Highlights
- •Carvacrol inhibited PDGF-BB-stimulated RASMC migration and proliferation.
- •Carvacrol attenuated PDGF-BB-induced NOX1 expression and phosphorylation of p38 MAPK and ERK1/2 in RASMCs.
- •PDGF-BB-stimulated ROS generation was suppressed by carvacrol in RASMCs.
- •Treatment with carvacrol inhibited PDGF-BB-induced vascular sprout outgrowth.
- •Balloon injury-evoked neointima formation was reduced by carvacrol administration.
Abstract
Objective
Carvacrol (2-methyl-5-(1-methylethyl) phenol), a cyclic monoterpene, exerts protective
activities in a variety of pathological states including tumor growth, inflammation,
and oxidative stress. However, it is unknown whether carvacrol affects events in vascular
cells during the development of atherosclerotic neointima. We investigated the effects
of carvacrol on the migration and proliferation of rat aortic smooth muscle cells
(RASMCs) and on vascular neointima formation.
Methods and results
Carvacrol significantly inhibited platelet-derived growth factor (PDGF)-BB-stimulated
RASMC migration and proliferation in a concentration-dependent manner. Cell viability
was not affected by treatment with carvacrol. Carvacrol attenuated the expression
of NADPH oxidase (NOX) 1 and the phosphorylation of p38 mitogen-activated protein
kinase (MAPK) and extracellular signal-regulated kinase 1/2 in response to PDGF-BB.
Moreover, carvacrol suppressed the PDGF-BB-stimulated generation of H2O2 and inhibited the activity of NOX in RASMCs. Treatment with carvacrol inhibited PDGF-BB-induced
aortic sprout outgrowth, balloon injury-evoked vascular neointima formation, and expression
of proliferating cell nuclear antigen in the neointima.
Conclusion
These findings indicate that carvacrol inhibits migration and proliferation of RASMCs
by suppressing the reactive oxygen species-mediated MAPK signaling pathway in these
cells, thereby attenuating vascular neointimal formation. Carvacrol may be a promising
agent for preventing vascular restenosis or atherosclerosis.
Keywords
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References
- The pathogenesis of atherosclerosis: a perspective for the 1990s.Nature. 1993; 362: 801-809
- Syk contributes to PDGF-BB-mediated migration of rat aortic smooth muscle cells via MAPK pathways.Cardiovasc Res. 2007; 74: 159-168
- Protein tyrosine phosphatase SHP-2 is positively involved in platelet-derived growth factor-signaling in vascular neointima formation via the reactive oxygen species-related pathway.J. Pharmacol. Sci. 2011; 115: 164-175
- Molecular mechanisms in intimal hyperplasia.J. Pathol. 2000; 190: 300-309
- Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions.Endocr. Rev. 2001; 22: 153-183
- Mechanisms of platelet-derived growth factor-induced chemotaxis.Int. J. Cancer. 2001; 91: 757-762
- Mechanical stress-initiated signal transductions in vascular smooth muscle cells.Cell. Signal. 2000; 12: 435-445
- Clinically used estrogens differentially inhibit human aortic smooth muscle cell growth and mitogen-activated protein kinase activity.Arterioscler. Thromb. Vasc. Biol. 2000; 20: 964-972
- Spleen tyrosine kinase participates in Src-mediated migration and proliferation by PDGF-BB in rat aortic smooth muscle cells.Arch. Pharm. Res. 2007; 30: 761-769
- Reactive oxygen species signaling in vascular smooth muscle cells.Cardiovasc Res. 2006; 71: 216-225
- Platelet derived growth factor-induced reactive oxygen species in the lens epithelial cells: the redox signaling.Exp. Eye Res. 2004; 78: 1057-1067
- Gene transfer of redox factor-1 inhibits neointimal formation: involvement of platelet-derived growth factor-beta receptor signaling via the inhibition of the reactive oxygen species-mediated Syk pathway.Circ. Res. 2009; 104: 219-227
- Redox signaling in cardiovascular health and disease.Free Radic. Biol. Med. 2013; 61C: 473-501
- Reactive oxygen species as mediators of signal transduction in cardiovascular disease.Trends Cardiovasc Med. 1998; 8: 59-64
- Reactive oxygen species in the vasculature: molecular and cellular mechanisms.Hypertension. 2003; 42: 1075-1081
- Src and Cas mediate JNK activation but not ERK1/2 and p38 kinases by reactive oxygen species.J. Biol. Chem. 2000; 75: 11706-11712
- DJ-1/park7 protects against neointimal formation via the inhibition of vascular smooth muscle cell growth.Cardiovasc Res. 2013; 97: 553-561
- Carvacrol rich plants in Turkey.Chem. Nat. Comp. 1995; 31: 37-42
- Effect of carvacrol on hepatic marker enzymes and antioxidant status in D-galactosamine-induced hepatotoxicity in rats.Fundam. Clin. Pharmacol. 2009; 23: 757-765
- Anti-ulcer activity of essential oil constituents.Molecules. 2014; 19: 5717-5747
- In vitro antioxidant, antimicrobial, and antiviral activities of the essential oil and various extracts from herbal parts and callus cultures of Origanum acutidens.J. Agric. Food Chem. 2004; 52: 3309-3312
- Biological and pharmacological activities of carvacrol and carvacrol bearing essential oils.Curr. Pharm. Des. 2008; 14: 3106-3119
- Carvacrol attenuates mechanical hypernociception and inflammatory response.Naunyn Schmiedeb. Arch. Pharmacol. 2012; 385: 253-263
- Anti-proliferative and pro-apoptotic effect of carvacrol on human hepatocellular carcinoma cell line HepG-2.Cytotechnology. 2012; 64: 43-51
- PDGF and cardiovascular disease.Cytokine Growth Factor Rev. 2004; 15: 237-254
- Cordycepin attenuates neointimal formation by inhibiting reactive oxygen species-mediated responses in vascular smooth muscle cells in rats.J. Pharmacol. Sci. 2009; 109: 403-412
- Protein tyrosine phosphatase PTPεM negatively regulates PDGFβ-receptor signaling induced by high glucose and PDGF in vascular smooth muscle cells.Am. J. Physiol. Cell. Physiol. 2010; 299 (C1144–C1152)
- Platelet-derived growth factor. Distinct signal transduction pathways associated with migration versus proliferation.Ann. N. Y. Acad. Sci. 1995; 766: 416-430
- p38 mitogen-activated protein kinase contributes to angiotensin II-stimulated migration of rat aortic smooth muscle cells.J. Pharmacol. Sci. 2007; 105: 74-81
- The vascular smooth muscle cell in arterial pathology: a cell that can take on multiple roles.Cardiovasc Res. 2012; 95: 194-204
- Antisense proliferating cell nuclear antigen oligonucleotides inhibit intimal hyperplasia in a rat carotid artery injury model.J. Clin. Invest. 1994; 93: 2351-2356
- Antisense therapy for angioplasty restenosis. Some critical considerations.Circulation. 1995; 92: 1981-1993
- Free radicals and antioxidants in normal physiological functions and human disease.Int. J. Biochem. Cell. Biol. 2007; 39: 44-84
- Inhibitory effects of Zataria multiflora essential oil and its main components on nitric oxide and hydrogen peroxide production in lipopolysaccharide-stimulated macrophages.J. Pharm. Pharmacol. 2012; 64: 1491-1500
- Antioxidant actions of thymol, carvacrol, 6-gingerol, zingerone and hydroxytyrosol.Food Chem. Toxicol. 1994; 32: 31-36
- Effects of tempol and redox-cycling nitroxides in models of oxidative stress.Pharmacol. Ther. 2010; 126: 119-145
- Cell permeable ROS scavengers, tiron and tempol, rescue PC12 cell death caused by pyrogallol or hypoxia/reoxygenation.Neurosci. Res. 2003; 45: 1-8
- Biologically active metal-independent superoxide dismutase mimics.Biochemistry. 1990; 29: 2802-2807
- Inhibitory effects of Zataria multiflora essential oil and its main components on nitric oxide and hydrogen peroxide production in glucose-stimulated human monocyte.Food Chem. Toxicol. 2012; 50: 3079-3085
- Antioxidants relieve phosphatase inhibition and reduce PDGF signaling in cultured VSMCs and in restenosis.Arterioscler. Thromb. Vasc. Biol. 2006; 26: 2644-2651
- Synchronous activation of ERK1/2, p38MAPK and PKB/Akt signaling by H2O2 in vascular smooth muscle cells: potential involvement in vascular disease.Int. J. Mol. Med. 2003; 11: 229-234
Article info
Publication history
Published online: March 28, 2015
Accepted:
March 21,
2015
Received in revised form:
March 1,
2015
Received:
November 10,
2014
Identification
Copyright
© 2015 Elsevier Ireland Ltd. Published by Elsevier Inc. All rights reserved.
