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Losartan attenuates aortic endothelial apoptosis induced by chronic intermittent hypoxia partly via the phospholipase C pathway

  • Sleep Breathing Physiology and Disorders • Original Article
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Abstract

Purpose

Endoplasmic reticulum (ER) stress is known to play key roles in the development of endothelial cell apoptosis induced by chronic intermittent hypoxia (CIH), and the angiotensin II–phospholipase C–inositol-1,4,5-triphosphate (AngII-PLC-IP3) pathway has been demonstrated to induce ER stress. To explore whether the AngII-PLC-IP3 pathway is involved in the vascular damage induced by CIH, we examined whether the AngII-PLC-IP3 pathway is involved in ER stress induced by CIH and whether losartan, a selective angiotensin II type 1 receptor (AT1R) blocker, could suppress endothelial cell apoptosis induced by CIH.

Methods

Adult male Sprague Dawley rats were subjected to 8 h/day of intermittent hypoxia/normoxia, with or without losartan, a selective AT1R blocker, and/or U73122, a selective PLC inhibitor, for 8 weeks. Endothelial cell apoptosis, ER stress markers, and levels of PLC-γ1 and IP3R expression were determined.

Results

Losartan prevented increases in PLC-γ1 and IP3R protein levels and inhibited ER stress markers induced by CIH. Addition of U73122 reproduced all the protective effects of losartan. Losartan administration before CIH significantly ameliorated CIH-induced endothelial cell apoptosis.

Conclusions

This study showed that the AngII-PLC-IP3 pathway is involved in ER stress induced by CIH and that pre-losartan administration ameliorates endothelial cell apoptosis following CIH partly via inhibition of the AngII-PLC-IP3 pathway and ER stress.

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References

  1. Gottlieb DJ, Yenokyan G, Newman AB, O’Connor GT, Punjabi NM, Quan SF, Redline S, Resnick HE, Tong EK, Diener-West M, Shahar E (2010) Prospective study of obstructive sleep apnea and incident coronary heart disease and heart failure: the sleep heart health study. Circulation 122:352–360. doi:10.1161/CIRCULATIONAHA.109.901801

    Article  PubMed  PubMed Central  Google Scholar 

  2. Peppard PE, Young T, Palta M, Skatrud J (2000) Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 342:1378–1384. doi:10.1056/NEJM200005113421901

    Article  CAS  PubMed  Google Scholar 

  3. Jean-Philippe Baguet GBRT (2012) Mechanisms of cardiac dysfunction. Cardiology 9:679–688

    PubMed  Google Scholar 

  4. Marcus NJ, Philippi NR, Bird CE, Li YL, Schultz HD, Morgan BJ (2012) Effect of AT1 receptor blockade on intermittent hypoxia-induced endothelial dysfunction. Respir Physiol Neurobiol 183:67–74. doi:10.1016/j.resp.2012.05.025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. de Gasparo M, Catt KJ, Inagami T, Wright JW, Unger T (2000) International union of pharmacology. XXIII. The angiotensin II receptors. Pharmacol Rev 52:415–472

    PubMed  Google Scholar 

  6. Goldenberg I, Grossman E, Jacobson KA, Shneyvays V, Shainberg A (2001) Angiotensin II-induced apoptosis in rat cardiomyocyte culture: a possible role of AT1 and AT2 receptors. J Hypertens 19:1681–1689. doi:10.1097/00004872-200109000-00022

    Article  CAS  PubMed  Google Scholar 

  7. Vivar R, Soto C, Copaja M, Mateluna F, Aranguiz P, Muñoz JP, Chiong M, Garcia L, Letelier A, Thomas WG, Lavandero S, Díaz-Araya G (2008) Phospholipase C/protein kinase C pathway mediates angiotensin II-dependent apoptosis in neonatal rat cardiac fibroblasts expressing AT1 receptor. J Cardiovasc Pharmacol 52:184–190. doi:10.1097/FJC.0b013e318181fadd

    Article  CAS  PubMed  Google Scholar 

  8. Deliu E, Brailoiu GC, Eguchi S, Hoffman NE, Rabinowitz JE, Tilley DG, Madesh M, Koch WJ, Brailoiu E (2014) Direct evidence of intracrine angiotensin II signaling in neurons. Am J Physiol Cell Physiol 306:C736–C744. doi:10.1152/ajpcell.00131.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Zhao Y, Zhang X, Li J, Bian Y, Sheng M, Liu B, Fu Z, Zhang Y, Yang B (2016) Jujuboside B reduces vascular tension by increasing Ca2+ influx and activating endothelial nitric oxide synthase. PLoS One 11:e149386. doi:10.1371/journal.pone.0149386

    Google Scholar 

  10. Rosado JA, Sage SO (2001) Activation of store-mediated calcium entry by secretion-like coupling between the inositol 1,4,5-trisphosphate receptor type II and human transient receptor potential (hTrp1) channels in human platelets. Biochem J 356:191–198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Dietrich A, Kalwa H, Gudermann T (2010) TRPC channels in vascular cell function. Thromb Haemost 103:262–270. doi:10.1160/TH09-08-0517

    Article  CAS  PubMed  Google Scholar 

  12. Jain A, Olovsson M, Burton GJ, Yung HW (2012) Endothelin-1 induces endoplasmic reticulum stress by activating the PLC-IP(3) pathway: implications for placental pathophysiology in preeclampsia. Am J Pathol 180:2309–2320. doi:10.1016/j.ajpath.2012.03.005

    Article  CAS  PubMed  Google Scholar 

  13. Bascands JL, Girolami JP, Troly M, Escargueil-Blanc I, Nazzal D, Salvayre R, Blaes N (2001) Angiotensin II induces phenotype-dependent apoptosis in vascular smooth muscle cells. Hypertension 38:1294–1299. doi:10.1161/hy1201.096540

    Article  CAS  PubMed  Google Scholar 

  14. Rhee SG (2001) Regulation of phosphoinositide-specific phospholipase C. Annu Rev Biochem 70:281–312. doi:10.1146/annurev.biochem.70.1.281

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Rebecchi MJ, Pentyala SN (2000) Structure, function, and control of phosphoinositide-specific phospholipase C. Physiol Rev 80:1291–1335

    CAS  PubMed  Google Scholar 

  16. Baumann S, Fas SC, Giaisi M, Müller WW, Merling A, Gülow K, Edler L, Krammer PH, Li-Weber M (2008) Wogonin preferentially kills malignant lymphocytes and suppresses T-cell tumor growth by inducing PLCgamma1- and Ca2+-dependent apoptosis. Blood 111:2354–2363. doi:10.1182/blood-2007-06-096198

    Article  CAS  PubMed  Google Scholar 

  17. Watanabe T, Suzuki J, Yamawaki H, Sharma VK, Sheu SS, Berk BC (2005) Losartan metabolite EXP3179 activates Akt and endothelial nitric oxide synthase via vascular endothelial growth factor receptor-2 in endothelial cells: angiotensin II type 1 receptor-independent effects of EXP3179. Circulation 112:1798–1805. doi:10.1161/CIRCULATIONAHA.104.509760

    Article  CAS  PubMed  Google Scholar 

  18. Li D, Yang B, Philips MI, Mehta JL (1999) Proapoptotic effects of ANG II in human coronary artery endothelial cells: role of AT1 receptor and PKC activation. Am J Phys 276:H786–H792

    CAS  Google Scholar 

  19. Hou C, Kirchner T, Singer M, Matheis M, Argentieri D, Cavender D (2004) In vivo activity of a phospholipase C inhibitor, 1-(6-((17beta-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione (U73122), in acute and chronic inflammatory reactions. J Pharmacol Exp Ther 309:697–704. doi:10.1124/jpet.103.060574

    Article  CAS  PubMed  Google Scholar 

  20. Kathy K, Griendling SERT, Michael A, JARW G (1986) Sustained diacylglycerol formation from inositol phospholipids in angiotensin 11-stimulated vascular smooth muscle cells. J Biol Chem 261:5901–5906

    Google Scholar 

  21. Catt KJ, Balla T, Baukal AJ, Hausdorff WP, Aguilera G (1988) Control of glomerulosa cell function by angiotensin II: transduction by G-proteins and inositol polyphosphates. Clin Exp Pharmacol Physiol 15:501–515. doi:10.1111/j.1440-1681.1988.tb01108.x

    Article  CAS  PubMed  Google Scholar 

  22. Touyz RM (2005) Intracellular mechanisms involved in vascular remodelling of resistance arteries in hypertension: role of angiotensin II. Exp Physiol 90:449–455. doi:10.1113/expphysiol.2005.030080

    Article  CAS  PubMed  Google Scholar 

  23. Lea JP, Jin SG, Roberts BR, Shuler MS, Marrero MB, Tumlin JA (2002) Angiotensin II stimulates calcineurin activity in proximal tubule epithelia through AT-1 receptor-mediated tyrosine phosphorylation of the PLC-gamma1 isoform. J Am Soc Nephrol 13:1750–1756. doi:10.1097/01.ASN.0000022029.50356.2C

    Article  CAS  PubMed  Google Scholar 

  24. Ma Y, Hendershot LM (2004) ER chaperone functions during normal and stress conditions. J Chem Neuroanat 28:51–65. doi:10.1016/j.jchemneu.2003.08.007

    Article  CAS  PubMed  Google Scholar 

  25. Ron D, Walter P (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 8:519–529. doi:10.1038/nrm2199

    Article  CAS  PubMed  Google Scholar 

  26. Wei MC, Zong WX, Cheng EH, Lindsten T, Panoutsakopoulou V, Ross AJ, Roth KA, MacGregor GR, Thompson CB, Korsmeyer SJ (2001) Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 292:727–730. doi:10.1126/science.1059108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Yang YY, Shang J, Liu HG (2013) Role of endoplasmic reticular stress in aortic endothelial apoptosis induced by intermittent/persistent hypoxia. Chin Med J Peking 126:4517–4523. doi:10.3760/cma.j.issn.0366-6999.20130602

    CAS  Google Scholar 

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Acknowledgements

This study was funded by the National Natural Science Foundation of China (grants 81570080 and 81370185).

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Authors and Affiliations

  1. Department of Respiratory and Critical Care Medicine, Tongji Hospital, Huazhong University of Science and Technology, No. 1095 Jiefang Road, Wuhan, 430030, China

    Jie Ren, Yan Deng, Guang-cai Li, Yue-ying Pan, Sheng Xie, Meng Jin & Hui-guo Liu

  2. The Third Hospital Affiliated to Kunming Medical University, No. 174 People’s West Road, Kunming, 650106, China

    Wei Liu

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  1. Jie Ren
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Correspondence to Hui-guo Liu.

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Ren, J., Liu, W., Deng, Y. et al. Losartan attenuates aortic endothelial apoptosis induced by chronic intermittent hypoxia partly via the phospholipase C pathway. Sleep Breath 21, 679–689 (2017). https://doi.org/10.1007/s11325-017-1479-4

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  • DOI: https://doi.org/10.1007/s11325-017-1479-4

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