dl-Propargylglycine protects against myocardial injury induced by chronic intermittent hypoxia through inhibition of endoplasmic reticulum stress
- 27 Downloads
Chronic intermittent hypoxia (CIH), an important basis of the pathogenesis of organ damage induced by obstructive sleep apnea syndrome (OSAS), is associated with myocardial injury, such as left ventricular dysfunction, apoptosis, and oxidative stress. Endogenous hydrogen sulfide (H2S) plays an important role in maintaining cardiovascular functions. Many studies have demonstrated that exogenous H2S has protective effects against myocardial injury induced by various cardiovascular diseases, and inhibiting the generation of endogenous H2S has opposite effects. However, the effect of dl-propargylglycine (PAG), an effective inhibitor of cystathionine γ-lyase (CSE)-synthesized H2S, on the regulation myocardial injury remains controversial.
The present study was aimed to explore the influence of PAG on myocardial injury induced in rats by CIH.
Sprague-Dawley rats were randomly divided into a normal control (NC) group, a CIH group, a NC + PAG group, and a CIH + PAG group. After establishing the CIH model in rats, blood pressure, left ventricular function, oxidative stress, apoptosis, and the level of endoplasmic reticulum (ER) stress were detected.
In NC rats, PAG had no effect on blood pressure, but induced myocardial dysfunction and up-regulated oxidative stress and apoptosis of the myocardium. In the CIH + PAG group, pretreatment with PAG significantly reduced blood pressure and improved the left ventricular ejection fraction (LVEF) and the left ventricular fractional shortening (LVFS) compared to the CIH group. Significantly lower levels of oxidative stress, apoptosis, and the ER stress were detected in the CIH + PAG group than in the CIH group.
These results suggest that PAG can protect the myocardium against CIH-induced injury through inhibition of endoplasmic reticulum stress.
KeywordsChronic intermittent hypoxia dl-Propargylglycine Myocardial injury Apoptosis Oxidative stress Endoplasmic reticulum stress
We appreciate the assistance of Dr. Jing Feng and Prof. Baoyuan Chen (Respiratory Department, Tianjin Medical University General Hospital, China) for their support with the intermittent hypoxia chamber and the gas control delivery system used in this study to establish the CIH rat model.
The National Natural Science Foundation of China provided financial support in the form of national natural science funding (Nos. 81070065 and 81370181). The sponsor had no role in the design or conduct of this research.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. This article does not contain any studies with human participants performed by any of the authors.
- 1.Marin JM, Agusti A, Villar I, Forner M, Nieto D, Carrizo SJ, Barbe F, Vicente E, Wei Y, Nieto FJ, Jelic S (2012) Association between treated and untreated obstructive sleep apnea and risk of hypertension. JAMA 307(20):2169–2176. https://doi.org/10.1001/jama.2012.3418 CrossRefPubMedPubMedCentralGoogle Scholar
- 5.Theodoropoulos K, Lykouras D, Karkoulias K, Damania D, Leou K, Lagiou O, Meelu OA, Rigopoulou A, Dangas GD, Hahalis G, Spiropoulos K, Starakis I (2017) Association between the severity of newly diagnosed obstructive sleep apnea and subclinical carotid atherosclerosis in patients without overt cardiovascular disease. European Rev Medical Pharmacological Sci 21(7):1568–1575Google Scholar
- 6.Yuan X, Zhu D, Guo XL, Deng Y, Shang J, Liu K, Liu HG (2015) Telmisartan attenuates myocardial apoptosis induced by chronic intermittent hypoxia in rats: modulation of nitric oxide metabolism and inflammatory mediators. Sleep Breath 19(2):703–709. https://doi.org/10.1007/s11325-014-1081-y CrossRefPubMedGoogle Scholar
- 7.Ding W, Zhang X, Huang H, Ding N, Zhang S, Hutchinson SZ, Zhang X (2014) Adiponectin protects rat myocardium against chronic intermittent hypoxia-induced injury via inhibition of endoplasmic reticulum stress. PLoS One 9(4):e94545. https://doi.org/10.1371/journal.pone.0094545 CrossRefPubMedPubMedCentralGoogle Scholar
- 11.Burguera EF, Meijide-Failde R, Blanco FJ (2016) Hydrogen sulfide and inflammatory joint diseases. Curr Drug TargetsGoogle Scholar
- 14.Sivarajah A, McDonald MC, Thiemermann C (2006) The production of hydrogen sulfide limits myocardial ischemia and reperfusion injury and contributes to the cardioprotective effects of preconditioning with endotoxin, but not ischemia in the rat. Shock (Augusta, Ga) 26(2):154–161. https://doi.org/10.1097/01.shk.0000225722.56681.64 CrossRefGoogle Scholar
- 15.Polhemus DJ, Calvert JW, Butler J, Lefer DJ (2014) The cardioprotective actions of hydrogen sulfide in acute myocardial infarction and heart failure. Scientifica (Cairo) 2014:768607. doi: https://doi.org/10.1155/2014/768607, 1, 8
- 16.Lambert JP, Nicholson CK, Amin H, Amin S, Calvert JW (2014) Hydrogen sulfide provides cardioprotection against myocardial/ischemia reperfusion injury in the diabetic state through the activation of the RISK pathway. Medical Gas Res 4(1):20. https://doi.org/10.1186/s13618-014-0020-0 CrossRefGoogle Scholar
- 17.Polhemus DJ, Kondo K, Bhushan S, Bir SC, Kevil CG, Murohara T, Lefer DJ, Calvert JW (2013) Hydrogen sulfide attenuates cardiac dysfunction after heart failure via induction of angiogenesis. Circulation Heart Failure 6(5):1077–1086. https://doi.org/10.1161/circheartfailure.113.000299 CrossRefPubMedGoogle Scholar
- 20.Sun Q, Collins R, Huang S, Holmberg-Schiavone L, Anand GS, Tan CH, van-den-Berg S, Deng LW, Moore PK, Karlberg T, Sivaraman J (2009) Structural basis for the inhibition mechanism of human cystathionine gamma-lyase, an enzyme responsible for the production of H(2)S. J Biol Chem 284(5):3076–3085. https://doi.org/10.1074/jbc.M805459200 CrossRefPubMedGoogle Scholar
- 21.Shirozu K, Tokuda K, Marutani E, Lefer D, Wang R, Ichinose F (2014) Cystathionine gamma-lyase deficiency protects mice from galactosamine/lipopolysaccharide-induced acute liver failure. Antioxid Redox Signal 20(2):204–216. https://doi.org/10.1089/ars.2013.5354 CrossRefPubMedPubMedCentralGoogle Scholar
- 23.Oosterhuis NR, Frenay AR, Wesseling S, Snijder PM, Slaats GG, Yazdani S, Fernandez BO, Feelisch M, Giles RH, Verhaar MC, Joles JA, van Goor H (2015) DL-propargylglycine reduces blood pressure and renal injury but increases kidney weight in angiotensin-II infused rats. Nitric Oxide : Biology Chemistry / Official J Nitric Oxide Soc 49:56–66. https://doi.org/10.1016/j.niox.2015.07.001 CrossRefGoogle Scholar
- 25.Xu J, Zhou Q, Xu W, Cai L (2012) Endoplasmic reticulum stress and diabetic cardiomyopathy. Exp Diabetes Res 2012:827971. doi: https://doi.org/10.1155/2012/827971, 1, 12
- 29.Chen L, Zhang J, Gan TX, Chen-Izu Y, Hasday JD, Karmazyn M, Balke CW, Scharf SM (2008) Left ventricular dysfunction and associated cellular injury in rats exposed to chronic intermittent hypoxia. J Applied Physiology (Bethesda, Md : 1985) 104(1):218–223. https://doi.org/10.1152/japplphysiol.00301.2007 CrossRefGoogle Scholar
- 30.Lu D, Liu J, Jiao J, Long B, Li Q, Tan W, Li P (2013) Transcription factor Foxo3a prevents apoptosis by regulating calcium through the apoptosis repressor with caspase recruitment domain. J Biol Chem 288(12):8491–8504. https://doi.org/10.1074/jbc.M112.442061 CrossRefPubMedPubMedCentralGoogle Scholar
- 31.Liu YF, Chu YY, Zhang XZ, Zhang M, Xie FG, Zhou M, Wen HH, Shu AH (2017) TGFbeta1 protects myocardium from apoptosis and oxidative damage after ischemia reperfusion. European Rev Medical Pharmacological Sci 21(7):1551–1558Google Scholar
- 36.Matsumoto C, Hayashi T, Kitada K, Yamashita C, Miyamura M, Mori T, Ukimura A, Ohkita M, Jin D, Takai S, Miyazaki M, Okada Y, Kitaura Y, Matsumura Y (2009) Chymase plays an important role in left ventricular remodeling induced by intermittent hypoxia in mice. Hypertension 54(1):164–171. https://doi.org/10.1161/hypertensionaha.109.131391 CrossRefPubMedGoogle Scholar
- 37.Inamoto S, Yoshioka T, Yamashita C, Miyamura M, Mori T, Ukimura A, Matsumoto C, Matsumura Y, Kitaura Y, Hayashi T (2010) Pitavastatin reduces oxidative stress and attenuates intermittent hypoxia-induced left ventricular remodeling in lean mice. Hypertension Res : Official J Japanese Soc Hypertension 33(6):579–586. https://doi.org/10.1038/hr.2010.36 CrossRefGoogle Scholar
- 42.Belaidi E, Thomas A, Bourdier G, Moulin S, Lemarie E, Levy P, Pepin JL, Korichneva I, Godin-Ribuot D, Arnaud C (2016) Endoplasmic reticulum stress as a novel inducer of hypoxia inducible factor-1 activity: its role in the susceptibility to myocardial ischemia-reperfusion induced by chronic intermittent hypoxia. Int J Cardiol 210:45–53. https://doi.org/10.1016/j.ijcard.2016.02.096 CrossRefPubMedGoogle Scholar
- 43.Bos EM, Wang R, Snijder PM, Boersema M, Damman J, Fu M, Moser J, Hillebrands JL, Ploeg RJ, Yang G, Leuvenink HG, van Goor H (2013) Cystathionine gamma-lyase protects against renal ischemia/reperfusion by modulating oxidative stress. J Am Soc Nephrology : JASN 24 (5):759–770. doi: https://doi.org/10.1681/asn.2012030268
- 44.Guo C, Liang F, Shah Masood W, Yan X (2014) Hydrogen sulfide protected gastric epithelial cell from ischemia/reperfusion injury by Keap1 s-sulfhydration, MAPK dependent anti-apoptosis and NF-kappaB dependent anti-inflammation pathway. Eur J Pharmacol 725:70–78. https://doi.org/10.1016/j.ejphar.2014.01.009 CrossRefPubMedGoogle Scholar
- 45.Jin S, Pu SX, Hou CL, Ma FF, Li N, Li XH, Tan B, Tao BB, Wang MJ, Zhu YC (2015) Cardiac H2S generation is reduced in ageing diabetic mice. Oxidative Med Cell Longev 2015:758358. doi: https://doi.org/10.1155/2015/758358, 1, 14
- 50.Jin HF, Du JB, Li XH, Wang YF, Liang YF, Tang CS (2006) Interaction between hydrogen sulfide/cystathionine gamma-lyase and carbon monoxide/heme oxygenase pathways in aortic smooth muscle cells. Acta Pharmacol Sin 27(12):1561–1566. https://doi.org/10.1111/j.1745-7254.2006.00425.x CrossRefPubMedGoogle Scholar