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Biochim Biophys Acta. 2016 Apr;1862(4):611-621. doi: 10.1016/j.bbadis.2016.01.010. Epub 2016 Jan 13.

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

Author information

1
Institute for Cardiometabolism and Nutrition (ICAN), Paris F-75013, France.
2
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.
3
PECMV Platform, Sorbonne Universités, UPMC Univ Paris 06, Paris F-75013, France.
4
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.

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.

KEYWORDS:

Cardiomyopathy; High fat diet; Insulin pathway; Metabolic syndrome; MicroRNA

PMID:
26775030
DOI:
10.1016/j.bbadis.2016.01.010
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