Thalidomide attenuates nitric oxide-driven angiogenesis by interacting with soluble guanylyl cyclase.

Abstract

BACKGROUND AND PURPOSE Nitric oxide (NO) promotes angiogenesis by activating endothelial cells. Thalidomide arrests angiogenesis by interacting with the NO pathway, but its putative targets are not known. Here, we have attempted to identify these targets. EXPERIMENTAL APPROACH Cell-based angiogenesis assays (wound healing of monolayers and tube formation in ECV304, EAhy926 and bovine arterial endothelial cells), along with ex vivo and in vivo angiogenesis assays, were used to explore interactions between thalidomide and NO. We also carried out in silico homology modelling and docking studies to elucidate possible molecular interactions of thalidomide and soluble guanylyl cyclase (sGC). KEY RESULTS Thalidomide inhibited pro-angiogenic functions in endothelial cell cultures, whereas 8-bromo-cGMP, sildenafil (a phosphodiesterase inhibitor) or a NO donor [sodium nitroprusside (SNP)] increased these functions. The inhibitory effects of thalidomide were reversed by adding 8-bromo-cGMP or sildenafil, but not by SNP. Immunoassays showed a concentration-dependent decrease of cGMP in endothelial cells with thalidomide, without affecting the expression level of sGC protein. These results suggested that thalidomide inhibited the activity of sGC. Molecular modelling and docking experiments revealed that thalidomide could interact with the catalytic domain of sGC, which would explain the inhibitory effects of thalidomide on NO-dependent angiogenesis. CONCLUSION AND IMPLICATIONS Our results showed that thalidomide interacted with sGC, suppressing cGMP levels in endothelial cells, thus exerting its anti-angiogenic effects. These results could lead to the formulation of thalidomide-based drugs to curb angiogenesis by targeting sGC.

DOI: 10.1111/j.1476-5381.2009.00446.x

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@article{Majumder2009ThalidomideAN, title={Thalidomide attenuates nitric oxide-driven angiogenesis by interacting with soluble guanylyl cyclase.}, author={Syamantak Majumder and Megha Rajaram and Ajit Muley and Himabindu S Reddy and K P Tamilarasan and Gopi Krishna Kolluru and Swaraj Sinha and Jamila H Siamwala and Ravi Gupta and R Ilavarasan and S Venkataraman and K C Sivakumar and Sharmila Anishetty and Pradeep G Kumar and Suvro Chatterjee}, journal={British journal of pharmacology}, year={2009}, volume={158 7}, pages={1720-34} }