Celastrol alleviates angiotensin II‑mediated vascular smooth muscle cell senescence via induction of autophagy

Xu,Xian‑Jie; Zhao,Wei‑Bo; Feng,Shi‑Bin; Sun,Cheng; Chen,Qiang; Ni,Bing; Hu,Hou‑Yuan

doi:10.3892/mmr.2017.7533

Celastrol alleviates angiotensin II‑mediated vascular smooth muscle cell senescence via induction of autophagy

Authors:
- Xian‑Jie Xu
- Wei‑Bo Zhao
- Shi‑Bin Feng
- Cheng Sun
- Qiang Chen
- Bing Ni
- Hou‑Yuan Hu
View Affiliations

Affiliations: Department of Cardiology, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China, Department of Pathophysiology and High Altitude Pathology, Third Military Medical University, Chongqing 400038, P.R. China
Published online on: September 20, 2017 https://doi.org/10.3892/mmr.2017.7533
Pages: 7657-7664

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

Reactive oxygen species (ROS) production has been implicated in the promotion of cellular senescence. Celastrol, a quinone methide triterpenoid isolated from the Celastraceae family, exerts antioxidant effects and enhances autophagy in various cell types. Since autophagy serves an important role in regulating ROS, it was hypothesized that the antioxidant effect of celastrol is via enhanced autophagy, thus inhibiting cell senescence. Therefore, the present study used a Senescence β‑Galactosidase Staining kit, western blot analysis and cell cycle analysis to investigate whether celastrol alleviates angiotensin (Ang) II‑induced cellular senescence by upregulating autophagy in vascular smooth muscle cells (VSMCs). The results demonstrated that celastrol reduced Ang II‑induced senescence of VSMCs. Ang II‑induced generation of ROS and the subsequent VSMC senescence were counteracted by pretreatment with celastrol, determined by a ROS assay kit. Celastrol significantly upregulated VSMC autophagy, which reduced intracellular ROS and the subsequent cellular senescence induced by Ang II. Furthermore, celastrol markedly suppressed activity of the mechanistic target of rapamycin signaling pathway in VSMCs. In conclusion, the present study demonstrated that celastrol counteracts VSMC senescence probably by reducing ROS production via activation of autophagy, which may hold promise for the prevention and treatment of aging‑associated cardiovascular disorders such as atherosclerosis.

View Figures

View References

1	Wang JC and Bennett M: Aging and atherosclerosis: Mechanisms, functional consequences, and potential therapeutics for cellular senescence. Circ Res. 111:245–259. 2012. View Article : Google Scholar : PubMed/NCBI
2	Childs BG, Durik M, Baker DJ and van Deursen JM: Cellular senescence in aging and age-related disease: From mechanisms to therapy. Nat Med. 21:1424–1435. 2015. View Article : Google Scholar : PubMed/NCBI
3	Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano EE, Linskens M, Rubelj I, Pereira-Smith O, et al: A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA. 92:9363–9367. 1995; View Article : Google Scholar : PubMed/NCBI
4	Kunieda T, Minamino T, Nishi J, Tateno K, Oyama T, Katsuno T, Miyauchi H, Orimo M, Okada S, Takamura M, et al: Angiotensin II induces premature senescence of vascular smooth muscle cells and accelerates the development of atherosclerosis via a p21-dependent pathway. Circulation. 114:953–960. 2006. View Article : Google Scholar : PubMed/NCBI
5	Wiley CD, Velarde MC, Lecot P, Liu S, Sarnoski EA, Freund A, Shirakawa K, Lim HW, Davis SS, Ramanathan A, et al: Mitochondrial dysfunction induces senescence with a distinct secretory phenotype. Cell Metab. 23:303–314. 2016. View Article : Google Scholar : PubMed/NCBI
6	Correia-Melo C, Hewitt G and Passos JF: Telomeres, oxidative stress and inflammatory factors: Partners in cellular senescence? Longev Healthspan. 3:12014. View Article : Google Scholar : PubMed/NCBI
7	Herbert KE, Mistry Y, Hastings R, Poolman T, Niklason L and Williams B: Angiotensin II-mediated oxidative DNA damage accelerates cellular senescence in cultured human vascular smooth muscle cells via telomere-dependent and independent pathways. Circ Res. 102:201–208. 2008. View Article : Google Scholar : PubMed/NCBI
8	Zhao L, Li AQ, Zhou TF, Zhang MQ and Qin XM: Exendin-4 alleviates angiotensin II-induced senescence in vascular smooth muscle cells by inhibiting Rac1 activation via a cAMP/PKA-dependent pathway. Am J Physiol Cell Physiol. 307:C1130–C1141. 2014. View Article : Google Scholar : PubMed/NCBI
9	Lee KY, Kim JR and Choi HC: Genistein-induced LKB1-AMPK activation inhibits senescence of VSMC through autophagy induction. Vascul Pharmacol. 81:75–82. 2016. View Article : Google Scholar : PubMed/NCBI
10	Bian M, Du X, Cui J, Wang P, Wang W, Zhu W, Zhang T and Chen Y: Celastrol protects mouse retinas from bright light-induced degeneration through inhibition of oxidative stress and inflammation. J Neuroinflammation. 13:502016. View Article : Google Scholar : PubMed/NCBI
11	Ma X, Xu L, Alberobello AT, Gavrilova O, Bagattin A, Skarulis M, Liu J, Finkel T and Mueller E: Celastrol protects against obesity and metabolic dysfunction through activation of a HSF1-PGC1α transcriptional axis. Cell Metab. 22:695–708. 2015. View Article : Google Scholar : PubMed/NCBI
12	Wang YL, Lam KK, Cheng PY and Lee YM: Celastrol prevents circulatory failure via induction of heme oxygenase-1 and heat shock protein 70 in endotoxemic rats. J Ethnopharmacol. 162:168–175. 2015. View Article : Google Scholar : PubMed/NCBI
13	Gu L, Bai W, Li S, Zhang Y, Han Y, Gu Y, Meng G, Xie L, Wang J, Xiao Y, et al: Celastrol prevents atherosclerosis via inhibiting LOX-1 and oxidative stress. PLoS One. 8:e654772013. View Article : Google Scholar : PubMed/NCBI
14	Der Sarkissian S, Cailhier JF, Borie M, Stevens LM, Gaboury L, Mansour S, Hamet P and Noiseux N: Celastrol protects ischaemic myocardium through a heat shock response with up-regulation of haeme oxygenase-1. Br J Pharmacol. 171:5265–5279. 2014. View Article : Google Scholar : PubMed/NCBI
15	Hu H, Straub A, Tian Z, Bassler N, Cheng J and Peter K: Celastrol, a triterpene extracted from Tripterygium wilfordii Hook F, inhibits platelet activation. J Cardiovasc Pharmacol. 54:240–245. 2009. View Article : Google Scholar : PubMed/NCBI
16	Lu C, Zhang X, Zhang D, Pei E, Xu J, Tang T, Ye M, Uzan G, Zhi K, Li M and Zuo K: Short time tripterine treatment enhances endothelial progenitor cell function via heat shock protein 32. J Cell Physiol. 230:1139–1147. 2015. View Article : Google Scholar : PubMed/NCBI
17	Li L, Tan J, Miao Y, Lei P and Zhang Q: ROS and Autophagy: Interactions and molecular regulatory mechanisms. Cell Mol Neurobiol. 35:615–621. 2015. View Article : Google Scholar : PubMed/NCBI
18	Tai S, Hu XQ, Peng DQ, Zhou SH and Zheng XL: The roles of autophagy in vascular smooth muscle cells. Int J Cardiol. 211:1–6. 2016. View Article : Google Scholar : PubMed/NCBI
19	Nussenzweig SC, Verma S and Finkel T: The role of autophagy in vascular biology. Circ Res. 116:480–488. 2015. View Article : Google Scholar : PubMed/NCBI
20	Grootaert MO, da Costa Martins PA, Bitsch N, Pintelon I, De Meyer GR, Martinet W and Schrijvers DM: Defective autophagy in vascular smooth muscle cells accelerates senescence and promotes neointima formation and atherogenesis. Autophagy. 11:2014–2032. 2015. View Article : Google Scholar : PubMed/NCBI
21	Feng S, Hu Y, Peng S, Han S, Tao H, Zhang Q, Xu X, Zhang J and Hu H: Nanoparticles responsive to the inflammatory microenvironment for targeted treatment of arterial restenosis. Biomaterials. 105:167–184. 2016. View Article : Google Scholar : PubMed/NCBI
22	Chen Q, Bei JJ, Liu C, Feng SB, Zhao WB, Zhou Z, Yu ZP, Du XJ and Hu HY: HMGB1 induces secretion of matrix vesicles by macrophages to enhance ectopic mineralization. PLoS One. 11:e01566862016. View Article : Google Scholar : PubMed/NCBI
23	Tsai IC, Pan ZC, Cheng HP, Liu CH, Lin BT and Jiang MJ: Reactive oxygen species derived from NADPH oxidase 1 and mitochondria mediate angiotensin II-induced smooth muscle cell senescence. J Mol Cell Cardiol. 98:18–27. 2016. View Article : Google Scholar : PubMed/NCBI
24	Davalli P, Mitic T, Caporali A, Lauriola A and D'Arca D: ROS, cell senescence, and novel molecular mechanisms in aging and age-related diseases. Oxid Med Cell Longev. 2016:35651272016. View Article : Google Scholar : PubMed/NCBI
25	Yin H and Pickering JG: Cellular senescence and vascular disease: Novel routes to better understanding and therapy. Can J Cardiol. 32:612–623. 2016. View Article : Google Scholar : PubMed/NCBI
26	Zhong Z, Sanchez-Lopez E and Karin M: Autophagy, inflammation, and immunity: A troika governing cancer and its treatment. Cell. 166:288–298. 2016. View Article : Google Scholar : PubMed/NCBI
27	Rubinsztein DC, Marino G and Kroemer G: Autophagy and aging. Cell. 146:682–695. 2011. View Article : Google Scholar : PubMed/NCBI
28	Shan H, Guo D, Li X, Zhao X, Li W and Bai X: From autophagy to senescence and apoptosis in Angiotensin II-treated vascular endothelial cells. APMIS. 122:985–992. 2014. View Article : Google Scholar : PubMed/NCBI
29	Mei Y, Thompson MD, Cohen RA and Tong X: Autophagy and oxidative stress in cardiovascular diseases. Biochim Biophys Acta. 1852:243–251. 2015. View Article : Google Scholar : PubMed/NCBI
30	Deng YN, Shi J, Liu J and Qu QM: Celastrol protects human neuroblastoma SH-SY5Y cells from rotenone-induced injury through induction of autophagy. Neurochem Int. 63:1–9. 2013. View Article : Google Scholar : PubMed/NCBI
31	Zhao J, Sun Y, Shi P, Dong JN, Zuo LG, Wang HG, Gong JF, Li Y, Gu LL, Li N, et al: Celastrol ameliorates experimental colitis in IL-10 deficient mice via the up-regulation of autophagy. Int Immunopharmacol. 26:221–228. 2015. View Article : Google Scholar : PubMed/NCBI
32	Yu X, Tao W, Jiang F, Li C, Lin J and Liu C: Celastrol attenuates hypertension-induced inflammation and oxidative stress in vascular smooth muscle cells via induction of heme oxygenase-1. Am J Hypertens. 23:895–903. 2010. View Article : Google Scholar : PubMed/NCBI
33	Shinojima N, Yokoyama T, Kondo Y and Kondo S: Roles of the Akt/mTOR/p70S6K and ERK1/2 signaling pathways in curcumin-induced autophagy. Autophagy. 3:635–637. 2007. View Article : Google Scholar : PubMed/NCBI
34	Lee HW, Jang KS, Choi HJ, Jo A, Cheong JH and Chun KH: Celastrol inhibits gastric cancer growth by induction of apoptosis and autophagy. BMB Rep. 47:697–702. 2014. View Article : Google Scholar : PubMed/NCBI
35	Klionsky DJ, Abdelmohsen K, Abe A, Abedin MJ, Abeliovich H, Arozena A Acevedo, Adachi H, Adams CM, Adams PD, Adeli K, et al: Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy. 12:1–222. 2016. View Article : Google Scholar : PubMed/NCBI
36	Moscat J and Diaz-Meco MT: p62 at the crossroads of autophagy, apoptosis, and cancer. Cell. 137:1001–1004. 2009. View Article : Google Scholar : PubMed/NCBI
37	Rodriguez-Arribas M, Yakhine-Diop SM, González-Polo RA, Niso-Santano M and Fuentes JM: Turnover of lipidated LC3 and autophagic cargoes in mammalian cells. Methods Enzymol. 587:55–70. 2017. View Article : Google Scholar : PubMed/NCBI
38	Wang S, Wang C, Yan F, Wang T, He Y, Li H, Xia Z and Zhang Z: N-acetylcysteine attenuates diabetic myocardial ischemia reperfusion injury through inhibiting excessive autophagy. Mediators Inflamm. 2017:92572912017. View Article : Google Scholar : PubMed/NCBI
39	Kim JH, Lee JO, Lee SK, Kim N, You GY, Moon JW, Sha J, Kim SJ, Park SH and Kim HS: Celastrol suppresses breast cancer MCF-7 cell viability via the AMP-activated protein kinase (AMPK)-induced p53-polo like kinase 2 (PLK-2) pathway. Cell Signal. 25:805–813. 2013. View Article : Google Scholar : PubMed/NCBI
40	Yu Y, Koehn CD, Yue Y, Li S, Thiele GM, Hearth-Holmes MP, Mikuls TR, O'Dell JR, Klassen LW, Zhang Z and Su K: Celastrol inhibits inflammatory stimuli-induced neutrophil extracellular trap formation. Curr Mol Med. 15:401–410. 2015. View Article : Google Scholar : PubMed/NCBI