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Differential Expression of Dicer, miRNAs, and Inflammatory Markers in Diabetic Ins2+/− Akita Hearts

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Abstract

Diabetic cardiomyopathy is a leading cause of morbidity and mortality, and Insulin2 mutant (Ins2+/−) Akita is a genetic mice model of diabetes relevant to humans. Dicer, miRNAs, and inflammatory cytokines are associated with heart failure. However, the differential expression of miRNAs, dicer, and inflammatory molecules are not clear in diabetic cardiomyopathy of Akita. We measured the levels of miRNAs, dicer, pro-inflammatory tumor necrosis factor alpha (TNFα), and anti-inflammatory interleukin 10 (IL-10) in C57BL/6J (WT) and Akita hearts. The results revealed increased heart to body weight ratio and robust expression of brain natriuretic peptide (BNP: a hypertrophy marker) suggesting cardiac hypertrophy in Akita. The multiplex RT-PCR, qPCR, and immunoblotting showed up regulation of dicer, whereas miRNA array elicited spread down regulation of miRNAs in Akita including dramatic down regulation of let-7a, miR-130, miR-142-3p, miR-148, miR-338, miR-345-3p, miR-384-3p, miR-433, miR-450, miR-451, miR-455, miR-494, miR-499, miR-500, miR-542-3p, miR-744, and miR-872. Conversely, miR-295 is induced in Akita. Cardiac TNFα is upregulated at mRNA (RT-PCR and qPCR), protein (immunoblotting), and cellular (immunohistochemistry and confocal microscopy) levels, and is robust in hypertrophic cardiomyocytes suggesting direct association of TNFα with hypertrophy. Contrary to TNFα, cardiac IL-10 is downregulated in Akita. In conclusion, induction of dicer and TNFα, and attenuation of IL-10 and majority of miRNA are associated with cardiomyopathy in Akita and could be used for putative therapeutic target for heart failure in diabetics.

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Acknowledgments

The financial supports from American Heart Association Grant (11BGIA 7690055) and National Institute of Health (HL-113281) to P.K.M. and National Institute of Health (HL-108621 and HL-74185) to S.C.T. is gratefully acknowledged.

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  1. Department of Cellular & Integrative Physiology, University of Nebraska Medical Center, 985850 Nebraska Medical Center, Omaha, NE, 68198, USA

    Vishalakshi Chavali & Paras Kumar Mishra

  2. Department of Physiology & Biophysics, School of Medicine, University of Louisville, Louisville, KY, 40202, USA

    Suresh C. Tyagi

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  1. Vishalakshi Chavali
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Correspondence to Vishalakshi Chavali or Paras Kumar Mishra.

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Chavali, V., Tyagi, S.C. & Mishra, P.K. Differential Expression of Dicer, miRNAs, and Inflammatory Markers in Diabetic Ins2+/− Akita Hearts. Cell Biochem Biophys 68, 25–35 (2014). https://doi.org/10.1007/s12013-013-9679-4

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