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Lopez-Pastrana J , Ferrer LM , Li YF , Xiong X , Xi H , Cueto R , Nelson J , Sha X , Li X , Cannella AL , Imoukhuede PI , Qin X , Choi ET , Wang H , Yang XF
Inhibition of Caspase-1 Activation in Endothelial Cells Improves Angiogenesis: A NOVEL THERAPEUTIC POTENTIAL FOR ISCHEMIA
J Biol Chem. 2015 Jul 10;290(28) :17485-94
PMID: 26037927    PMCID: PMC4498083    URL: http://www.ncbi.nlm.nih.gov/pubmed/26037927
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Deficient angiogenesis may contribute to worsen the prognosis of myocardial ischemia, peripheral arterial disease, ischemic stroke, etc. Dyslipidemic and inflammatory environments attenuate endothelial cell (EC) proliferation and angiogenesis, worsening the prognosis of ischemia. Under these dyslipidemic and inflammatory environments, EC-caspase-1 becomes activated and induces inflammatory cell death that is defined as pyroptosis. However, the underlying mechanism that correlates caspase-1 activation with angiogenic impairment and the prognosis of ischemia remains poorly defined. By using flow cytometric analysis, enzyme and receptor inhibitors, and hind limb ischemia model in caspase-1 knock-out (KO) mice, we examined our novel hypothesis, i.e. inhibition of caspase-1 in ECs under dyslipidemic and inflammatory environments attenuates EC pyroptosis, improves EC survival mediated by vascular endothelial growth factor receptor 2 (VEGFR-2), angiogenesis, and the prognosis of ischemia. We have made the following findings. Proatherogenic lipids induce higher caspase-1 activation in larger sizes of human aortic endothelial cells (HAECs) than in smaller sizes of HAECs. Proatherogenic lipids increase pyroptosis significantly more in smaller sizes of HAECs than in larger sizes of the cells. VEGFR-2 inhibition increases caspase-1 activation in HAECs induced by lysophosphatidylcholine treatment. Caspase-1 activation inhibits VEGFR-2 expression. Caspase-1 inhibition improves the tube formation of lysophosphatidylcholine-treated HAECs. Finally, caspase-1 depletion improves angiogenesis and blood flow in mouse hind limb ischemic tissues. Our results have demonstrated for the first time that inhibition of proatherogenic caspase-1 activation in ECs improves angiogenesis and the prognosis of ischemia.
Lopez-Pastrana, Jahaira Ferrer, Lucas M Li, Ya-Feng Xiong, Xinyu Xi, Hang Cueto, Ramon Nelson, Jun Sha, Xiaojin Li, Xinyuan Cannella, Ann L Imoukhuede, Princess I Qin, Xuebin Choi, Eric T Wang, Hong Yang, Xiao-Feng eng 2015/06/04 06:00 J Biol Chem. 2015 Jul 10;290(28):17485-94. doi: 10.1074/jbc.M115.641191. Epub 2015 Jun 2.