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MiR-216a: a link between endothelial dysfunction and autophagy.

ABSTRACT: 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??g/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.

SUBMITTER: Menghini R

PROVIDER: S-EPMC4040670 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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MiR-216a: a link between endothelial dysfunction and autophagy.

Menghini R R Casagrande V V Marino A A Marchetti V V Cardellini M M Stoehr R R Rizza S S Martelli E E Greco S S Mauriello A A Ippoliti A A Ippoliti A A Martelli F F Lauro R R Federici M M

Cell death & disease 20140130

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 endo ...[more]

PMID: 24481443

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Project description:Background: Cellular communication among different types of vascular cells is indispensable for maintenance of vascular homeostasis and prevention of atherosclerosis (AS). However, the biological mechanism involved in cellular communication among these cells and whether this biological mechanism can be used to treat AS remain unknown. This study hypothesizes that endothelial autophagy mediates the cellular communication of vascular tissue through exosome-mediated delivery of AS-related genes.Methods: ApoE-/- mice fed with high-fat diet (HFD) were received rapamycin to activate autophagy, or were intravenously injected with adeno-associated virus (AAV) vectors carrying shRNA against Atg7 mRNA under the Tie (tyrosine kinase) promoter to specifically inhibit endothelial autophagy. miRNA microarray, in vivo and in vitro experiments and human vascular tissues/blood vessels were used to explore the molecular mechanisms of atheroprotective effect of endothelial autophagy. Exosomes were isolated and characterized. Immunofluorescence and exosomes coculture experiments were conducted to examine the role of endothelial autophagy in regulating communication between endothelial cells (ECs) and smooth muscle cells (SMCs) via exosome.Results: Endothelial autophagy was inhibited in ECs of thoracic aortas in HFD fed ApoE-/- mice. Furthermore, rapamycin alleviated HFD-triggered atherosclerotic burden and endothelial dysfunction, while endothelial-specific depletion of Atg7 aggravated atherosclerotic burden. miRNA microarray, in vivo and in vitro experiments and human vascular tissues analysis revealed that endothelial autophagy alleviated endothelial dysfunction by downregulating miR-204-5p expression by directly targeting BCL2 to regulate apoptosis in ECs. Moreover, endothelial autophagy decreased miR-204-5p expression by loading this molecule into multivesicular bodies and secreting them out of cells via exosomes, and ECs-derived exosomal miR-204-5p could be transferred to SMCs, antagonized SMCs calcification.Conclusions: Our study first revealed that endothelial autophagy was a critical regulator of atherogenesis by transferring miR-204-5p from ECs to SMCs by exosomes, and endothelial autophagy activation by rapamycin, could alleviate AS in a “one stone hit two birds” manner.

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MiR-216a: a link between endothelial dysfunction and autophagy.

Publications

MiR-216a: a link between endothelial dysfunction and autophagy.

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