Valsartan has the potential to attenuate neointimal hyperplasia and to suppress the inflammatory response. This study aimed to evaluate the role of valsartan in neointimal hyperplasia and the toll-like receptor 4 (TLR4)-nitric oxide synthase (NOS) pathway in the balloon-injured rat aorta.Forty-eight Wistar rats were randomly allocated to three groups: sham control (control), balloon-injured group (surgery), and balloon-injured+valsartan-treated group (valsartan). Rats were killed at 14 and 28 days after balloon-injury, and then the aortic tissues were collected for morphometric analysis as well as for measurements of the mRNA or protein expression of angiotensin II, angiotensin II type 1 (AT1) receptor, angiotensin II type 2 (AT2) receptor, TLR4, endothelial nitric oxide synthase (eNOS), inducible NOS (iNOS), serine/arginine-rich splicing factor 1(SRSF1) and extracellular signal regulated kinase (ERK). Valsartan at a dose of 20 mg/kg/day markedly decreased neointimal hyperplasia in the aorta of balloon-injured rats, and significantly reduced the mRNA or protein expression of TLR4, AT1 receptor, SRSF1 and phosphorylated-ERK (p-ERK) as well as the aortic levels of iNOS (all p < 0.05). Moreover, valsartan increased the eNOS level and AT2 receptor mRNA and protein expression levels (all p < 0.05). Valsartan prevented neointimal hyperplasia and inhibited SRSF1 expression and the TLR4-iNOS-ERK-AT1 receptor pathway in the balloon-injured rat aorta.

Department of Cardiology Affilicated Hospital of Qingdao University Qingdao China

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ALRAIES MC, DARMOCH F, TUMMALA R, WAKSMAN R. Diagnosis and management challenges of in-stent restenosis in coronary arteries. World J Cardiol. 2017;9:640–651. doi: 10.4330/wjc.v9.i8.640. PubMed DOI PMC

ARAÚJO PV, RIBEIRO MS, DALIO MB, ROCHA LA, VIARO F, DELLALIBERA JOVILIANO R, PICCINATO CE, ÉVORA PR, JOVILIANO EE. Interleukins and inflammatory markers in in-stent restenosis after femoral percutaneous transluminal angioplasty. Ann Vasc Surg. 2015;29:731–737. doi: 10.1016/j.avsg.2014.12.006. PubMed DOI

BUCCHERI D, PIRAINO D, ANDOLINA G, CORTESE B. Understanding and managing in-stent restenosis: a review of clinical data, from pathogenesis to treatment. J Thorac Dis. 2016;8:E1150–E62. doi: 10.21037/jtd.2016.10.93. PubMed DOI PMC

CHYU KY, DIMAYUGA P, ZHU J, NILSSON J, KAUL S, SHAH PK, CERCEK B. Decreased neointimal thickening after arterial wall injury in inducible nitric oxide synthase knockout mice. Circ Res. 1999;85:1192–1198. doi: 10.1161/01.RES.85.12.1192. PubMed DOI

DE BATISTA PR, PALACIOS R, MARTIN A, HERNANZ R, MEDICI CT, SILVA MA, ROSSI EM, AGUADO A, VASSALLO DV, SALAICES M, ALONSO MJ. Toll-like receptor 4 upregulation by angiotensin II contributes to hypertension and vascular dysfunction through reactive oxygen species production. PLoS One. 2014;9:e104020. doi: 10.1371/journal.pone.0104020. PubMed DOI PMC

DEN DEKKER WK, CHENG C, PASTERKAMP G, DUCKERS HJ. Toll like receptor 4 in atherosclerosis and plaque destabilization. Atherosclerosis. 2010;209:314–320. doi: 10.1016/j.atherosclerosis.2009.09.075. PubMed DOI

FORSTERMANN U, SESSA WC. Nitric oxide synthases: regulation and function. Eur Heart J. 2012;33:829–837. 37a–37d. doi: 10.1093/eurheartj/ehr304. PubMed DOI PMC

GRANGER DN, VOWINKEL T, PETNEHAZY T. Modulation of the inflammatory response in cardiovascular disease. Hypertension. 2004;43:924–931. doi: 10.1161/01.HYP.0000123070.31763.55. PubMed DOI

GOULOPOULOU S, MCCARTHY CG, WEBB RC. Toll-like Receptors in the Vascular System: Sensing the Dangers Within. Pharmacol Rev. 2016;68:142–167. doi: 10.1124/pr.114.010090. PubMed DOI PMC

GUIHUA L, WANG L, SANQING J, REN W, LIN Z, DAOKUO Y, RONGJING D. Influence of valsartan-eluting stent on neointima formation. J Cardiovasc Dis Res. 2010;1:19–22. doi: 10.4103/0975-3583.59980. PubMed DOI PMC

HADI NR, AL-AMRAN FG, HUSSIEN YA, AL-YASIRI IK, AL-TURFY M. The cardioprotective potential of valsartan in myocardial ischaemia reperfusion injury. Cent Eur J Immunol. 2015;40:159–166. doi: 10.5114/ceji.2015.52829. PubMed DOI PMC

HUANG QF, LI Y, WANG JG. Overview of clinical use and side effect profile of valsartan in Chinese hypertensive patients. Drug Des Devel Ther. 2014;8:79–86. doi: 10.2147/DDDT.S38617. PubMed DOI PMC

IWASHITA M, SAKODA H, KUSHIYAMA A, FUJISHIRO M, OHNO H, NAKATSU Y, FUKUSHIMA T, KUMAMOTO S, TSUCHIYA Y, KIKUCHI T, KURIHARA H, AKAZAWA H, KOMURO I, KAMATA H, NISHIMURA F, ASANO T. Valsartan, independently of AT1 receptor or PPARgamma, suppresses LPS-induced macrophage activation and improves insulin resistance in cocultured adipocytes. Am J Physiol Endocrinol Metab. 2012;302:E286–296. doi: 10.1152/ajpendo.00324.2011. PubMed DOI

HEO SK, YUN HJ, NOH EK, PARK WH, PARK SD. LPS induces inflammatory responses in human aortic vascular smooth muscle cells via Toll-like receptor 4 expression and nitric oxide production. Immunol Lett. 2008;120:57–64. doi: 10.1016/j.imlet.2008.07.002. PubMed DOI

HERNANZ R, MARTINEZ-REVELLES S, PALACIOS R, MARTIN A, CACHOFEIRO V, AGUADO A, GARCÍA-REDONDO L, BARRÚS MT, DE BATISTA PR, BRIONES AM, SALAICES M, ALONSO MJ. Toll-like receptor 4 contributes to vascular remodelling and endothelial dysfunction in angiotensin II-induced hypertension. Br J Pharmacol. 2015;172:3159–3176. doi: 10.1111/bph.13117. PubMed DOI PMC

HU Z, WANG H, FAN G, ZHANG H, WANG X, MAO J, ZHAO Y, AN Y, HUANG Y, LI C, CHANG L, CHU X, LI LI, LI Y, ZHANG Y, QIN G, GAO X, ZHANG B. Danhong injection mobilizes endothelial progenitor cells to repair vascular endothelium injury via upregulating the expression of Akt, eNOS and MMP-9. Phytomedicine. 2019;61:152850. doi: 10.1016/j.phymed.2019.152850. PubMed DOI

JANSSENS S, FLAHERTY D, NONG Z, VARENNE O, VAN PELT N, HAUSTERMANS C, ZOLDHELYI P, GERARD R, COLLEN D. Human endothelial nitric oxide synthase gene transfer inhibits vascular smooth muscle cell proliferation and neointima formation after balloon injury in rats. Circulation. 1998;97:1274–1281. doi: 10.1161/01.CIR.97.13.1274. PubMed DOI

JI Y, LIU J, WANG Z, LIU N. Angiotensin II induces inflammatory response partly via toll-like receptor 4-dependent signaling pathway in vascular smooth muscle cells. Cell Physiol Biochem. 2009;23:265–276. doi: 10.1159/000218173. PubMed DOI

JOVILIANO EE, PICCINATO CE, DELLALIBERA-JOVILIANO R, MORIYA T, EVORA PR. Inflammatory markers and restenosis in peripheral percutaneous angioplasty with intravascular stenting: current concepts. Ann Vasc Surg. 2011;25:846–855. doi: 10.1016/j.avsg.2011.02.026. PubMed DOI

KIBBE M, BILLIAR T, TZENG E. Inducible nitric oxide synthase and vascular injury. Cardiovasc Res. 1999;43:650–657. doi: 10.1016/S0008-6363(99)00130-3. PubMed DOI

KINTSCHER U, MARX N, MARTUS P, STOPPELHAAR M, SCHIMKUS J, SCHNEIDER A, WALCHER D, KÜMMEL A, WINKLER R, KAPPERT K, DÖRFFEL Y, SCHOLZE J, UNGER T. Effect of high-dose valsartan on inflammatory and lipid parameters in patients with Type 2 diabetes and hypertension. Diabetes Res Clin Pract. 2010;89:209–215. doi: 10.1016/j.diabres.2010.04.018. PubMed DOI

LEE GL, WU JY, TSAI CS, LIN CY, TSAI YT, LIN CS, WANG YF, YET SF, HSU YJ, KUO CC. TLR4-Activated MAPK-IL-6 Axis Regulates Vascular Smooth Muscle Cell Function. Int J Mol Sci. 2016;17:E1394. doi: 10.3390/ijms17091394. PubMed DOI PMC

LIANG S, AIQUN M, JIWU L, PING Z. TLR3 and TLR4 as potential clinical biomarkers for in-stent restenosis in drug-eluting stents patients. Immunol Res. 2016;64:424–430. doi: 10.1007/s12026-015-8685-6. PubMed DOI

LI K, DING WH, SHI LB, ZHANG LF, HAN XN, TANG CS. Role of vascular remodeling for urotensin II in rat thoracic aorta after balloon injury. Chin J Pathophys. 2008;4:674–679.

LI Y, CAI S, WANG Q, ZHOU J, HOU B, YU H, GE Z, GUAN R, LIU X. Valsartan attenuates intimal hyperplasia in balloon-injured rat aortic arteries through modulating the angiotensin-converting enzyme 2-angiotensin-(1–7)-Mas receptor axis. Arch Biochem Biophys. 2016;598:11–17. doi: 10.1016/j.abb.2016.03.028. PubMed DOI

LI YH, AN Y, WANG QX, MAN YL, LIU P, REN BB. Effects of valsartan on aortic angiotensin converting enzyme 2 expression after aortic balloon injury in rats. Zhonghua Xin Xue Guan Bing Za Zhi. 2012;40:697–701. PubMed

LI Y, WANG Q, XU Q, CAI S, ZHOU J, REN B, SUN T, LIU X, YU H. Valsartan decreases neointimal hyperplasia in balloon-injured rat aortic arteries by upregulating HO-1 and inhibiting angiotensin II type 1 receptor. Life Sci. 2014;110:70–76. doi: 10.1016/j.lfs.2014.06.021. PubMed DOI

LLORIAN M, GOODING C1, BELLORA N, HALLEGGER M, BUCKROYD A, WANG X, RAJGOR D, KAYIKCI M, FELTHAM J, ULE J, EYRAS E, SMITH CWJ :The alternative splicing program of differentiated smooth muscle cells involves concerted non-productive splicing of post-transcriptional regulators. Nucleic Acids Res. 2016;44:8933–8950. doi: 10.1093/nar/gkw560. PubMed DOI PMC

SAROV-BLAT L, MORGAN JM, FERNANDEZ P, JAMES R, FANG Z, HURLE MR, BAIDOO C, WILLETTE RN, LEPORE JJ, JENSEN SE, SPRECHER DL. Inhibition of p38 mitogen-activated protein kinase reduces inflammation after coronary vascular injury in humans. Arterioscler Thromb Vasc Biol. 2010;30:2256–2263. doi: 10.1161/ATVBAHA.110.209205. PubMed DOI

SHOKRI M, BAGHERI B, GARJANI A, SOHRABI B, HABIBZADEH A, KAZEMI B, MOVASSAGHPOUR AA. Everolimus-eluting stents reduce monocyte expression of toll-like receptor 4. Adv Pharm Bull. 2015;5(Suppl 1):643–647. doi: 10.15171/apb.2015.087. PubMed DOI PMC

SONG Y, HOU M, LI Z, LUO C, OU JS, YU H, YAN J, LU L. TLR4/NF-kappaB/Ceramide signaling contributes to Ox-LDL-induced calcification of human vascular smooth muscle cells. Eur J Pharmacol. 2017;794:45–51. doi: 10.1016/j.ejphar.2016.11.029. PubMed DOI

PARAMASIVAM G, DEVASIA T, JAYARAM A, UK AR, RAO MS, VIJAYVERGIYA R, NAYAK K. In-stent restenosis of drug-eluting stents in patients with diabetes mellitus: Clinical presentation, angiographic features, and outcomes. Anatol J Cardiol. 2020;23:28–34. doi: 10.14744/AnatolJCardiol.2019.72916. PubMed DOI PMC

PETERS S. Comparison of efficacy of low-(80 mg/day) and high-(160–320 mg/day) dose valsartan in the prevention of in-stent restenosis after implantation of bare-metal stents in type B2/C coronary artery lesions. Am J Cardiovasc Drugs. 2008;8(2):83–87. doi: 10.1007/BF03256585. PubMed DOI

VALLEJO JG. Role of toll-like receptors in cardiovascular diseases. Clin Sci (Lond) 2011;121:1–10. doi: 10.1042/CS20100539. PubMed DOI

XIE N, CHEN M, DAI R, ZHANG Y, ZHAO H, SONG Z, ZHANG L, LI Z, FENG Y, GAO H, WANG L, ZHANG T, XIAO RP, WU J, CAO CM. SRSF1 promotes vascular smooth muscle cell proliferation through a Δ133p53/EGR1/KLF5 pathway. Nat Commun. 2017;8:16016. doi: 10.1038/ncomms16016. PubMed DOI PMC

YANG J, JIANG H, YANG J, DING JW, CHEN LH, LI S, ZHANG XD. Valsartan preconditioning protects against myocardial ischemia-reperfusion injury through TLR4/NF-kappaB signaling pathway. Mol Cell Biochem. 2009;330:39–46. doi: 10.1007/s11010-009-0098-1. PubMed DOI

YONEDA S, ABE S, KANAYA T, ODA K, NISHINO S, KAGEYAMA M, TAGUCHI I, MASAWA N, INOUE T. Late-phase inflammatory response as a feature of in-stent restenosis after drug-eluting stent implantation. Coron Artery Dis. 2013;24:368–373. doi: 10.1097/MCA.0b013e32836222ec. PubMed DOI

YUAN L, DUAN X, DONG J, LU Q, ZHOU J, ZHAO Z, BAO J, JING Z. p21-Activated kinase 4 promotes intimal hyperplasia and vascular smooth muscle cells proliferation during superficial femoral artery restenosis after angioplasty. Biomed Res Int. 2017;2017:5296516. doi: 10.1155/2017/5296516. PubMed DOI PMC

YU S, CHEN Y, CHEN S, YE N, LI Y, SUN Y. klotho inhibits proliferation and migration of angiotensin ii-induced vascular smooth muscle cells (VSMCs) by modulating NF-kappaB p65, akt, and extracellular signal regulated kinase (ERK) signaling activities. Med Sci Monit. 2018;24:4851–4860. doi: 10.12659/MSM.908038. PubMed DOI PMC

ZAQOUT S, BECKER LL, KAINDL AM. Immunofluorescence staining of paraffin sections step by step. Front Neuroanat. 2020;14:582218. doi: 10.3389/fnana.2020.582218. PubMed DOI PMC

ZOU G, ZHU J, LIU Z, WU L, XU R, CHEN H, DENG P, DENG C. Detoxification and activating blood circulation decoction reduces restenosis involving the TLR4/NF-κB pathway after balloon injury. Prostaglandins Other Lipid Mediat. 2019;140:1–8. doi: 10.1016/j.prostaglandins.2018.11.002. PubMed DOI