Effect of S-diclofenac, a novel hydrogen sulfide releasing derivative inhibit rat vascular smooth muscle cell proliferation
Introduction
Hydrogen sulfide (H2S) is produced in nature primarily through the decomposition of dead plant and animal matter by anaerobic sulfur bacteria (Beauchamp et al., 1984). It is now becoming increasingly apparent that H2S is also synthesized naturally from l-cysteine in mammalian tissues in a reaction catalyzed by two enzymes, cystathionine-γ-lyase and cystathionine-ß-synthetase (Wang, 2002, Kamoun, 2004). Thus, whilst H2S was once considered as an environment pollutant, has transited rapidly to biologically relevant mediator with potential roles in several physiological processes and disease states in the body (Wang, 2002, Szabo, 2007). It has been shown, for example, that H2S plays a role in the regulation of vascular function in both normal and disease state (Zhao and Wang, 2002, Yusuf et al., 2006). Vascular smooth muscle cell proliferation has long been considered to be a key event in the remodeling of vascular wall following vascular injury in diseases such as atherosclerosis and vascular restenosis after invasive intervention (Dzau et al., 2002). More recently, the precise role of cell proliferation in atherogenesis has received more attention including muscle contraction, cell migration and apoptosis (Gizard et al., 2005).
The recent discovery of H2S as an endogenously produced gaseous second messenger capable of modulating many physiological process in the body including vasodilation (Wang, 2002, Wang, 2003), like that of nitric oxide (NO) an another gasotransmitter, prompted us to investigate the potential role of H2S on the smooth muscle cell growth. Recently, it has been reported that H2S exhibits vasodilation (Yusuf et al., 2006), mediates the vasoactivity of garlic (Benavides et al., 2007) and attenuates myocardial ischemia–reperfusion injury by preservation of mitochondrial function (Elrod et al., 2007) in rats. Therefore, the novel gasotransmitter H2S is emerging apart from nitric oxide is an important physiological mediator in the cardiovascular system. Cell growth is controlled by multiple, interrelated signaling pathways with many cell cycle regulatory checkpoints involved. However, the precise mechanism(s) by which H2S alters cell growth and its role in controlling the cell cycle is not well understood (Baskar et al., 2007a), but the recent works suggests that the precise role of H2S on the cardiovascular function is likely to be more complex (Szabo, 2007). In this study, we have examined the effects of a novel H2S donor; S-diclofenac (Isenberg et al., 2007, Li et al., 2007, Sidhapuriwala et al., 2007, Wallace et al., 2007, Rossoni et al., 2008) on cell survival, cell cycle alterations and proteins associated with cell growth and apoptosis in rat aortic vascular smooth muscle cells.
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Cell culture and treatment
Normal rat aortic (A-10) and immortalized with SV40 (CRL-2018) smooth muscle cells (SMC) were obtained from the American Type Culture Collection (Manassas, VA, U.S.A). Cells were grown in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% v/v fetal bovine serum (FBS), 1% of l-glutamine, 100-units/ml penicillin and 100-μg/ml streptomycin. All reagents were obtained from GIBGO, Carlsbad, CA, U.S.A. The cultures were maintained at 37 °C in a humidified 5% CO2 atmosphere. A novel H2
Cytotoxicity by cell survival assay
In the present study, we have studied the effects of S-diclofenac (a novel H2S donor) and its parent molecule diclofenac on the cell proliferation of rat aortic vascular smooth muscle cells. In a preliminary study, we first investigated the effect of S-diclofenac (10–100 μM) on cell survival by the colony forming efficiency on the primary (A-10) and immortalized with SV40 transformed smooth muscle cells. DMSO was used as a vehicle to dissolve the diclofenac and S-diclofenac. We have conducted
Discussion
In recent years, it has become clear that hydrogen sulfide (H2S) plays a number of biological roles (Szabo, 2007) and functions as a novel gasotransmitter in the body alongside nitric oxide (NO) and carbon monoxide (CO) (Wang, 2002, Wang, 2003, Moore et al., 2003). Recently, it has been reported that H2S acts as a vasodilation agent in rats (Zhao et al., 2001, Yusuf et al., 2006) and also mediates the activity of garlic (Benavides et al., 2007) and attenuates myocardial ischemia–reperfusion
Acknowledgements
We would like to thank the Department of Clinical Research (grant no. DCR/P2/2007), Singapore General Hospital and the Office of Life Science (grant no. R-184-000-074-712), National University of Singapore, Singapore.
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