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Wei-Wen Kuo,¹ Chieh-Hsi Wu,¹ Shin-Da Lee,² James A. Lin,³ Chia-Yih Chu,⁴ Jin-Ming Hwang,⁴ Kwo-Chang Ueng,⁵ Mu-Hsin Chang,⁶ Yu-Lan Yeh,⁷ Chau-Jong Wang,⁸ Jer-Yuh Liu,⁸ and Chih-Yang Huang⁸

¹Department of Biological Science and Technology, China Medical University, Taichung, Taiwan; ²Department of Physical Therapy, Chung-Shan Medical University, Taichung, Taiwan; ³Department of Veterinary Medicine, National Chung-Hsing University, Taichung, Taiwan; ⁴School of Applied Chemistry, and ⁵Department of Internal Medicine, Chung-Shan Medical University, Taichung, Taiwan; ⁶Division of Cardiology, Armed Forces Taichung General Hospital, Taichung, Taiwan; ⁷Department of Pathology, Changhua Christian Hospital, Changhua, Taiwan; ⁸Institute of Biochemistry and Biotechnology, Chung-Shan Medical University, Taichung, Taiwan

Abstract
Exposure to environmental tobacco smoke has been epidemiologically linked to heart disease among nonsmokers. However, the molecular mechanism behind the pathogenesis of cardiac disease is unknown. In this study, we found that Wistar rats, exposed to tobacco cigarette smoke at doses of 5, 10, or 15 cigarettes for 30 min twice a day for 1 month, had a dose-dependently reduced heart weight to body weight ratio and enhanced interstitial fibrosis as identified by histopathologic analysis. The mRNA and activity of matrix metalloprotease-2 (MMP-2) , representing the progress of cardiac remodeling, were also elevated in the heart. In addition, we used reverse-transcriptase polymerase chain reaction and Western blotting to demonstrate significantly increased levels of the apoptotic effecter caspase-3 in treated animal hearts. Dose-dependently elevated mRNA and protein levels of Fas, and promoted apoptotic initiator caspase-8 (active form) , a molecule of a death-receptor-dependent pathway, coupled with unaltered or decreased levels of cytosolic cytochrome c and the apoptotic initiator caspase-9 (active form) , molecules of mitochondria-dependent pathways, may be indicative of cardiac apoptosis, which is Fas death-receptor apoptotic-signaling dependent, but not mitochondria pathway dependent in rats exposed to second-hand smoke (SHS) . With regard to the regulation of survival pathway, using dot blotting, we found cardiac insulin-like growth factor-1 (IGF-1) and IGF-1 receptor mRNA levels to be significantly increased, indicating that compensative effects of IGF-1 survival signaling could occur. In conclusion, we found that the effects of SHS on cardiomyocyte are mediated by the Fas death-receptor-dependent apoptotic pathway and might be related to the epidemiologic incidence of cardiac disease of SHS-exposed nonsmokers. Key words: cardiac survival IGF-1 signaling, caspases, death-receptor-dependent pathway, mitochondria-dependent pathway, second-hand smoke (SHS) . Environ Health Perspect 113: 1349-1353 (2005) . doi:10.1289/ehp.7479 available via http://dx.doi.org/ [Online 1 June 2005]

Address correspondence to C.-Y. Huang, Institute of Biochemistry and Biotechnology, Chung-Shan Medical University No. 110, Section 1, Chien Kuo N. Rd., Taichung 402, Taiwan, ROC. Telephone: 886-4-24730022 ext. 11682. Fax: 886-4-24739030. E-mail: chuang1@csmu.edu.tw

This work was supported by grant NSC 89-2320-B-040-053 from the National Science Council of the Republic of China.

The authors declare they have no competing financial interests.

Received 9 August 2004 ; accepted 1 June 2005.

Correction

In the manuscript originally published online, there were errors in authors' names and affiliations ; they have been corrected here.