Buttke, et al., 1994). Unlike most of using evans blue&TTC double stain to identify the myocardial infarct size (Price, et al., 2011), we have utilized troponin I to examine the degree of infarction (Mair, et al., 1995; Hallén, et al., 2009). Our data indicate it have better cardioprotection when blocking TXA2-TP- signaling.
39
VIII. Conclusion
In summary, this study can divide into two parts. (1) In order to elaborate the relationship between TXA2-TP- signaling and ET-1 on heart microcirculation and function. Inhibition of TXA2 -TP-signaling gives a cardioprotection when faced with challenges from ET-1 and TXA2 and substantiates that TXA2-TP-signaling is located upstream of ET-1 via pharmacological experiments. (2) In order to evaluate whether injury evoked by I/R was attenuated with blocking TXA2-TP- signaling. I/R model was performed to explain reducing of apoptosis, oxidative, inflammation, pyroptosis and degree of infarction. This research will benefit the development of new therapeutic strategies, or to ameliorate the old treatments in the future.
40
IX. Reference
Bell, R. M., Bøtker, H. E., Carr, R. D., Davidson, S. M., Downey, J. M., Dutka, D. P., Ovize, M. (2016). 9th Hatter Biannual Meeting: position document on
ischaemia/reperfusion injury, conditioning and the ten commandments of cardioprotection. Basic research in cardiology, 111(4), 41.
Braunwald, E., Kloner, R. A. (1985). Myocardial reperfusion: a double-edged sword?.
Journal of Clinical Investigation, 76(5), 1713.
Broegger, T., Jacobsen, J. C. B., Secher Dam, V., Boedtkjer, D. M. B., Kold-Petersen, H., Pedersen, F. S., Matchkov, V. V. (2011). Bestrophin is important for the rhythmic but not the tonic contraction in rat mesenteric small arteries. Cardiovascular research, 91(4), 685-693.
Buttke, T. M., Sandstrom, P. A. (1994). Oxidative stress as a mediator of apoptosis.
Immunology today, 15(1), 7-10.
Chien, C. T., Shyue, S. K., Lai, M. K. (2007). Bcl-xL augmentation potentially reduces ischemia/reperfusion induced proximal and distal tubular apoptosis and autophagy. Transplantation, 84(9), 1183-1190.
Chien, C. Y., Chien, C. T., Wang, S. S. (2014). Progressive thermopreconditioning attenuates rat cardiac ischemia/reperfusion injury by mitochondria-mediated antioxidant and antiapoptotic mechanisms. The Journal of thoracic and cardiovascular surgery, 148(2), 705-713.
41
Chung, S. D., Lai, T. Y., Chien, C. T., Yu, H. J. (2012). Activating Nrf-2 signaling depresses unilateral ureteral obstruction-evoked mitochondrial stress-related autophagy, apoptosis and pyroptosis in kidney. PloS one, 7(10), e47299.
DeFilippis, A. P., Oloyede, O. S., Andrikopoulou, E., Saenger, A. K., Palachuvattil, J.
M., Fasoro, Y. A., Gerstenblith, G. (2013). Thromboxane A2 generation, in the absence of platelet COX-1 activity, in patients with and without atherothrombotic myocardial infarction. Circulation Journal, 77(11), 2786-2792.
Ezzati, M., Vander Hoorn, S., Rodgers, A., Lopez, A. D., Mathers, C. D., Murray, C. J.
(2003). Estimates of global and regional potentil health gains from reducing muliple major risk factors. The Lancet, 362(9380), 271-280.
Filep, J. G., Fournier, A., Földes‐Filep, É. (1994). Endothelin‐1‐induced myocardial ischaemia and oedema in the rat: involvement of the ETA receptor, platelet‐activating factor and thromboxane A2. British journal of pharmacology, 112(3), 963-971.
Fitzgerald, D. J., Roy, L., Catella, F., FitzGerald, G. A. (1986). Platelet activation in unstable coronary disease. New England Journal of Medicine, 315(16), 983-989.
Frank, A., Bonney, M., Bonney, S., Weitzel, L., Koeppen, M., Eckle, T. (2012, September). Myocardial ischemia reperfusion injury: from basic science to clinical bedside. In Seminars in cardiothoracic and vascular anesthesia (Vol. 16, No. 3, pp.
123-132). Sage CA: Los Angeles, CA: SAGE Publications.
42
Giaid, A., Yanagisawa, M., Langleben, D., Michel, R. P., Levy, R., Shennib, H., Stewart, D. J. (1993). Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. New England Journal of Medicine, 328(24), 1732-1739.
Gottlieb, R. A., Burleson, K. O., Kloner, R. A., Babior, B. M., Engler, R. L. (1994).
Reperfusion injury induces apoptosis in rabbit cardiomyocytes. Journal of Clinical Investigation, 94(4), 1621.
Hallén, J., Buser, P., Schwitter, J., Petzelbauer, P., Geudelin, B., Fagerland, M. W., Atar, D. (2009). Relation of cardiac troponin I measurements at 24 and 48 hours to magnetic resonance–determined infarct size in patients with ST-elevation myocardial infarction. The American journal of cardiology, 104(11), 1472-1477.
Hashmi, S., Al-Salam, S. (2015). Acute myocardial infarction and myocardial ischemia-reperfusion injury: a comparison. International journal of clinical and experimental pathology, 8(8), 8786.
Huang, R. Y., Li, M. Y., Ng, C. S., Wan, I. Y., Kong, A. W., Du, J., Chen, G. G.
(2013). Thromboxane A2 receptor α promotes tumor growth through an
autoregulatory feedback pathway. Journal of molecular cell biology, 5(6), 380-390.
Kloner, R. A. (1993). Does reperfusion injury exist in humans?. Journal of the American College of Cardiology, 21(2), 537-545.
Kuzuya, T., Hoshida, S., Nishida, M., Kim, Y., Kamada, T., Tada, M. (1987).
43
Increased production or arachidonate metabolites in an occlusion-reperfusion model of canine myocardial infarction. Cardiovascular research, 21(8), 551-558.
Lieberthal, W., Menza, S. A., Levine, J. S. (1998). Graded ATP depletion can cause necrosis or apoptosis of cultured mouse proximal tubular cells. American Journal of Physiology-Renal Physiology, 274(2), F315-F327.
Mair, J., Wagner, I., Morass, B., Fridrich, L., Lechleitner, P., Dienstl, F., Puschendorf, B. (1995). Cardiac troponin I release correlates with myocardial infarction size.
European journal of clinical chemistry and clinical biochemistry, 33(11), 869-872.
Mcmurray, J. J., Ray, S. G., Abdullah, I., Dargie, H. J., Morton, J. J. (1992). Plasma endothelin in chronic heart failure. Circulation, 85(4), 1374-1379.
Mullane, K. M., Fornabaio, D. (1988). Thromboxane synthetase inhibitors reduce infarct size by a platelet-dependent, aspirin-sensitive mechanism. Circulation research, 62(4), 668-678.
Nakahata, N. (2008). Thromboxane A 2: physiology/pathophysiology, cellular signal transduction and pharmacology. Pharmacology & therapeutics, 118(1), 18-35.
Nichols, W. W., Mehta, J., Wargovich, T. J., Franzini, D., Lawson, D. (1989). Reduced myocardial neutrophil accumulation and infarct size following thromboxane
synthetase inhibitor or receptor antagonist. Angiology, 40(3), 209-221.
44
Nowak, K. L., Chonchol, M., Ikizler, T. A., Farmer-Bailey, H., Salas, N., Chaudhry, R., Hung, A. M. (2017). IL-1 Inhibition and Vascular Function in CKD. Journal of the American Society of Nephrology, 28(3), 971-980.
Oyama, J. I., Blais, C., Liu, X., Pu, M., Kobzik, L., Kelly, R. A., Bourcier, T. (2004).
Reduced myocardial ischemia-reperfusion injury in toll-like receptor 4-deficient mice.
Circulation, 109(6), 784-789.
Price, A. N., Cheung, K. K., Lim, S. Y., Yellon, D. M., Hausenloy, D. J., Lythgoe, M.
F. (2011). Rapid assessment of myocardial infarct size in rodents using multi-slice inversion recovery late gadolinium enhancement CMR at 9.4 T. Journal of
Cardiovascular Magnetic Resonance, 13(1), 44.
Qiu, H., Liu, J. Y., Wei, D., Li, N., Yamoah, E. N., Hammock, B. D., Chiamvimonvat, N. (2012). Cardiac-generated prostanoids mediate cardiac myocyte apoptosis after myocardial ischaemia. Cardiovascular research, 95(3), 336-345.
Raedschelders, K., Ansley, D. M., Chen, D. D. (2012). The cellular and molecular origin of reactive oxygen species generation during myocardial ischemia and reperfusion. Pharmacology & therapeutics, 133(2), 230-255.
Santoro, A., Mandreoli, M. (2014). Chronic renal disease and risk of cardiovascular morbidity-mortality. Kidney and Blood Pressure Research, 39(2-3), 142-146.
Setianto, B. Y., Hartopo, A. B., Sukmasari, I., Puspitawati, I. (2016). On-admission
45
high endothelin-1 level independently predicts in-hospital adverse cardiac events following ST-elevation acute myocardial infarction. International journal of cardiology, 220, 72-76.
Shen, R. F., Tai, H. H. (1998). Thromboxanes: synthase and receptors. Journal of biomedical science, 5(3), 153-172.
Shiraishi, J., Tatsumi, T., Keira, N., Akashi, K., Mano, A., Yamanaka, S., Fliss, H.
(2001). Important role of energy-dependent mitochondrial pathways in cultured rat cardiac myocyte apoptosis. American Journal of Physiology-Heart and Circulatory Physiology, 281(4), H1637-H1647.
Sui, D. Y., Qu, S. C., Yu, X. F., Chen, Y. P., Ma, X. Y. (2004). Protective effect of ASS on myocardial ischemia-reperfusion injury in rats. Zhongguo Zhong yao za zhi=
Zhongguo zhongyao zazhi= China journal of Chinese materia medica, 29(1), 71-74.
Suma, H. (2013). Gastroepiploic artery graft in coronary artery bypass grafting.
Annals of cardiothoracic surgery, 2(4), 493.
Thomas, D. W., Mannon, R. B., Mannon, P. J., Latour, A., Oliver, J. A., Hoffman, M., Coffman, T. M. (1998). Coagulation defects and altered hemodynamic responses in mice lacking receptors for thromboxane A2. Journal of Clinical Investigation, 102(11), 1994.
Vinten-Johansen, J. (2004). Involvement of neutrophils in the pathogenesis of lethal
46
myocardial reperfusion injury. Cardiovascular research, 61(3), 481-497.
Wang, C., Luo, Z., Kohan, D., Wellstein, A., Jose, P. A., Welch, W. J., Wang, D.
(2015). Thromboxane Prostanoid Receptors Enhance Contractions, Endothelin-1 and Oxidative Stress in Microvessels From Mice With Chronic Kidney Disease.
Hypertension, HYPERTENSIONAHA-115.
Wu, C. Y., Yeh, Y. C., Chien, C. T., Chao, A., Sun, W. Z., Cheng, Y. J. (2015). Laser speckle contrast imaging for assessing microcirculatory changes in multiple
splanchnic organs and the gracilis muscle during hemorrhagic shock and fluid resuscitation. Microvascular research, 101, 55-61.
Yamamoto, T., Hosoki, K., Karasawa, T. (1993). Possible involvement of endothelin in thromboxane A2 receptor agonist (U-46619)-induced angina in the rat. European journal of pharmacology, 250(1), 189-191.
Yanagisawa, M., Kurihara, H., Kimura, S., Tomobe, Y., Kobayashi, M., Mitsui, Y., Masaki, T. (1988). A novel potent vasoconstrictor peptide produced by vascular endothelial cells. nature, 332(6163), 411-415.
Yang, J. R., Yao, F. H., Zhang, J. G., Ji, Z. Y., Li, K. L., Zhan, J., He, Y. N. (2014).
Ischemia-reperfusion induces renal tubule pyroptosis via the CHOP-caspase-11 pathway. American Journal of Physiology-Renal Physiology, 306(1), F75-F84.
Yellon, D. M., Hausenloy, D. J. (2007). Myocardial reperfusion injury. New England
47 Journal of Medicine, 357(11), 1121-1135.
Yu, I. S., Lin, S. R., Huang, C. C., Tseng, H. Y., Huang, P. H., Shi, G. Y., Wu, K. K.
(2004). TXAS-deleted mice exhibit normal thrombopoiesis, defective hemostasis, and resistance to arachidonate-induced death. Blood, 104(1), 135-142.
Zweier, J. L. (1988). Measurement of superoxide-derived free radicals in the
reperfused heart. Evidence for a free radical mechanism of reperfusion injury. Journal
reperfused heart. Evidence for a free radical mechanism of reperfusion injury. Journal