Mechanism of H2S‑mediated ROCK inhibition of total flavones of Rhododendra against myocardial ischemia injury

Jiao,Yi; Li,Ya‑Nan; Chen,Zhi‑Wu; Guo,Yan

doi:10.3892/etm.2019.8004

Mechanism of H2S‑mediated ROCK inhibition of total flavones of Rhododendra against myocardial ischemia injury

Authors:
- Yi Jiao
- Ya‑Nan Li
- Zhi‑Wu Chen
- Yan Guo
View Affiliations

Affiliations: Department of Human Anatomy, Anhui Medical University, Hefei, Anhui 230032, P.R. China, Department of Pharmacology, Anhui Medical University, Hefei, Anhui 230032, P.R. China
Published online on: September 13, 2019 https://doi.org/10.3892/etm.2019.8004
Pages: 3783-3792
Copyright: © Jiao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Our previous studies have indicated that pretreatment with total flavones of Rhododendra flower (TFR) may protect against myocardial ischemic injuries in rats and mice. The cystathionine γ‑lyase/hydrogen sulfide (CSE/H2S) pathway have been associated with several cardiovascular diseases, but the effect of TFR on the Rho‑associated protein kinase (ROCK) and CSE/H2S signaling pathways remains unknown. In the present study, the protective effects of TFR as a ROCK inhibitor in a mice model of myocardial infarction induced by isoproterenol (ISO) were investigated, and the hearts from the wild type and CSE knockout (KO) mice were examined. It was identified that the CSE KO mice exhibited decreased levels of ST segment elevation following anoxia/reoxygenation damage, increased LDH and CK‑MB levels, aggravated pathological damage, and increased ROCK1, ROCK2 and MLC1 protein levels. In the CSE KO mice, there were no marked changes of the above experimental results between the TFR group and the model group. These results suggested that TFR‑based inhibition of the RhoA/ROCK signal pathway may be mediated by the CSE‑H2S signalling pathway and may be a novel therapeutic target for myocardial ischemia injury.

View Figures

View References

1	Zhao K, Li H, Li S and Yang G: Regulation of cystathionine gamma-lyase/H₂S system and its pathological implication. Front Biosci (Landmark Ed). 19:1355–1369. 2014. View Article : Google Scholar : PubMed/NCBI
2	Chang L, Geng B, Yu F, Zhao J, Jiang H, Du J and Tang C: Hydrogen sulfide inhibits myocardial injury induced by homocysteine in rats. Amino Acids. 34:573–585. 2008. View Article : Google Scholar : PubMed/NCBI
3	Sivarajah A, Collino M, Yasin M, Benetti E, Gallicchio M, Mazzon E, Cuzzocrea S, Fantozzi R and Thiemermann C: Anti-apoptotic and anti-inflammatory effects of hydrogen sulfide in a mice model of regional myocardial I/R. Shock. 31:267–274. 2009. View Article : Google Scholar : PubMed/NCBI
4	Yang G, Li H, Tang G, Wu L, Zhao K, Cao Q, Xu C and Wang R: Increased neointimal formation in cystathionine gamma-lyase deficient mice: Role of hydrogen sulfide in α5β1-integrin and matrix metalloproteinase-2 expression in smooth muscle cells. J Mol Cell Cardiol. 52:677–688. 2012. View Article : Google Scholar : PubMed/NCBI
5	Mani S, Li H, Untereiner A, Wu L, Yang G, Austin RC, Dickhout JG, Lhoták Š, Meng QH and Wang R: Decreased endogenous production of hydrogen sulfide accelerates atherosclerosis. Circulation. 127:2523–2534. 2013. View Article : Google Scholar : PubMed/NCBI
6	Wang R: Two's company, three's a crowd: can H2S be the third endogenous gaseous transmitter? FASEB J. 16:1792–1798. 2002. View Article : Google Scholar : PubMed/NCBI
7	Wang R: The gasotransmitter role of hydrogen sulfide. Antioxid Redox Signal. 5:493–501. 2003. View Article : Google Scholar : PubMed/NCBI
8	Yang G, Wu L, Jiang B, Yang W, Qi J, Cao K, Meng Q, Mustafa AK, Mu W, Zhang S, et al: H2S as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine gamma-lyase. Science. 322:587–590. 2008. View Article : Google Scholar : PubMed/NCBI
9	Li H, Mani S, Cao W, Yang G, Lai C, Wu L and Wang R: Interaction of hydrogen sulfide and estrogen on the proliferation of vascular smooth muscle cells. PLoS One. 7:e416142012. View Article : Google Scholar : PubMed/NCBI
10	Loirand G, Guérin P and Pacaud P: Rho kinases in cardiovascular physiology and pathophysiology. Circ Res. 98:322–334. 2006. View Article : Google Scholar : PubMed/NCBI
11	Dong M, Yan BP, Liao JK, Lam YY, Yip GW and Yu CM: Rho-kinase inhibition: A novel therapeutic target for the treatment of cardiovascular diseases. Drug Discov Today. 15:622–629. 2010. View Article : Google Scholar : PubMed/NCBI
12	Satoh K, Fukumoto Y and Shimokawa H: Rho-kinase: Important new therapeutic target in cardiovascular diseases. Am J Physiol Heart Circ Physiol. 301:H287–H296. 2011. View Article : Google Scholar : PubMed/NCBI
13	Shimokawa H and Satoh K: 2015 ATVB plenary lecture translational research on rho-kinase in cardiovascular medicine. Arterioscler Thromb Vasc Boil. 35:1756–1769. 2015. View Article : Google Scholar
14	Zhang J, Li XX, Bian HJ, Liu XB, Ji XP and Zhang Y: Inhibition of the activity of Rho kinase reduces cardiomyocyte apoptosis in heart ischemia/reperfusion via suppressing JNK-mediated AIF translocation. Clin Chim Acta. 401:76–80. 2009. View Article : Google Scholar : PubMed/NCBI
15	Li Y, Zhu W, Tao J, Xin P, Liu M, Li J and Wei M: Fasudil protects the heart against ischemia-reperfusion injury by attenuating endoplasmic reticulum stress and modulating SERCA activity: The differential role for PI3K/Akt and JAK2/STAT3 signaling pathways. PLoS One. 7:e481152012. View Article : Google Scholar : PubMed/NCBI
16	Dai SJ, Chen RY and Yu DQ: Studies on the flavonoid compounds of Rhododendron anthopogonoides. Zhongguo Zhong Yao Za Zhi. 29:44–47. 2004.(In Chinese). PubMed/NCBI
17	Huang Y, Yin P, Jiang DF, Wang CY, Tan R, Wan L, Zhang Y and Fan G: Quality standard of rhododendron flos. World Sci Technol. 16:151–155. 2014.
18	Yuan LP, Chen ZW, Li F, Dong LY and Chen FH: Protective effect of total flavones of Rhododendra on ischemic myocardial injury in rabbits. Am J Chin Med. 34:483–492. 2006.(In Chinese). View Article : Google Scholar : PubMed/NCBI
19	Zhang JH, Chen ZW and Wu Z: Late protective effect of pharmacological preconditioning with total flavones of Rhododendra against myocardial ischemia-reperfusion injury. Can J Physiol Pharmacol. 86:131–138. 2008. View Article : Google Scholar : PubMed/NCBI
20	Jiao Y, Fan YF, Wang YL, Zhang JY, Chen S and Chen ZW: Protective effect and mechanism of total flavones from rhododendron simsii Planch flower on cultured Rat cardiomyocytes with anoxia and reoxygenation. Evid Based Complement Alternat Med. 2015:8635312015. View Article : Google Scholar : PubMed/NCBI
21	Hausenloy DJ, Tsang A and Yellon DM: The reperfusion injury salvage kinase pathway: A common target for both ischemic preconditioning and postconditioning. Trends Cardiovasc Med. 15:69–75. 2005. View Article : Google Scholar : PubMed/NCBI
22	Terrell AM, Crisostomo PR, Wairiuko GM, Wang M, Morrell ED and Meldrum DR: Jak/STAT/SOCS signaling circuits and associated cytokine-mediated inflammation and hypertrophy in the heart. Shock. 26:226–234. 2006. View Article : Google Scholar : PubMed/NCBI
23	Demirynrek S, Kara AF, Celik A, Babül A, Tarakçioglu M and Demiryürek AT: Effects of fasudil. A Rho-kinase inhibitor.on myocardial preconditioning in anesthetized mice. Eur J Pharmacol. 527:129–140. 2005. View Article : Google Scholar : PubMed/NCBI
24	Janet C, Garber R, Wayne B, Joseph T, Bielitzki, Leigh AC, John C, Donovan, et al: Guide for the Care and Use of Laboratory Animals of the National Institutes of HealthNIH Publication; 85-23. revised. 2011
25	Rona G, Chappel CI, Balazs T and Gaudry R: An infarct-like myocardial lesion and other toxic manifestations produced by isoproterenol in the rat. AMA Arch Pathol. 67:443–455. 1959.PubMed/NCBI
26	Xu X, Li H, Gong Y, Zheng H and Zhao D: Hydrogen sulfide ameliorated lipopolysaccharide-induced acute lung injury by inhibiting autophagy through PI3K/Akt/mTOR pathway in mice. Biochem Biophys Res Commun. 507:514–518. 2018. View Article : Google Scholar : PubMed/NCBI
27	Chau VQ, Salloum FN, Hoke NN, Abbate A and Kukreja RC: Mitigation of the progression of heart failure with sildenafil involves inhibition of RhoA/Rho-kinase pathway. Am J Physiol Heart Circ Physiol. 300:H2272–H2279. 2011. View Article : Google Scholar : PubMed/NCBI
28	Yatani A, Irie K, Otani T, Abdellatif M and Wei L: RhoA GTPase regulates L-type Ca2+ currents in cardiac myocytes. Am J Physiol Heart Circ Physiol. 288:H650–H659. 2005. View Article : Google Scholar : PubMed/NCBI
29	Shimokawa H, Hiramori K, Iinuma H, Hosoda S, Kishida H, Osada H, Katagiri T, Yamauchi K, Yui Y, Minamino T, et al: Anti-anginal effect of fasudil, a Rho-kinase inhibitor, in patients with stable effort angina: A multicenter study. J Cardiovasc Pharmacol. 40:751–761. 2002. View Article : Google Scholar : PubMed/NCBI
30	Saito Y, Kondo H and Hojo Y: Granzyme B as a novel factor involved in cardiovascular diseases. J Cardiol. 57:141–147. 2011. View Article : Google Scholar : PubMed/NCBI
31	Hamid SA, Bower HS and Baxter GF: Rho kinase activation plays a major role as a mediator of irreversible injury in reperfused myocardium. Am J Physiol Heart Circ Physiol. 292:2598–2606. 2007. View Article : Google Scholar
32	Hu Y, Chen X, Pan TT, Neo KL, Lee SW, Khin ES, Moore PK and Bian JS: Cardioprotection induced by hydrogen sulfide preconditioning involves activation of ERK and PI3K/Akt pathways. Pflugers Arch. 455:607–616. 2008. View Article : Google Scholar : PubMed/NCBI
33	Uehata M, Ishizaki T, Satoh H, Ono T, Kawahara T, Morishita T, Tamakawa H, Yamagami K, Inui J, Maekawa M and Narumiya S: Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension. Nature. 389:990–994. 1997. View Article : Google Scholar : PubMed/NCBI
34	Abe K, Shimokawa H, Morikawa K, Uwatoku T, Oi K, Matsumoto Y, Hattori T, Nakashima Y, Kaibuchi K, Sueishi K and Takeshit A: Long-term treatment with a Rho-kinase inhibitor improves monocrotaline-induced fatal pulmonary hypertension in rats. Circ Res. 94:385–393. 2004. View Article : Google Scholar : PubMed/NCBI
35	Chen ZW, Ma CG, Fang M and Xu SY: The blocking effect of hyperin on the inward flow of calcium ion. Yao Xue Xue Bao. 29:15–19. 1994.(In Chinese). PubMed/NCBI
36	Kimura H: Hydrogen sulfide as a neuromodulator. Mol Neurobiol. 26:13–19. 2002. View Article : Google Scholar : PubMed/NCBI
37	Geng B, Yang J, Qi Y, Zhao J, Pang Y, Du J and Tang C: H2S generated by heart in rat and its effects on cardiac function. Biochem Biophys Res Commun. 313:362–368. 2004. View Article : Google Scholar : PubMed/NCBI
38	Zhu YZ, Wang ZJ, Ho P, Loke YY, Zhu YC, Huang SH, Tan CS, Whiteman M, Lu J and Moore PK: Hydrogen sulfide and its possible roles in myocardial ischemia in experimental rats. J Appl Physiol (1985). 102:261–268. 2007. View Article : Google Scholar : PubMed/NCBI
39	Jin HF, Wang Y, Wang XB, Sun Y, Tang CS and Du JB: Sulfur dioxide preconditioning increases antioxidative capacity in rat with myocardial ischemia reperfusion (I/R) injury. Nitric Oxide. 32:56–61. 2013. View Article : Google Scholar : PubMed/NCBI
40	Tsai CY, Wang CC, Lai TY, Tsu HN, Wang CH, Liang HY and Kuo WW: Antioxidant effects of diallyl trisulfide on high glucose-induced apoptosis are mediated by the PI3K/Akt-dependent activation of Nrf2 in cardiomyocytes. Int J Cardiol. 168:1286–1297. 2013. View Article : Google Scholar : PubMed/NCBI