Nicotine enhances angiotensin II-induced mitogenic response in vascular smooth muscle cells and fibroblasts.
OBJECTIVE
The pathogenetic mechanism of tobacco-related cardiovascular diseases is still not well defined. We examined the potential possibility of an interaction between nicotine, a major component of cigarette smoke, and angiotensin II (Ang II), which plays an important role in the pathogenesis of cardiovascular diseases characterized by Ang II type 1 (AT1) receptor-mediated abnormal growth of vascular smooth muscle cells (VSMC) and fibroblasts.


RESULTS
Nicotine or Ang II-stimulated [3H]thymidine incorporation and c-fos expression in adult rat aortic VSMC and adventitial fibroblast. The nicotine-induced DNA synthesis was not affected by valsartan, an AT1 receptor-specific blocker, or PD123319, an Ang II type 2 (AT2) receptor-specific antagonist. Nicotine or Ang II stimulation rapidly increased extracellular signal-regulated kinase (ERK) activation, tyrosine- and serine-phosphorylation of signal transducer and activator of transcription (STAT)1 and STAT3, and p38 mitogen-activated protein kinase (p38 MAPK), in both cell types. Interestingly, co-administration of nicotine and Ang II at lower doses, which did not affect cell growth, induced DNA synthesis and c-fos expression accompanied by enhancement of ERK, STAT, and p38MAPK activity. PD98059, a mitogen-activated protein kinase/ERK kinase inhibitor, or SB23058, a p38MAPK inhibitor, significantly attenuated the vasotrophic effect of nicotine and Ang II.


CONCLUSIONS
These results suggest that nicotine exerts a growth-promoting effect on vascular cells and enhances the Ang II-induced vasotrophic effect, which is at least partly mediated by the activation of ERK, STAT, and p38MAPK.
Li
Jian-Mei
JM
Department of Medical Biochemistry, Ehime University School of Medicine, Onsen-gun, Japan.
Cui
Tai-Xing
TX
Shiuchi
Tetsuya
T
Liu
Hong-Wei
HW
Min
Li-Juan
LJ
Okumura
Midori
M
Jinno
Toyohisa
T
Wu
Lan
L
Iwai
Masaru
M
Horiuchi
Masatsugu
M
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology; D004261:DNA Replication / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D017930:Genes, Reporter; D016762:Genes, fos; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008938:Mitosis / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection
D000804:Angiotensin II; D009538:Nicotine