| First Author | Feng S | Year | 2017 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 37 |
| Issue | 11 | Pages | 2087-2101 |
| PubMed ID | 28882872 | Mgi Jnum | J:269190 |
| Mgi Id | MGI:6272091 | Doi | 10.1161/ATVBAHA.117.309249 |
| Citation | Feng S, et al. (2017) Mechanical Activation of Hypoxia-Inducible Factor 1alpha Drives Endothelial Dysfunction at Atheroprone Sites. Arterioscler Thromb Vasc Biol 37(11):2087-2101 |
| abstractText | OBJECTIVE: Atherosclerosis develops near branches and bends of arteries that are exposed to low shear stress (mechanical drag). These sites are characterized by excessive endothelial cell (EC) proliferation and inflammation that promote lesion initiation. The transcription factor HIF1alpha (hypoxia-inducible factor 1alpha) is canonically activated by hypoxia and has a role in plaque neovascularization. We studied the influence of shear stress on HIF1alpha activation and the contribution of this noncanonical pathway to lesion initiation. APPROACH AND RESULTS: Quantitative polymerase chain reaction and en face staining revealed that HIF1alpha was expressed preferentially at low shear stress regions of porcine and murine arteries. Low shear stress induced HIF1alpha in cultured EC in the presence of atmospheric oxygen. The mechanism involves the transcription factor nuclear factor-kappaB that induced HIF1alpha transcripts and induction of the deubiquitinating enzyme Cezanne that stabilized HIF1alpha protein. Gene silencing revealed that HIF1alpha enhanced proliferation and inflammatory activation in EC exposed to low shear stress via induction of glycolysis enzymes. We validated this observation by imposing low shear stress in murine carotid arteries (partial ligation) that upregulated the expression of HIF1alpha, glycolysis enzymes, and inflammatory genes and enhanced EC proliferation. EC-specific genetic deletion of HIF1alpha in hypercholesterolemic apolipoprotein E-defecient mice reduced inflammation and endothelial proliferation in partially ligated arteries, indicating that HIF1alpha drives inflammation and vascular dysfunction at low shear stress regions. CONCLUSIONS: Mechanical low shear stress activates HIF1alpha at atheroprone regions of arteries via nuclear factor-kappaB and Cezanne. HIF1alpha promotes atherosclerosis initiation at these sites by inducing excessive EC proliferation and inflammation via the induction of glycolysis enzymes. |
