MiR-216a: a link between endothelial dysfunction and autophagy.
Endothelial dysfunction and impaired autophagic activity have a crucial role in aging-related diseases such as cardiovascular dysfunction and atherosclerosis. We have identified miR-216a as a microRNA that is induced during endothelial aging and, according to the computational analysis, among its targets includes two autophagy-related genes, Beclin1 (BECN1) and ATG5. Therefore, we have evaluated the role of miR-216a as a molecular component involved in the loss of autophagic function during endothelial aging. The inverse correlation between miR-216a and autophagic genes was conserved during human umbilical vein endothelial cells (HUVECs) aging and in vivo models of human atherosclerosis and heart failure. Luciferase experiments indicated BECN1, but not ATG5 as a direct target of miR-216a. HUVECs were transfected in order to modulate miR-216a expression and stimulated with 100 μg/ml oxidized low-density lipoprotein (ox-LDL) to induce a stress repairing autophagic process. We found that in young HUVECs, miR-216a overexpression repressed BECN1 and ATG5 expression and the ox-LDL induced autophagy, as evaluated by microtubule-associated protein 1 light chain 3 (LC3B) analysis and cytofluorimetric assay. Moreover, miR-216a stimulated ox-LDL accumulation and monocyte adhesion in HUVECs. Conversely, inhibition of miR-216a in old HUVECs rescued the ability to induce a protective autophagy in response to ox-LDL stimulus. In conclusion, mir-216a controls ox-LDL induced autophagy in HUVECs by regulating intracellular levels of BECN1 and may have a relevant role in the pathogenesis of cardiovascular disorders and atherosclerosis.
Department of Systems Medicine, University of Rome 'Tor Vergata', Rome, Italy.
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Menghini
Department of Systems Medicine, University of Rome 'Tor Vergata', Rome, Italy.
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Casagrande
Department of Systems Medicine, University of Rome 'Tor Vergata', Rome, Italy.
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Marino
Department of Systems Medicine, University of Rome 'Tor Vergata', Rome, Italy.
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Marchetti
Department of Systems Medicine, University of Rome 'Tor Vergata', Rome, Italy.
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Cardellini
Department of Systems Medicine, University of Rome 'Tor Vergata', Rome, Italy.
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Stoehr
Department of Systems Medicine, University of Rome 'Tor Vergata', Rome, Italy.
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Rizza
Department of Biopathology and Imaging, University of Rome 'Tor Vergata', Rome, Italy.
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Martelli
Molecular Cardiology Laboratory, IRCCS-Policlinico San Donato, Milan, Italy.
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Greco
Department of Biopathology and Imaging, University of Rome 'Tor Vergata', Rome, Italy.
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Mauriello
Department of Biopathology and Imaging, University of Rome 'Tor Vergata', Rome, Italy.
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Ippoliti
Molecular Cardiology Laboratory, IRCCS-Policlinico San Donato, Milan, Italy.
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Martelli
Department of Systems Medicine, University of Rome 'Tor Vergata', Rome, Italy.
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Lauro
Department of Systems Medicine, University of Rome 'Tor Vergata', Rome, Italy.
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Federici
D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism
C502778:ATG5 protein, human; D051017:Apoptosis Regulatory Proteins; D000071187:Autophagy-Related Protein 5; C491997:BECN1 protein, human; D000071186:Beclin-1; D008077:Lipoproteins, LDL; C575482:MIRN216 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; D008869:Microtubule-Associated Proteins; C099252:oxidized low density lipoprotein