Short-Term Versus Long-Term Intermittent Hypobaric Hypoxia on Cardiac Fibrosis and Fas Death Receptor Dependent Apoptotic Pathway in Rat Hearts

Yueh-Min Lin；Shu-Kuei Huang；Hsueh-Fang Wang；Li-Mien Chen；Fuu-Jen Tsai；Hsi-Hsien Hsu；Chia-Hua Kuo；Paulus S. Wang；Chih-Yang Huang；Shin-Da Lee

cardiac fibrosis ； cell apoptosis ； high altitude ； Fas pathway ； time course

The Chinese Journal of Physiology

51卷5期（2008 / 10 / 01）

308 - 316

英文

It is unknown if short-term and long-term intermittent hypobaric hypoxic challenges both exert pro-apoptotic effects on Fas death receptor-dependent apoptotic pathway in rat hearts. Seventy-two Sprague-Dawley rats were randomly assigned into two groups. First, short-term intermittent hypobaric hypoxia (STIHH)-normobaric normoxia (n=12), hypobaric hypoxia (380 mmHg, 12% O2, 8 hrs/day) for 1 day (n=12), and for 4 days (n=12) and second, long-term intermittent hypobaric hypoxia (LTIHH)-normobaric normoxia (n=12), hypobaric hypoxia for 1 week (n=12) and 2 weeks (n=12). After STIHH or LTIHH challenge, Fas receptor related pathway and histopathological analysis in the excised left ventricle was determined by Western blotting, RT-PCR, Hematoxylin-eosin staining, Masson trichrome staining and TUNEL assay. Fas death receptor and TNFα were significantly decreased after STIHH whereas Fas receptor, TNFα, FAS-associated death domain (FADD), and caspase 8 were increased after LTIHH. In addition, cardiomyocyte disarray and fibrosis were observed in 1 week LTIHH. Cardiac hypertrophy and more severe disarray, fibrosis and cardiac apoptotic activities were observed in 2 week LTIHH. STIHH exerts anti-apoptotic effects on hearts such as downregulation of TNFα and Fas receptor whereas LTIHH exerts pro-apoptotic effects such as upregulation of TNFα and Fas-mediated apoptotic pathways and lead to cardiac fibrosis and apoptosis. Our findings imply that short-term versus long-term intermittent hypobaric hypoxia exerted protective versus deleterious effects on hearts.

1. Jong, G.P.,Ma, T.,Chou, P.,Chang, M.H.,Wu, C.H.,Lis, P.C.,Lee, S.D.,Liu, J.Y.,Kuo, W.W.,Huang, C.Y.(2006).Serum MMP-9 activity as a diagnosing marker for the developing heart failure of post MI patients.Chinese J. Physiol.,49,104-109.
   連結：
2. Abbate, A.,Biondi-Zoccai, G.G.,Baldi, A.,Trani, C.,Biasucci, L.M.,Vetrovec, G.W.(2003).The `Open-Artery Hypothesis`: new clinical and pathophysiologic insights.Cardiology,100,196-206.
3. Anversa, P.,Nadal-Ginard, B.(2002).Myocyte renewal and ventricular remodelling.Nature,415,240-243.
4. Biondi-Zoccai, G.G.,Abbate, A.,Vasaturo, F.,Scarpa, S.,Santini, D.,Leone, A.M.,Parisi, Q.,De Giorgio, F.,Bussani, R.,Silvestri, F.,Baldi, F.,Biasucci, L.M.,Baldi, A.(2004).Increased apoptosis in remote non-infarcted myocardium in multivessel coronary disease.Int. J. Cardiol.,94,105-110.
5. Bishopric, N.H.,Andreka, P.,Slepak, T.,Webster, K.A.(2001).Molecular mechanisms of apoptosis in the cardiac myocyte.Curr. Opin. Pharmacol.,1,141-150.
6. Chao, W.,Shen, Y.,Li, L.,Rosenzweig, A.(2002).Importance of FADD signaling in serum deprivation- and hypoxia-induced cardiomyocyte apoptosis.J. Biol. Chem.,277,31639-31645.
7. Culver, C.A.,Michalowski, S.M.,Maia, R.C.,Laster, S.M.(2005).The anti-apoptotic effects of nordihydroguaiaretic acid: inhibition of cPLA2 activation during TNF-induced apoptosis arises from inhibition of calcium signaling.Life Sci.,77,2457-2470.
8. D`Armiento, J.(2002).Matrix metalloproteinase disruption of the extracellular matrix and cardiac dysfunction.Trends Cardiovasc. Med.,12,97-101.
9. Date, T.,Mochizuki, S.,Belanger, A.J.,Yamakawa, M.,Luo, Z.,Vincent, K.A.,Cheng, S.H.,Gregory, R.J.,Jiang, C.(2003).Differential effects of membrane and soluble Fas ligand on cardiomyocytes: role in ischemia/reperfusion injury.J. Mol. Cell. Cardiol.,35,811-821.
10. Dong, J.W.,Zhu, H.F.,Zhu, W.Z.,Ding, H.L.,Ma, T.M.,Zhou, Z.N.(2003).Intermittent hypoxia attenuates ischemia/reperfusion induced apoptosis in cardiac myocytes via regulating Bcl-2/Bax expression.Cell Res.,13,385-391.
11. Haunstetter, A.,Izumo, S.(1998).Apoptosis: basic mechanisms and implications for cardiovascular disease.Circ. Res.,82,1111-1129.
12. Hoppeler, H.,Vogt, M.(2001).Hypoxia training for sea-level performance. Training high-living low.Adv. Exp. Med. Biol.,502,61-73.
13. Jeremias, I.,Kupatt, C.,Martin-Villalba, A.,Habazettl, H.,Schenkel, J.,Boekstegers, P.,Debatin, K.M.(2000).Involvement of CD95/Apo1/ Fas in cell death after myocardial ischemia.Circulation,102,915-920.
14. Kim, S.,Iwao, H.(2000).Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases.Pharmacol. Rev.,52,11-34.
15. Kuo, W.W.,Liu, C.J.,Chen, L.M.,Wu, C.H.,Chu, C.H.,Liu, J.Y.,Lu, M.C.,Lin, J.A.,Lee, S.D.,Huang, C.Y.(2006).Cardiomyoblast apoptosis induced by insulin-like growth factor (IGF)-I resistance is IGF-II dependent and synergistically enhanced by angiotensin II.Apoptosis,11,1075-1089.
16. Lee, S.D.,Chu, C.H.,Huang, E.J.,Lu, M.C.,Liu, J.Y.,Liu, C.J.,Hsu, H.H.,Lin, J.A.,Kuo, W.W.,Huang, C.Y.(2006).Roles of insulinlike growth factor II in cardiomyoblast apoptosis and in hypertensive rat heart with abdominal aorta ligation.Am. J. Physiol. Endocrinol. Metab.,291,306-314.
17. Lee, S.D.,Kuo, W.W.,Lin, J.A.,Chu, Y.F.,Wang, C.K.,Yeh, Y.L.,Wang, P.S.,Liu, J.Y.,Chang, M.H.,Huang, C.Y.(2007).Effects of long-term intermittent hypoxia on mitochondrial and Fas death receptor dependent apoptotic pathways in rat hearts.Int. J. Cardiol.,116,348-356.
18. Lee, S.D.,Kuo, W.W.,Wu, C.H.,Lin, Y.M.,Lin, J.A.,Lu, M.C.,Yang, A.L.,Liu, J.Y.,Wang, P.S.,Liu, C.J.,Chen, L.M.,Huang, C.Y.(2006).Effects of short-and long-term hypobaric hypoxia on Bcl2 family in rat heart.Int. J. Cardiol.,108,376-384.
19. Lee, S.D.,Tzang, B.S.,Kuo, W.W.,Lin, Y.M.,Yang, A.L.,Chen, S.H.,Tsai, F.J.,Wu, F.L.,Lu, M.J.,Huang, C.Y.(2007).Cardiac Fas receptor-dependent apoptotic pathway in obese Zucker rats.Obesity,15,2407-2415.
20. Lee, S.D.,Wu, C.C.,Chang, Y.C.,Chang, S.H.,Wu, C.H.,Wu, J.P.,Hwang, J.M.,Kuo, W.W.,Liu, J.Y.,Huang, C.Y.(2006).Porphyromonas gingivalis-induced cellular hypertrophy and MMP-9 activity via different signaling pathways in H9c2 cardiomyoblast cells.J. Periodontol.,77,684-691.
21. Lee, S.D.,Wu, C.C.,Kuo, W.W.,Lin, J.A.,Hwang, J.M.,Lu, M.C.,Chen, L.M.,Hsu, H.H.,Wang, C.K.,Chang, S.H.,Huang, C.Y.(2006).Porphyromonas gingivalis-related cardiac cell apoptosis was majorly co-activated by p38 and extracellular signal-regulated kinase pathways.J. Periodontal. Res.,41,39-46.
22. Liao, X.,Wang, X.,Gu, Y.,Chen, Q.,Chen, L.Y.(2005).Involvement of death receptor signaling in mechanical stretch-induced cardiomyocyte apoptosis.Life Sci.,77,160-174.
23. Lin, T.B.,Lo, M.J.,Huang, C.Y.,Ting, H.,Lee, S.D.(2005).GABAergic modulation of ventilatory response to acute and sustained hypoxia in obese Zucker rats.Int. J. Obes (Lond).,29,188-195.
24. Lu, M.C.,Kuo, W.W.,Tzang, B.S.,Wu, F.L.,Chen, Y.S.,Huang, C.Y.,Lee, S.D.(2007).More activated cardiac mitochondrial dependent apoptotic pathway in obese Zucker rat.Obesity,15,2634-2642.
25. Narula, J.,Pandey, P.,Arbustini, E.,Haider, N.,Narula, N.,Kolodgie, F.D.,Dal Bello, B.,Semigran, M.J.,Bielsa-Masdeu, A.,Dec, G.W.,Israels, S.,Ballester, M.,Virmani, R.,Saxena, S.,Kharbanda, S.(1999).Apoptosis in heart failure: release of cytochrome c from mitochondria and activation of caspase-3 in human cardiomyopathy.Proc. Natl. Acad. Sci. USA.,96,8144-8149.
26. Sadanandan, S.,Hochman, J.S.(2000).Early reperfusion, late reperfusion, and the open artery hypothesis: an overview.Prog. Cardiovasc. Dis.,42,397-404.
27. Scarabelli, T.M.,Stephanou, A.,Pasini, E.,Comini, L.,Raddino, R.,Knight, R.A.,Latchman, D.S.(2002).Different signaling pathways induce apoptosis in endothelial cells and cardiac myocytes during ischemia/reperfusion injury.Circ. Res.,90,745-748.
28. Sorescu, D.,Griendling, K.K.(2002).Reactive oxygen species, mitochondria, and NAD(P)H oxidases in the development and progression of heart failure.Congest Heart Fail,8,132-140.
29. Stephanou, A.,Scarabelli, T.M.,Brar, B.K.,Nakanishi, Y.,Matsumura, M.,Knight, R.A.,Latchman, D.S.(2001).Induction of apoptosis and Fas receptor/Fas ligand expression by ischemia/reperfusion in cardiac myocytes requires serine 727 of the STAT-1 transcription factor but not tyrosine 701.J. Biol. Chem.,276,28340-38347.
30. Takeshita, K.,Hayashi, M.,Iino, S.,Kondo, T.,Inden, Y.,Iwase, M.,Kojima, T.,Hirai, M.,Ito, M.,Loskutoff, D.J.,Saito, H.,Murohara, T.,Yamamoto, K.(2004).Increased expression of plasminogen activator inhibitor-1 in cardiomyocytes contributes to cardiac fibrosis after myocardial infarction.Am. J. Pathol.,164,449-456.
31. Tanaka, M.,Ito, H.,Adachi, S.,Akimoto, H.,Nishikawa, T.,Kasajima, T.,Marumo, F.,Hiroe, M.(1994).Hypoxia induces apoptosis with enhanced expression of Fas antigen messenger RNA in cultured neonatal rat cardiomyocytes.Circ. Res.,75,426-433.
32. Teicher, B.A.(1995).Physiologic mechanisms of therapeutic resistance. Blood flow and hypoxia.Hematol. Oncol. Clin. North. Am.,9,475-506.
33. Wu, M.K.,Wang, C.K.,Bai, Y.M.,Huang, C.Y.,Lee, S.D.(2007).Outcomes of obese, clozapine-treated inpatients with schizophrenia placed on a six-month diet and physical activity program.Psychiatr. Serv.,58,544-550.
34. Yang, A.L.,Lo, M.J.,Ting, H.,Chen, J.S.,Huang, C.Y.,Lee, S.D.(2007).GABAA and GABAB receptors differentially modulate volume and frequency in ventilatory compensation in obese Zucker rats.J. Appl. Physiol.,102,350-357.
35. Yang, A.L.,Su, C.T.,Lin, K.L.,Chao, J.I.,You, H.P.,Lee, S.D.(2006).Exercise training improves insulin-induced and insulin-like growth factor-1-induced vasorelaxation in rat aortas.Life Sci.,79,2017-2021.
36. Yaniv, G.,Shilkrut, M.,Lotan, R.,Berke, G.,Larisch, S.,Binah, O.(2002).Hypoxia predisposes neonatal rat ventricular myocytes to apoptosis induced by activation of the Fas (CD95/Apo-1) receptor: Fas activation and apoptosis in hypoxic myocytes.Cardiovasc. Res.,54,611-623.
37. Yu, C.M.,Tipoe, G.L.,Wing-Hon Lai, K.,Lau, C.P.(2001).Effects of combination of angiotensin-converting enzyme inhibitor and angiotensin receptor antagonist on inflammatory cellular infiltration and myocardial interstitial fibrosis after acute myocardial infarction.J. Am. Coll. Cardiol.,38,1207-1215.

1. 陳聰毅、王冠捷(2017)。運動誘發鳶尾素對肥胖合併間歇性低氧引起心肌纖維化的影響。大專體育學刊，19(3)，272-287。
2. 黃森芳、黃國欽、陳聰毅(2015)。運動對阻塞型睡眠呼吸中止症引發心臟功能損傷之影響：鈉氫離子交換蛋白的角色。中華體育季刊，29(4)，301-310。