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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:80.)
© 2004 American Heart Association, Inc.

Vascular Biology

Nicotine Enhances Angiotensin II-Induced Mitogenic Response in Vascular Smooth Muscle Cells and Fibroblasts

Jian-Mei Li^*; Tai-Xing Cui^*; Tetsuya Shiuchi; Hong-Wei Liu; Li-Juan Min; Midori Okumura; Toyohisa Jinno; Lan Wu; Masaru Iwai; Masatsugu Horiuchi

From the Department of Medical Biochemistry, Ehime University School of Medicine, Ehime 791 to 0295, Japan.

Correspondence to Masatsugu Horiuchi, MD, PhD, FAHA, Department of Medical Biochemistry, Ehime University School of Medicine, Shitsukawa, Shigenobu, Onsen-gun, Ehime 791-0295, Japan. E-mail horiuchi{at}m.ehime-u.ac.jp

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.

Methods and 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.

Key Words: angiotensin II • nicotine • ERK • STAT • vascular smooth muscle cell • vascular adventitial fibroblast

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