| First Author | Singh NK | Year | 2011 |
| Journal | Blood | Volume | 118 |
| Issue | 20 | Pages | 5701-12 |
| PubMed ID | 21841162 | Mgi Jnum | J:178807 |
| Mgi Id | MGI:5300149 | Doi | 10.1182/blood-2011-04-347468 |
| Citation | Singh NK, et al. (2011) 12/15-Lipoxygenase gene knockout severely impairs ischemia-induced angiogenesis due to lack of Rac1 farnesylation. Blood 118(20):5701-12 |
| abstractText | To understand the mechanisms by which 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) activates Rac1 in the induction of angiogenesis, we studied the role of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and alphaPix. 15(S)-HETE stimulated Rac1 in a sustained manner in human dermal microvascular endothelial cells (HDMVECs). Simvastatin, a potent inhibitor of HMG-CoA reductase, suppressed 15(S)-HETE-induced Rac1 activation in HDMVECs affecting their migration and tube formation. 15(S)-HETE by inducing HMG-CoA reductase expression caused increased farnesylation and membrane translocation of Rac1 where it became activated by Src-dependent alphaPix stimulation. Mevalonate rescued 15(S)-HETE-induced Rac1 farnesylation and membrane translocation in HDMVECs and the migration and tube formation of these cells from inhibition by simvastatin. Down-regulation of alphaPix inhibited 15(S)-HETE-induced HDMVEC migration and tube formation. Hind-limb ischemia induced Rac1 farnesylation and activation leading to increased angiogenesis and these effects were blocked by simvastatin and rescued by mevalonate in WT mice. In contrast, hind-limb ischemia failed to induce Rac1 farnesylation and activation as well as angiogenic response in 12/15-Lox(-/-) mice. Activation of Src and alphaPix were also compromised at least to some extent in 12/15-Lox(-/-) mice compared with WT mice in response to hind-limb ischemia. Together, these findings demonstrate for the first time that HMG-CoA reductase plays a determinant role in 12/15-Lox-induced angiogenesis. |
