Genome wide transcriptional alterations during post-infarct remodeling in type 2 diabetic mice.

The cellular and molecular aspects of post-infarct left-ventricle remodeling in presence of type-2 diabetes is poorly understood. In this study we have addressed the cellular and molecular aspects underlying post-infarct left-ventricle remodeling in type 2 diabetic (T2DM) mice using genome-wide mRNA-sequencing. Myocardial infarction was induced by ligating left-anterior descending artery (LAD) in 12-14 month old T2DM and control mice. Cardiac MRI was performed at baseline, day 7 and 14 post-LAD ligation. Blood and tissue samples were collected for biochemical and immunohistochemical, molecular biology analysis after sacrification at day 7 and 14. Genome-wide mRNA sequencing analysis was performed from left-ventricular tissues collected at day 7 post-LAD ligation. Mitochondrial dynamics, Leukocyte recruitment and Collagen I deposition were analyzed using electron microscopy, fluorescent assisted cell sorting (FACS) and fourier-transform infra-red (FTIR) spectroscopy from left ventricular tissues collected at day 7 and 14 post-LAD ligation. Cardiac ejection fraction (EF) and stroke volume (SV) were significantly reduced along with increased mortality in T2DM compared to controls. Ingenuity pathway analyses of differentially expressed genes were enriched for mitochondrial dysfunction, TCA cycle and fatty acid oxidation. Additionally, upstream transcription factor analysis showed inhibition of PGC1a, PGC1b, ESRRA, ESRRB and TFAM in infarcted myocardium of T2DM mice. Electron microscopy analysis showed an altered mitochondrial dynamics and cardiomyocyte death in ischemic myocardium of T2DM mice. Leukocytes exhibited an altered phenotype in ischemic myocardium of T2DM mice. Neovascularization was impaired and collagen deposition was increased in ischemic myocardium of T2DM mice. We conclude that an altered mitochondrial dynamics, cell death modalities, leukocyte phenotype, neovascularization responses and fibrosis may contribute to an increased mortality after myocardial infarction in T2DM. Modulation of mitochondrial dynamics and cardiomyocyte cell death modalities may offer a novel therapeutic target. Overall design: Myocardial infarction was induced by ligating left anterior descending artery (LAD). Total RNA was isolated from remote, Infarct and border zones at day 7 after myocardial infarction. Poly (A)+RNA fraction was subjected to RNA sequencing using Illumina HiSeq.

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Durga Devi T, Babu M, Mäkinen P, Kaikkonen MU, Heinaniemi M, Laakso H, Ylä-Herttuala E, Rieppo L, Liimatainen T, Naumenko N, Tavi P, Ylä-Herttuala S