Endothelial Hypoxia-Inducible Factor-1α Promotes Atherosclerosis and Monocyte Recruitment by Upregulating MicroRNA-19a.
Chemokines mediate monocyte adhesion to dysfunctional endothelial cells (ECs) and promote arterial inflammation during atherosclerosis. Hypoxia-inducible factor (HIF)-1α is expressed in various cell types of atherosclerotic lesions and is associated with lesional inflammation. However, the impact of endothelial HIF-1α in atherosclerosis is unclear. HIF-1α was detectable in the nucleus of ECs covering murine and human atherosclerotic lesions. To study the role of endothelial HIF-1α in atherosclerosis, deletion of the Hif1a gene was induced in ECs from apolipoprotein E knockout mice (EC-Hif1a(-/-)) by Tamoxifen injection. The formation of atherosclerotic lesions, the lesional macrophage accumulation, and the expression of CXCL1 in ECs were reduced after partial carotid ligation in EC-Hif1a(-/-) compared with control mice. Moreover, the lesion area and the lesional macrophage accumulation were decreased in the aortas of EC-Hif1a(-/-) mice compared with control mice during diet-induced atherosclerosis. In vitro, mildly oxidized low-density lipoprotein or lysophosphatidic acid 20:4 increased endothelial CXCL1 expression and monocyte adhesion by inducing HIF-1α expression. Moreover, endothelial Hif1a deficiency resulted in downregulation of miR-19a in atherosclerotic arteries determined by microRNA profiling. In vitro, HIF-1α-induced miR-19a expression mediated the upregulation of CXCL1 in mildly oxidized low-density lipoprotein-stimulated ECs. These results indicate that hyperlipidemia upregulates HIF-1α expression in ECs by mildly oxidized low-density lipoprotein-derived unsaturated lysophosphatidic acid. Endothelial HIF-1α promoted atherosclerosis by triggering miR-19a-mediated CXCL1 expression and monocyte adhesion, indicating that inhibition of the endothelial HIF-1α/miR-19a pathway may be a therapeutic option against atherosclerosis.
From the Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany (S.A., P.H., E.K., F.-A.R., P.S., C.W., S.S., A.S.); Institute for Molecular Cardiovascular Research (S.A., A.S.), Department of Experimental Molecular Imaging (F.G., F.K.), and European Vascular Center Aachen-Maastricht (J.G., M.J.), RWTH Aachen University, Aachen, Germany; European Vascular Center Aachen-Maastricht, University Maastricht Medical Center, Maastricht, The Netherlands (J.G., M.J.); Cardiovascular Research Institute Maastricht, University Maastricht, Maastricht, The Netherlands (C.W.); and DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany (C.W., S.S., A.S.).
Shamima
S
Akhtar
From the Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany (S.A., P.H., E.K., F.-A.R., P.S., C.W., S.S., A.S.); Institute for Molecular Cardiovascular Research (S.A., A.S.), Department of Experimental Molecular Imaging (F.G., F.K.), and European Vascular Center Aachen-Maastricht (J.G., M.J.), RWTH Aachen University, Aachen, Germany; European Vascular Center Aachen-Maastricht, University Maastricht Medical Center, Maastricht, The Netherlands (J.G., M.J.); Cardiovascular Research Institute Maastricht, University Maastricht, Maastricht, The Netherlands (C.W.); and DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany (C.W., S.S., A.S.).
Petra
P
Hartmann
From the Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany (S.A., P.H., E.K., F.-A.R., P.S., C.W., S.S., A.S.); Institute for Molecular Cardiovascular Research (S.A., A.S.), Department of Experimental Molecular Imaging (F.G., F.K.), and European Vascular Center Aachen-Maastricht (J.G., M.J.), RWTH Aachen University, Aachen, Germany; European Vascular Center Aachen-Maastricht, University Maastricht Medical Center, Maastricht, The Netherlands (J.G., M.J.); Cardiovascular Research Institute Maastricht, University Maastricht, Maastricht, The Netherlands (C.W.); and DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany (C.W., S.S., A.S.).
Ela
E
Karshovska
From the Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany (S.A., P.H., E.K., F.-A.R., P.S., C.W., S.S., A.S.); Institute for Molecular Cardiovascular Research (S.A., A.S.), Department of Experimental Molecular Imaging (F.G., F.K.), and European Vascular Center Aachen-Maastricht (J.G., M.J.), RWTH Aachen University, Aachen, Germany; European Vascular Center Aachen-Maastricht, University Maastricht Medical Center, Maastricht, The Netherlands (J.G., M.J.); Cardiovascular Research Institute Maastricht, University Maastricht, Maastricht, The Netherlands (C.W.); and DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany (C.W., S.S., A.S.).
Fatuma-Ayaan
FA
Rinderknecht
From the Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany (S.A., P.H., E.K., F.-A.R., P.S., C.W., S.S., A.S.); Institute for Molecular Cardiovascular Research (S.A., A.S.), Department of Experimental Molecular Imaging (F.G., F.K.), and European Vascular Center Aachen-Maastricht (J.G., M.J.), RWTH Aachen University, Aachen, Germany; European Vascular Center Aachen-Maastricht, University Maastricht Medical Center, Maastricht, The Netherlands (J.G., M.J.); Cardiovascular Research Institute Maastricht, University Maastricht, Maastricht, The Netherlands (C.W.); and DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany (C.W., S.S., A.S.).
Pallavi
P
Subramanian
From the Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany (S.A., P.H., E.K., F.-A.R., P.S., C.W., S.S., A.S.); Institute for Molecular Cardiovascular Research (S.A., A.S.), Department of Experimental Molecular Imaging (F.G., F.K.), and European Vascular Center Aachen-Maastricht (J.G., M.J.), RWTH Aachen University, Aachen, Germany; European Vascular Center Aachen-Maastricht, University Maastricht Medical Center, Maastricht, The Netherlands (J.G., M.J.); Cardiovascular Research Institute Maastricht, University Maastricht, Maastricht, The Netherlands (C.W.); and DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany (C.W., S.S., A.S.).
Felix
F
Gremse
From the Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany (S.A., P.H., E.K., F.-A.R., P.S., C.W., S.S., A.S.); Institute for Molecular Cardiovascular Research (S.A., A.S.), Department of Experimental Molecular Imaging (F.G., F.K.), and European Vascular Center Aachen-Maastricht (J.G., M.J.), RWTH Aachen University, Aachen, Germany; European Vascular Center Aachen-Maastricht, University Maastricht Medical Center, Maastricht, The Netherlands (J.G., M.J.); Cardiovascular Research Institute Maastricht, University Maastricht, Maastricht, The Netherlands (C.W.); and DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany (C.W., S.S., A.S.).
Jochen
J
Grommes
From the Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany (S.A., P.H., E.K., F.-A.R., P.S., C.W., S.S., A.S.); Institute for Molecular Cardiovascular Research (S.A., A.S.), Department of Experimental Molecular Imaging (F.G., F.K.), and European Vascular Center Aachen-Maastricht (J.G., M.J.), RWTH Aachen University, Aachen, Germany; European Vascular Center Aachen-Maastricht, University Maastricht Medical Center, Maastricht, The Netherlands (J.G., M.J.); Cardiovascular Research Institute Maastricht, University Maastricht, Maastricht, The Netherlands (C.W.); and DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany (C.W., S.S., A.S.).
Michael
M
Jacobs
From the Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany (S.A., P.H., E.K., F.-A.R., P.S., C.W., S.S., A.S.); Institute for Molecular Cardiovascular Research (S.A., A.S.), Department of Experimental Molecular Imaging (F.G., F.K.), and European Vascular Center Aachen-Maastricht (J.G., M.J.), RWTH Aachen University, Aachen, Germany; European Vascular Center Aachen-Maastricht, University Maastricht Medical Center, Maastricht, The Netherlands (J.G., M.J.); Cardiovascular Research Institute Maastricht, University Maastricht, Maastricht, The Netherlands (C.W.); and DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany (C.W., S.S., A.S.).
Fabian
F
Kiessling
From the Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany (S.A., P.H., E.K., F.-A.R., P.S., C.W., S.S., A.S.); Institute for Molecular Cardiovascular Research (S.A., A.S.), Department of Experimental Molecular Imaging (F.G., F.K.), and European Vascular Center Aachen-Maastricht (J.G., M.J.), RWTH Aachen University, Aachen, Germany; European Vascular Center Aachen-Maastricht, University Maastricht Medical Center, Maastricht, The Netherlands (J.G., M.J.); Cardiovascular Research Institute Maastricht, University Maastricht, Maastricht, The Netherlands (C.W.); and DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany (C.W., S.S., A.S.).
Christian
C
Weber
From the Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany (S.A., P.H., E.K., F.-A.R., P.S., C.W., S.S., A.S.); Institute for Molecular Cardiovascular Research (S.A., A.S.), Department of Experimental Molecular Imaging (F.G., F.K.), and European Vascular Center Aachen-Maastricht (J.G., M.J.), RWTH Aachen University, Aachen, Germany; European Vascular Center Aachen-Maastricht, University Maastricht Medical Center, Maastricht, The Netherlands (J.G., M.J.); Cardiovascular Research Institute Maastricht, University Maastricht, Maastricht, The Netherlands (C.W.); and DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany (C.W., S.S., A.S.).
Sabine
S
Steffens
From the Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany (S.A., P.H., E.K., F.-A.R., P.S., C.W., S.S., A.S.); Institute for Molecular Cardiovascular Research (S.A., A.S.), Department of Experimental Molecular Imaging (F.G., F.K.), and European Vascular Center Aachen-Maastricht (J.G., M.J.), RWTH Aachen University, Aachen, Germany; European Vascular Center Aachen-Maastricht, University Maastricht Medical Center, Maastricht, The Netherlands (J.G., M.J.); Cardiovascular Research Institute Maastricht, University Maastricht, Maastricht, The Netherlands (C.W.); and DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany (C.W., S.S., A.S.). aschober@med.lmu.de.
Andreas
A
Schober
D000818:Animals; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D054360:Chemokine CXCL1 / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000494:pharmacology; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D009000:Monocytes / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000235:genetics; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction
D018932:Chemokine CCL2; D054360:Chemokine CXCL1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008077:Lipoproteins, LDL; C549214:MIRN19A microRNA, human; D035683:MicroRNAs; D016376:Oligonucleotides, Antisense; C099252:oxidized low density lipoprotein
atherosclerosis; chemokines; endothelial cells; microRNAs