Abstract
Although diabetes mellitus (DM) causes cardiomyopathy and exacerbates heart failure, the underlying molecular mechanisms for diabetic cardiomyopathy/heart failure are poorly understood. Insulin2 mutant (Ins2+/-) Akita is a mouse model of T1DM, which manifests cardiac dysfunction. However, molecular changes at cardiac transcriptome level that lead to cardiomyopathy remain unclear. To understand the molecular changes in the heart of diabetic Akita mice, we profiled cardiac transcriptome of Ins2+/- Akita and Ins2+/+ control mice using next generation sequencing (NGS) and microarray, and determined the implications of differentially expressed genes on various heart failure signaling pathways using Ingenuity pathway (IPA) analysis. First, we validated hyperglycemia, increased cardiac fibrosis, and cardiac dysfunction in twelve-week male diabetic Akita. Then, we analyzed the transcriptome levels in the heart. NGS analyses on Akita heart revealed 137 differentially expressed transcripts, where Bone Morphogenic Protein-10 (BMP10) was the most upregulated and hairy and enhancer of split-related (HELT) was the most downregulated gene. Moreover, twelve long non-coding RNAs (lncRNAs) were upregulated. The microarray analyses on Akita heart showed 351 differentially expressed transcripts, where vomeronasal-1 receptor-180 (Vmn1r180) was the most upregulated and WD Repeat Domain 83 Opposite Strand (WDR83OS) was the most downregulated gene. Further, miR-101c and H19 lncRNA were upregulated but Neat1 lncRNA was downregulated in Akita heart. Eleven common genes were upregulated in Akita heart in both NGS and microarray analyses. IPA analyses revealed the role of these differentially expressed genes in key signaling pathways involved in diabetic cardiomyopathy. Our results provide a platform to initiate focused future studies by targeting these genes and/or non-coding RNAs, which are differentially expressed in Akita hearts and are involved in diabetic cardiomyopathy.
Highlights
Insulin2 heterozygous (Ins2+/-) Akita mice is a spontaneous genetic model for type1 diabetes mellitus (T1DM) [1, 2]
Our results showed that both WT (140 base pair) and mutant (280 base pair) alleles were present in the Insulin2 heterozygous Akita mice (Fig 1A)
By using the filter criteria of twofold change and p< 0.05 value, we found a total of sixty-six differentially expressed non-coding RNAs in Akita heart by next generation sequencing (NGS) analyses, where twelve were long non-coding RNAs (Fig 4A)
Summary
Insulin heterozygous (Ins2+/-) Akita mice is a spontaneous genetic model for type diabetes mellitus (T1DM) [1, 2] They develop diabetic phenotype at the age of three-four weeks, and male mice show more severe phenotype than female mice [1]. At ten-week, male mice have elevated levels of blood glucose and glycohemoglobin (HbA1c) and reduced levels of insulin [3], the hallmarks of T1DM phenotype. They manifest progress in the diabetic complications including cardiomyopathy with aging, and die within 305 days, which is less than the half of the life span of non-diabetic mice (nearly 690 days) [1, 4]. Our goal was to determine the differential expressions of cardiac transcriptomes of Akita and to assess the potential roles of altered transcriptomes in molecular signaling leading to cardiomyopathy/heart failure
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