Abstract
Development of early stage atherosclerosis involves the activation of endothelial cells by oxidized low-density lipoprotein (oxLDL) with subsequent increases in endothelial permeability and expression of adhesion molecules favoring the adherence of monocytes to the endothelium. Cryptotanshinone (CTS), a major compound derived from the Chinese herb Salvia miltiorrhiza, is known for its protective effects against cardiovascular diseases. The aim of this study was to determine whether CTS could prevent the oxLDL-induced early atherosclerotic events. OxLDL (100 µg/mL) was used to increase endothelial permeability and induce monocyte-endothelial cell adhesion in human umbilical vein endothelial cells (HUVECs). Endothelial nitric oxide (NO) concentrations, a permeability-regulating molecule, and expressions of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were measured. Results show that a) endothelial hyperpermeability was suppressed by 94 % (p < 0.005), b) monocyte adhesion by 105 % (p < 0.01), and c) ICAM-1 and VCAM-1 expressions by 90 % (p < 0.01) and 150 % (p < 0.005), respectively, when CTS was applied. In contrast, CTS increased NO levels by 129 % (p < 0.01) and was found to be noncytotoxic in the concentrations between 1–10 µM. These findings indicate that CTS suppresses an increase in endothelial permeability, likely due to the restoration of NO bioavailability in endothelial cells. They also indicate that CTS may attenuate monocyte adhesion to endothelial cells through the inhibition of adhesion molecules' expression. Thus, CTS may play an important role in the prevention of early or pre-lesional stage of atherosclerosis.
Key words
cryptotanshinone - anti-atherosclerotic - oxLDL - endothelial permeability - monocyte adhesion
References
-
1
Kaperonis E A, Liapis C D, Kakisis J D, Dimitroulis D, Papavassiliou V G.
Inflammation and atherosclerosis.
Eur J Vasc Endovasc Surg.
2006;
31
386-393
-
2
Ou H C, Chou F P, Lin T M, Yang C H, Sheu Wayne H H.
Protective effects of honokiol against oxidized LDL-induced cytotoxicity and adhesion molecule expression in endothelial cells.
Chem Biol Interact.
2006;
161
1-13
-
3
Zhao S P, Xu D Y.
Oxidized lipoprotein enhanced the expression of P-selectin in cultured human umbilical vein endothelial cells.
Thromb Res.
2000;
100
501-510
-
4
Papaharalambus C A, Griendling K K.
Basic mechanisms of oxidative stress and reactive oxygen species in cardiovascular injury.
Trends Cardiovasc Med.
2007;
17
48-54
-
5
Harlan L M, Chan M A, Benedict S H.
Two different modes of costimulation predispose human T-lymphocytes to differential responses in the presence of HDL or oxidized LDL.
Atherosclerosis.
2007;
193
309-320
-
6
Napoli C, Ignarro L J.
Nitric oxide and atherosclerosis.
Nitric Oxide.
1996;
5
88-97
-
7
Furchgott R F.
The discovery of endothelium-derived relaxing factor and its importance in the identification of nitric oxide.
JAMA.
1996;
276
1186-1188
-
8
Lum H, Malik A B.
Regulation of vascular endothelial barrier function.
Am J Physiol Lung Cell Mol Physiol.
1994;
267
223-224
-
9
Kubes P, Suzuki M, Granger D N.
Nitric oxide: an endogenous modulator of leukocyte adhesion.
Proc Natl Acad Sci USA.
1991;
88
4651-4655
-
10
Lu Y, Foo L Y.
Polyphenolics of Salvia – a review.
Phytochemistry.
2002;
59
117-140
-
11
Akira Y, Fujimoto K, Tanonaka K, Hirai K, Takeo S.
Possible active components of tan-shen (Salvia miltiorrhiza) for protection of the myocardium against ischemia-induced derangements.
Planta Med.
1989;
55
51-54
-
12
Suh S J, Jin U H, Choi H J, Chang H W, Son J K, Lee S H.
Cryptotanshinone from Salvia miltiorrhiza BUNGE has an inhibitory effect on TNF-alpha-induced matrix metalloproteinase-9 production and HASMC migration via down-regulated NF-kappaB and AP-1.
Biochem Pharmacol.
2006;
72
1680-1689
-
13
Maruo N, Morita I, Shirao M, Murota S.
IL-6 increases endothelial permeability in vitro.
Endocrinology.
1992;
131
710-714
-
14
Wung B S, Ni C W, Wang D L.
ICAM-1 induction by TNF-α and IL-6 is mediated by distinct pathways via Rac in endothelial cells.
J Biomed Sci.
2005;
12
91-101
-
15
Karman R J, Garcia J G N, Hart C M.
Endothelial cell monolayer dysfunction caused by oxidized low density lipoprotein: attenuation by oleic acid.
Prostaglandins Leukot Essent Fatty Acids.
1997;
56
345-353
-
16
Downar D Z, Siennicka A, Kaczmarczyk M, Kolodziej B, Naruszewicz M.
Simvastatin modulates TNFα-induced adhesion molecules expression in human endothelial cells.
Life Sci.
2004;
75
1287-1302
-
17
Jin Y C, Kim C W, Kim Y M, Nizamutdinova I T, Ha Y M, Kim H J, Seo H G, Son K H, Jeon S J, Kang S S, Kim Y S, Kam S C, Lee J H, Chang K C.
Cryptotanshinone, a lipophilic compound of Salvia miltiorrriza root, inhibits TNF-α-induced expression of adhesion molecules in HUVEC and attenuates rat myocardial ischemia/reperfusion injury in vivo.
Eur J Pharmacol.
2009;
614
91-97
-
18
Jin D Z, Yin L L, Ji X Q, Zhu X Z.
Cryptotanshinone inhibits cyclooxygenase-2 enzyme activity but not its expression.
Eur J Pharmacol.
2006;
549
166-172
-
19
Jeon S J, Son K H, Kim Y S, Choi Y H, Kim H P.
Inhibition of prostaglandin and nitric oxide production in lipopolysaccharide-treated RAW 264.7 cells by tanshinones from the roots of Salvia miltiorrhiza Bunge.
Arch Pharm Res.
2008;
31
758-763
-
20
Cominacini L, Pasini A F, Garbin U, Davoli A, Tosetti M L, Campagnola M.
Oxidized low density lipoprotein (ox-LDL) binding to ox-LDL receptor-1 in endothelial cells induces the activation of NF-kappaB through an increased production of intracellular reactive oxygen species.
J Biol Chem.
2000;
275
12633-12638
-
21
Zeiher A M, Fisslthaler B, Schray-Utz B, Busse R.
Nitric oxide modulates the expression of monocyte chemoattractant protein 1 in cultured human endothelial cells.
Circ Res.
1995;
76
980-986
-
22
Zhou Z, Wang S Q, Liu Y, Miao A D.
Cryptotanshinone inhibits endothelin-1 expression and stimulates nitric oxide production in human vascular endothelial cells.
Biochim Biophys Acta.
2006;
1760
1-9
-
23
Steinkamp-Fenske K, Bollinger L, Voller N, Xua H, Yao Y, Bauer R, Förstermann U, Li H.
Ursolic acid from the Chinese herb danshen (Salvia miltiorrhiza L.) upregulates eNOS and downregulates Nox4 expression in human endothelial cells.
Atherosclerosis.
2007;
195
e104-e111
Dr. Zuraini Ahmad
Department of Biomedical Sciences
Faculty of Medicine and Health Sciences
Universiti Putra Malaysia
43400 UPM Serdang, Selangor
Malaysia
Telefon: +60 3 89 47 23 13
Fax: +60 3 89 43 61 78
eMail: zuraini@medic.upm.edu.my
