Differential regulation of proliferation, cell cycle control and gene expression in cultured human aortic and pulmonary artery endothelial cells by resveratrol

Resveratrol is a grape polyphenol with cardioprotective attributes, supported in part by its demonstrated anti-mitogenic, apoptosis-inducing and gene modulatory activities in various cell types known to play an integral role in atherogenesis. To test whether resveratrol exerts similar effects on systemic and pulmonary vasculature, cells derived from different anatomical sites, cultured human aortic and pulmonary artery endothelial cells, respectively denoted HAECs and HPAECs, were exposed to resveratrol for assessment of effects on proliferation, cell cycle distribution, induction of apoptosis, and specific gene expression. Resveratrol inhibited cell proliferation in a time- and dose-dependent manner in HAECs and HPAECs, accompanied by disruption of cell cycle control and progression as assayed by flow cytometry. Analysis of gene changes in resveratrol-treated endothelial cells by RT-PCR showed suppression of nitric oxide synthase (eNOS) and preproendothelin-1 (ppET-1) expression in both cell types. To discover group gene alterations resulting from exposure to resveratrol, changes in mRNA levels were determined by human signal transduction pathway finder cDNA array analysis. The results showed that resveratrol up-regulated levels of cyclin-dependent kinase inhibitor p57, egr-1, forkhead box A2 and c-jun in HAECs, and elevated expression of cathepsin D, ICAM-1, c-jun and patched 1 in HPAECs. In addition, treatment by resveratrol also resulted in attenuated expression of bcl-xl, fibronectin-1, HIP, mdm2, PIG3 and WSB1/SWIP-1 in HAECs, and CDX1, engrailed homolog 1, FASN, fibronectin-1, forkhead box A2, Hoxa-1, hsp27, PIG3, ELAM-1/E-selectin and WSB1/SWIP-1 in HPAECs. These results suggest that resveratrol acts by distinct and overlapping signaling pathways and mechanisms in HAECs and HPAECs, further supporting the notion that the cardioactive activities and effects of this grape polyphenol are contingent upon or influenced by the vascular bed of origin.