Resveratrol inhibits hypoxia-induced proliferation and migration of pulmonary artery vascular smooth muscle cells by inhibiting the phosphoinositide 3-kinase/protein kinase B signaling pathway

Guan,Zhanjiang; Shen,Li; Liang,Huan; Yu,Haitao; Hei,Bingchang; Meng,Xianguo; Yang,Lei

doi:10.3892/mmr.2017.6814

Resveratrol inhibits hypoxia-induced proliferation and migration of pulmonary artery vascular smooth muscle cells by inhibiting the phosphoinositide 3-kinase/protein kinase B signaling pathway

Authors:
- Zhanjiang Guan
- Li Shen
- Huan Liang
- Haitao Yu
- Bingchang Hei
- Xianguo Meng
- Lei Yang
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Affiliations: Intensive Care Unit, The Third Affiliated Hospital of Qiqihar Medical University, Qiqihar, Heilongjiang 161099, P.R. China, Emergency Department, The Third Affiliated Hospital of Qiqihar Medical University, Qiqihar, Heilongjiang 161099, P.R. China
Published online on: June 20, 2017 https://doi.org/10.3892/mmr.2017.6814
Pages: 1653-1660
Copyright: © Guan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Hypoxia is a risk factor for severe chronic obstructive pulmonary disease, which aggravates the disease and may cause mortality by inducing hypoxic pulmonary hypertension (HPH). Proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) may mediate this effect. Resveratrol is a phenolic compound extracted from a plant and has been reported to alleviate HPH, although the underlying mechanisms remained to be elucidated. In cancer, resveratrol has been reported to abrogate the phosphoinositide 3‑kinase/protein kinase B (AKT) signaling pathway, thereby inhibiting tumor development. Therefore, the present study aimed to investigate the role of resveratrol in preventing PASMCs from proliferating and migrating. Resveratrol was demonstrated to be inhibitory in a dose‑dependent manner on hypoxia‑induced cell proliferation and migration, and protein expression levels of phosphorylated AKT and AKT. Additionally, resveratrol was identified to act synergistically with LY‑294002, a phosphorylation inhibitor of AKT, but antagonistically with insulin‑like growth factor‑1, an agonist of AKT phosphorylation. This suggested that resveratrol may reduce proliferation and migration by diminishing expression and phosphorylation of AKT, thereby preventing development of HPH.

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1	Ogawa A, Yamadori I, Matsubara O and Matsubara H: Pulmonary tumor thrombotic microangiopathy with circulatory failure treated with imatinib. Intern Med. 52:1927–1930. 2013. View Article : Google Scholar : PubMed/NCBI
2	Afonso AS, Verhamme KM, Sturkenboom MC and Brusselle GG: COPD in the general population: Prevalence, incidence and survival. Respir Med. 105:1872–1884. 2011. View Article : Google Scholar : PubMed/NCBI
3	Csiszar A, Labinskyy N, Olson S, Pinto JT, Gupte S, Wu JM, Hu F, Ballabh P, Podlutsky A, Losonczy G, et al: Resveratrol prevents monocrotaline-induced pulmonary hypertension in rats. Hypertension. 54:668–675. 2009. View Article : Google Scholar : PubMed/NCBI
4	He X, Wang Y, Zhu J, Orloff M and Eng C: Resveratrol enhances the anti-tumor activity of the mTOR inhibitor rapamycin in multiple breast cancer cell lines mainly by suppressing rapamycin-induced AKT signaling. Cancer Lett. 301:168–176. 2011. View Article : Google Scholar : PubMed/NCBI
5	Ji Q, Liu X, Fu X, Zhang L, Sui H, Zhou L, Sun J, Cai J, Qin J, Ren J and Li Q: Resveratrol inhibits invasion and metastasis of colorectal cancer cells via MALAT1 mediated Wnt/β-catenin signal pathway. PLoS One. 8:e787002013. View Article : Google Scholar : PubMed/NCBI
6	Soto BL, Hank JA, Van de Voort TJ, Subramanian L, Polans AS, Rakhmilevich AL, Yang RK, Seo S, Kim K, Reisfeld RA, et al: The anti-tumor effect of resveratrol alone or in combination with immunotherapy in a neuroblastoma model. Cancer Immunology Immunotherapy. 60:731–738. 2011. View Article : Google Scholar : PubMed/NCBI
7	Brody H: Chronic obstructive pulmonary disease. Nature. 489:S12012. View Article : Google Scholar : PubMed/NCBI
8	Torpy JM, Goodman DM, Burke AE and Livingston EH: JAMA patient page. CHronic obstructive pulmonary disease. JAMA. 308:12812012. View Article : Google Scholar : PubMed/NCBI
9	Tuder RM and Petrache I: Pathogenesis of chronic obstructive pulmonary disease. J Clin Invest. 122:2749–2755. 2012. View Article : Google Scholar : PubMed/NCBI
10	Lahm T, Albrecht M, Fisher AJ, Selej M, Patel NG, Brown JA, Justice MJ, Brown MB, van Demark M, Trulock KM, et al: 17β-Estradiol attenuates hypoxic pulmonary hypertension via estrogen receptor-mediated effects. Am J Respir Crit Care Med. 185:965–980. 2012. View Article : Google Scholar : PubMed/NCBI
11	Lee SJ, Smith A, Guo L, Alastalo TP, Li M, Sawada H, Liu X, Chen ZH, Ifedigbo E, Jin Y, et al: Autophagic protein LC3B confers resistance against hypoxia-induced pulmonary hypertension. Am J Respir Crit Care Med. 183:649–658. 2011. View Article : Google Scholar : PubMed/NCBI
12	Testa JR and Bellacosa A: AKT plays a central role in tumorigenesis. Proc Natl Acad Sci USA. 98:10983–10985. 2001. View Article : Google Scholar : PubMed/NCBI
13	Sexton E, van Themsche C, LeBlanc K, Parent S, Lemoine P and Asselin E: Resveratrol interferes with AKT activity and triggers apoptosis in human uterine cancer cells. Mol Cancer. 5:452006. View Article : Google Scholar : PubMed/NCBI
14	Jiang H, Shang X, Wu H, Gautam SC, Al-Holou S, Li C, Kuo J, Zhang L and Chopp M: Resveratrol downregulates PI3K/Akt/mTOR signaling pathways in human U251 glioma cells. J Exp Ther Oncol. 8:25–33. 2009.PubMed/NCBI
15	Wu J, Yu Z and Su D: BMP4 protects rat pulmonary arterial smooth muscle cells from apoptosis by PI3K/AKT/Smad1/5/8 signaling. Int J Mol Sci. 15:13738–13754. 2014. View Article : Google Scholar : PubMed/NCBI
16	Yi B, Cui J, Ning JN, Wang GS, Qian GS and Lu KZ: Over-expression of PKGIα inhibits hypoxia-induced proliferation, Akt activation, and phenotype modulation of human PASMCs: The role of phenotype modulation of PASMCs in pulmonary vascular remodeling. Gene. 492:354–360. 2012. View Article : Google Scholar : PubMed/NCBI
17	Alexander MR and Owens GK: Epigenetic control of smooth muscle cell differentiation and phenotypic switching in vascular development and disease. Annu Rev Physiol. 74:13–40. 2012. View Article : Google Scholar : PubMed/NCBI
18	Deng L, Blanco FJ, Stevens H, Lu R, Caudrillier A, McBride M, McClure JD, Grant J, Thomas M, Frid M, et al: MicroRNA-143 activation regulates smooth muscle and endothelial cell crosstalk in pulmonary arterial hypertension. Circ Res. 117:870–883. 2015. View Article : Google Scholar : PubMed/NCBI
19	Lu A, Zuo C, He Y, Chen G, Piao L, Zhang J, Xiao B, Shen Y, Tang J, Kong D, et al: EP3 receptor deficiency attenuates pulmonary hypertension through suppression of Rho/TGF-β1 signaling. J Clin Invest. 125:1228–1242. 2015. View Article : Google Scholar : PubMed/NCBI
20	Wallerath T, Deckert G, Ternes T, Anderson H, Li H, Witte K and Förstermann U: Resveratrol, a polyphenolic phytoalexin present in red wine, enhances expression and activity of endothelial nitric oxide synthase. Circulation. 106:1652–1658. 2002. View Article : Google Scholar : PubMed/NCBI
21	Jimenez-Gomez Y, Mattison JA, Pearson KJ, Martin-Montalvo A, Palacios HH, Sossong AM, Ward TM, Younts CM, Lewis K, Allard JS, et al: Resveratrol improves adipose insulin signaling and reduces the inflammatory response in adipose tissue of rhesus monkeys on high-fat, high-sugar diet. Cell Metab. 18:533–545. 2013. View Article : Google Scholar : PubMed/NCBI
22	Andreadi C, Britton RG, Patel KR and Brown K: Resveratrol-sulfates provide an intracellular reservoir for generation of parent resveratrol, which induces autophagy in cancer cells. Autophagy. 10:524–525. 2014. View Article : Google Scholar : PubMed/NCBI
23	Mattison JA, Wang M, Bernier M, Zhang J, Park SS, Maudsley S, An SS, Santhanam L, Martin B, Faulkner S, et al: Resveratrol prevents high fat/sucrose diet-induced central arterial wall inflammation and stiffening in nonhuman primates. Cell Metab. 20:183–190. 2014. View Article : Google Scholar : PubMed/NCBI
24	Chicoine LG, Stewart JA Jr and Lucchesi PA: Is resveratrol the magic bullet for pulmonary hypertension? Hypertension. 54:473–474. 2009. View Article : Google Scholar : PubMed/NCBI
25	Yang DL, Zhang HG, Xu YL, Gao YH, Yang XJ, Hao XQ and Li XH: Resveratrol inhibits right ventricular hypertrophy induced by monocrotaline in rats. Clin Exp Pharmacol Physiol. 37:150–155. 2010. View Article : Google Scholar : PubMed/NCBI
26	Paffett ML, Lucas SN and Campen MJ: Resveratrol reverses monocrotaline-induced pulmonary vascular and cardiac dysfunction: A potential role for atrogin-1 in smooth muscle. Vascul Pharmacol. 56:64–73. 2012. View Article : Google Scholar : PubMed/NCBI
27	Huang Z, Wang L, Chen L, Zhang Y and Shi P: Induction of cell cycle arrest via the p21, p27-cyclin E, A/Cdk2 pathway in SMMC-7721 hepatoma cells by clioquinol. Acta Pharm. 65:463–471. 2015. View Article : Google Scholar : PubMed/NCBI
28	Yadav V, Sultana S, Yadav J and Saini N: Gatifloxacin induces S and G2-phase cell cycle arrest in pancreatic cancer cells via p21/p27/p53. PLoS One. 7:e477962012. View Article : Google Scholar : PubMed/NCBI
29	Shivakrupa R, Bernstein A, Watring N and Linnekin D: Phosphatidylinositol 3′-kinase is required for growth of mast cells expressing the kit catalytic domain mutant. Cancer Res. 63:4412–4419. 2003.PubMed/NCBI
30	Roche S, Koegl M and Courtneidge SA: The phosphatidylinositol 3-kinase alpha is required for DNA synthesis induced by some, but not all, growth factors. Proc Natl Acad Sci USA. 91:9185–9189. 1994. View Article : Google Scholar : PubMed/NCBI
31	Alessi DR, Andjelkovic M, Caudwell B, Cron P, Morrice N, Cohen P and Hemmings BA: Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J. 15:6541–6551. 1996.PubMed/NCBI
32	Rachid O and Alkhalaf M: Resveratrol Regulation of PI3K-AKT Signaling Pathway Genes in MDA-MB-231 Breast Cancer Cells. Cancer Genomics Proteomics. 3:383–388. 2006.
33	Chen B, Xue J, Meng X, Slutzky JL, Calvert AE and Chicoine LG: Resveratrol prevents hypoxia-induced arginase II expression and proliferation of human pulmonary artery smooth muscle cells via Akt-dependent signaling. Am J Physiol Lung Cell Mol Physiol. 307:L317–L325. 2014. View Article : Google Scholar : PubMed/NCBI
34	Goncharova EA, Ammit AJ, Irani C, Carroll RG, Eszterhas AJ, Panettieri RA and Krymskaya VP: PI3K is required for proliferation and migration of human pulmonary vascular smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 283:L354–L363. 2002. View Article : Google Scholar : PubMed/NCBI