title: miR-322 regulates insulin signaling pathway and protects against metabolic syndrome-induced cardiac dysfunction in mice.
abstract: We identified murine miR-322, orthologous to human miR-424, as a new regulator of insulin receptor, IGF-1 receptor and sirtuin 4 mRNA in vitro and in vivo in the heart and found that miR-322/424 is highly expressed in the heart of mice. C57Bl/6N mice fed 10weeks of high fat diet (HFD) presented signs of cardiomyopathy and a stable miR-322 cardiac level while cardiac function was slightly affected in 11week-old ob/ob which overexpressed miR-322. We thus hypothesized that mmu-miR-322 could be protective against cardiac consequences of hyperinsulinemia and hyperlipidemia. We overexpressed or knocked-down mmu-miR-322 using AAV9 and monitored cardiac function in wild-type C57Bl/6N mice fed a control diet (CD) or a HFD and in ob/ob mice. The fractional shortening progressively declined while the left ventricle systolic diameter increased in HFD mice infected with an AAVcontrol or with an AAVsponge (decreasing miR-322 bioavailability) but also in ob/ob mice infected with AAVsponge. Similar observations were also found in CD-fed mice infected with AAVsponge. On the contrary over-expressing miR-322 with AAVmiR-322 was efficient in protecting the heart from HFD effects in C57Bl/6N mice. This cardioprotection could be associated with the regulation of identified targets IGF1R, INSR and CD1, a decrease in insulin signaling pathway and an enrichment of genes involved in mitochondrial function and fatty acid oxidation as demonstrated by transcriptome analysis. Altogether, these results emphasize miR-322 as a new potential therapeutic target against cardiac consequences of metabolic syndrome, which represents an increasing burden in the western countries.
authors.affiliation: Institute for Cardiometabolism and Nutrition (ICAN), Paris F-75013, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Marchand
authors.affiliation: Institute for Cardiometabolism and Nutrition (ICAN), Paris F-75013, France; INSERM UMR-S 1166, Paris F-75013, France; Sorbonne Universités, Université Pierre et Marie Curie -UPMC Univ Paris 06, UMR-S 1166, Paris F-75013, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Atassi
authors.affiliation: PECMV Platform, Sorbonne Universités, UPMC Univ Paris 06, Paris F-75013, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Mougenot
authors.affiliation: Institute for Cardiometabolism and Nutrition (ICAN), Paris F-75013, France; INSERM UMR-S 1166, Paris F-75013, France; Sorbonne Universités, Université Pierre et Marie Curie -UPMC Univ Paris 06, UMR-S 1166, Paris F-75013, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Clergue
authors.affiliation: Institute for Cardiometabolism and Nutrition (ICAN), Paris F-75013, France; INSERM UMR-S 1166, Paris F-75013, France; Sorbonne Universités, Université Pierre et Marie Curie -UPMC Univ Paris 06, UMR-S 1166, Paris F-75013, France.
authors.forename: Veronica
authors.initials: V
authors.lastname: Codoni
authors.affiliation: Institute for Cardiometabolism and Nutrition (ICAN), Paris F-75013, France; INSERM UMR-S 1166, Paris F-75013, France; Sorbonne Universités, Université Pierre et Marie Curie -UPMC Univ Paris 06, UMR-S 1166, Paris F-75013, France.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Berthuin
authors.affiliation: Institute for Cardiometabolism and Nutrition (ICAN), Paris F-75013, France; INSERM UMR-S 1166, Paris F-75013, France; Sorbonne Universités, Université Pierre et Marie Curie -UPMC Univ Paris 06, UMR-S 1166, Paris F-75013, France.
authors.forename: Carole
authors.initials: C
authors.lastname: Proust
authors.affiliation: Institute for Cardiometabolism and Nutrition (ICAN), Paris F-75013, France; INSERM UMR-S 1166, Paris F-75013, France; Sorbonne Universités, Université Pierre et Marie Curie -UPMC Univ Paris 06, UMR-S 1166, Paris F-75013, France.
authors.forename: David-Alexandre
authors.initials: DA
authors.lastname: Trégouët
authors.affiliation: Institute for Cardiometabolism and Nutrition (ICAN), Paris F-75013, France; INSERM UMR-S 1166, Paris F-75013, France; Sorbonne Universités, Université Pierre et Marie Curie -UPMC Univ Paris 06, UMR-S 1166, Paris F-75013, France.
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Hulot
authors.affiliation: Institute for Cardiometabolism and Nutrition (ICAN), Paris F-75013, France; INSERM UMR-S 1166, Paris F-75013, France; Sorbonne Universités, Université Pierre et Marie Curie -UPMC Univ Paris 06, UMR-S 1166, Paris F-75013, France. Electronic address: anne-marie.lompre@upmc.fr.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Lompré
mesh_terms: D000818:Animals; D000229:Dependovirus; D004041:Dietary Fats / Q000009:adverse effects / Q000494:pharmacology; D005822:Genetic Vectors; D006331:Heart Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D006801:Humans; D006946:Hyperinsulinism / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D006949:Hyperlipidemias / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D008297:Male; D024821:Metabolic Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D051379:Mice; D008820:Mice, Obese; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D014161:Transduction, Genetic
chemical_list: D004041:Dietary Fats; D007328:Insulin; C582672:MIRN322 microRNA, mouse; C585349:MIRN322 microRNA, rat; D035683:MicroRNAs
keywords: Cardiomyopathy; High fat diet; Insulin pathway; Metabolic syndrome; MicroRNA