Shear stress attenuates endothelin and endothelin-converting enzyme expression through oxidative stress.
Shear stress is known to dilate blood vessels and exert an antiproliferative effect on vascular walls. These effects have partly been ascribed to shear stress-induced regulation of the secretion of endothelium-derived vasoactive substances. In this study, to elucidate the role of shear stress in endothelin production by endothelial cells, we examined the effect of physiological shear stress on the mRNA expression of endothelin-converting enzyme-1 (ECE-1) as well as endothelin-1 (ET-1) in cultured bovine carotid artery endothelial cells (BAECs) and human umbilical vein endothelial cells (HUVECs), using a parallel plate-type flow chamber. ECE-1 mRNA expression was significantly down-regulated by shear stress in an intensity- and time-dependent manner within the physiological range (1.5 to 15 dyn/cm(2)). ET-1 mRNA expression decreased together with ECE-1 mRNA expression. Shear stress at 15 dyn/cm(2) for 30 min induced a significant increase in the intracellular peroxide concentration, and the down-regulation of ECE-1 and ET-1 mRNA expression by shear stress was attenuated almost completely on treatment with N-acetyl cysteine (NAC), an antioxidant (20 mM). Furthermore, when H(2)O(2) (0.5 to 2 mM) was added to BAECs in static culture, the ECE-1 as well as ET-1 mRNA expression was attenuated in proportion to the concentration of H(2)O(2). It is suggested that endothelial cells sense shear stress as oxidative stress and transduce signal for the regulation of the gene expression of ECE as well as ET to attenuate vascular tone and inhibit the proliferation of vascular smooth muscle cells.
Masatsugu
Ken
K
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
Itoh
Hiroshi
H
Chun
Tae-Haw
TH
Saito
Takatoshi
T
Yamashita
Jun
J
Doi
Kentaro
K
Inoue
Mayumi
M
Sawada
Naoki
N
Fukunaga
Yasutomo
Y
Sakaguchi
Satsuki
S
Sone
Masakatsu
M
Yamahara
Kenichi
K
Yurugi
Takami
T
Nakao
Kazuwa
K
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D016282:Aspartic Acid Endopeptidases / Q000096:biosynthesis* / Q000235:genetics; D002339:Carotid Arteries / Q000166:cytology; D002417:Cattle; D002478:Cells, Cultured; D017931:DNA Primers / Q000235:genetics; D015342:DNA Probes / Q000235:genetics; D015536:Down-Regulation; D019332:Endothelin-1 / Q000096:biosynthesis* / Q000235:genetics; D000072396:Endothelin-Converting Enzymes; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008666:Metalloendopeptidases; D018384:Oxidative Stress / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D013314:Stress, Mechanical; D013997:Time Factors; D014471:Umbilical Veins / Q000166:cytology
D000975:Antioxidants; D017931:DNA Primers; D015342:DNA Probes; D019332:Endothelin-1; D012333:RNA, Messenger; D006861:Hydrogen Peroxide; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; C000606923:ECE1 protein, human; D000072396:Endothelin-Converting Enzymes; D000111:Acetylcysteine