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Second-hand smoke-induced cardiac fibrosis is related to the fas death receptor apoptotic pathway without mitochondria-dependent pathway involvement in rats.

Article Excerpt
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]

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Second-hand smoke (SHS), a mixture of smog produced from a burning cigarette and exhaled smoke, contains thousands of chemical constituents, most of which are harmful and cause human diseases such as lung cancer and cardiovascular disease (Boyle and Maisonneuve 1995; Bronnum-Hansen 2000; De Cesaris et al. 1992; Haugen 2002; MacDougall et al. 1983). However, most studies on this subject focus on the association of SHS with respiratory symptoms, impaired lung function, and increased bronchial responsiveness. Actually, epidemiologic studies have showed that exposure to SHS increases the incidence of cardiac disease 4-fold (Ciruzzi et al. 1998; Stefanadis et al. 1998), and the mortality of cardiac failure among passive smokers is 38% higher than in those who do not smoke or who are not exposed to SHS (Baud et al. 1991; Ecanow and Blake 1978). Pope et al. (2001) found that 2 hr of exposure to SHS significantly destroyed cardiac autonomic function, as evidenced by decrements in heart rate variability in 16 adult nonsmokers. However, so far the mechanisms behind cardiac disease in subjects exposed to SHS are poorly understood.

Apoptosis is a recognized mechanism for the elimination of redundant cells, although it may also inhibit cell proliferation. In fact, it has been suggested that apoptosis plays a critical role in the pathogenesis of human diseases, including cardiac disorders (Haunstetter and Izumo 1998). Apoptosis has been reported to contribute to the loss of cardiomyocytes, after which the collagen secreted by fibroblasts replaces the space of damaged cardiomyocytes in cardiomyopathy. Hence, the fibrosis following apoptosis is recognized as a predictor of adverse outcomes in subjects with cardiomyopathy (Kim and Iwao 2000; Narula et al. 1996). Therefore, the evaluation of the apoptosis and/or fibrosis process could be an excellent way of predicting the development of cardiomyopathy induced by SHS, although the specificity of the related signaling pathways involved in the development of apoptosis and/or fibrosis needs to be identified.

The induction of apoptosis is associated with the activation of aspartate-specific cysteine protease, including caspase-3 (Fernandes-Alnemri et al. 1994). Several studies have demonstrated that mitochondria may play an important role in apoptosis by releasing cytochrome c and activating caspase-9, which activates caspase-3 that is responsible for DNA-cleavage action (Liu et al. 1996; Reed and Paternostro 1999). In end-stage cardiomyopathy, cytosolic cytochrome c is also accumulated (Narula et al. 1999). In addition, the death-receptor-induced apoptotic pathway is reportedly involved in the pathogenesis of cardiac disease (Scheubel et al. 2002). This pathway is initiated by death-receptor agonists, including the Fas ligand. After ligand binding, Fas receptor oligomerization results in the...