miR-322 regulates insulin signaling pathway and protects against metabolic syndrome-induced cardiac dysfunction in mice

• Published in: Biochimica et biophysica acta 2016-04, Vol.1862 (4), p.611-621
• Main Authors: Marchand, Alexandre, Atassi, Fabrice, Mougenot, Nathalie, Clergue, Michel, Codoni, Veronica, Berthuin, Jeremy, Proust, Carole, Trégouët, David-Alexandre, Hulot, Jean-Sébastien, Lompré, Anne-Marie
• Format: Article
• Language: English
• Subjects: Animals; Cardiomyopathy; Dependovirus; Dietary Fats - adverse effects; Dietary Fats - pharmacology; Genetic Vectors; Heart Diseases - genetics; Heart Diseases - metabolism; Heart Diseases - pathology; Heart Diseases - therapy; High fat diet; Humans; Hyperinsulinism - genetics; Hyperinsulinism - metabolism; Hyperinsulinism - pathology; Hyperinsulinism - therapy; Hyperlipidemias - genetics; Hyperlipidemias - metabolism; Hyperlipidemias - pathology; Hyperlipidemias - therapy; Insulin - genetics; Insulin - metabolism; Insulin pathway; Male; Metabolic syndrome; Metabolic Syndrome - genetics; Metabolic Syndrome - metabolism; Metabolic Syndrome - pathology; Metabolic Syndrome - therapy; Mice; Mice, Obese; MicroRNA; MicroRNAs - biosynthesis; MicroRNAs - genetics; Rats; Rats, Wistar; Signal Transduction; Transduction, Genetic
• ISSN: 0925-4439; 0006-3002; 1879-260X
• DOI: 10.1016/j.bbadis.2016.01.010

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. [Display omitted] •miR-322 targets key receptors of insulin signaling pathway and sirtuin 4.•miR-322 over-expression protects the heart from high fat diet consequences.•miR-322 inhibition induces cardiac dysfunction in control diet fed and ob/ob mice•miR-322 promotes mitochondrial respiratory chain and fatty acid metabolism genes.