Session Speaker

Uridine Adenosine Tetraphosphate, Up4a: The New Target for Drug Development of Vascular Diseases
Xi-Long Zheng
Canada

Up4A was discovered in 2005 as a novel endothelium-derived contractile factor, EDCF released from endothelial cells (Jankowski et al., 2005). We further established that Up4A induced contraction of rat pulmonary arterial tissues. This action was found through activation of a suramin-sensitive P2Y receptor (Gui et al., 2008). Importantly, we have found that high blood concentration of Up4A is correlated to high blood pressure in children and the development of neointima formation in carotid arteries (Jankowski et al., 2007). Our in vitro studies showed that Up4A stimulates the proliferation of human vascular smooth muscle cells (SMCs). The mechanism involves P2Y receptor activation as well. More recently, using cultured human vascular SMCs, we demonstrated that intracellular signalling mechanism underlying Up4A-induced proliferation of SMCs involves activation of Erk1/2 and Erk1/2-dependent S6K pathways. Taken together, our research has revealed that Up4A is a potent vasoconstrictor and a mitogen for vascular SMCs, and could become the target of drug development to treat hypertension and other proliferative vascular diseases, including atherosclerosis and restenosis after angioplasty.

References:
Gui Y, Walsh MP, Jankowski V, Jankowski J and Zheng XL (2008) Up4A stimulates endothelium independent contraction of isolated rat pulmonary artery. Am. J. Physiol. Lung Cell. Mol. Physiol. 294:L733-738.

Jankowski V, Meyer AA, Schlattmann P, Gui Y, Zheng XL, Stamcou I, Radtke K, Tran TN, van der Giet M, Tolle M, Zidek W and Jankowski J (2007) Increased uridine adenosine tetraphosphate concentrations in plasma of juvenile hypertensives. Arterioscler. Thromb. Vasc. Biol. 27: 1776-1781.

Jankowski V, Tolle M, Vanholder R, Schonfelder G, van der Giet M, Henning L, Schluter H, Paul M, Zidek W and Jankowski J (2005) Uridine adenosine tetraphosphate: a novel endothelium- derived vasoconstrictive factor. Nat. Med. 11: 223-227.