Generating Ins2+/−/miR-133aTg Mice to Model miRNA-Driven Cardioprotection of Human Diabetic Heart

Hamid R. Shahshahan, Tyler N. Kambis, Sumit Kar, Santosh K. Yadav, Paras K. Mishra

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

Diabetes mellitus (DM) is caused either due to insulin deficiency (T1DM) or insulin resistance (T2DM). DM increases the risk of heart failure by diabetic cardiomyopathy (DMCM), a cardiac muscle disorder that leads to a progressive decline in diastolic function, and ultimately systolic dysfunction. Mouse models of T1DM and T2DM exhibit clinical signs of DMCM. Growing evidence implicates microRNA (miRNA), an endogenous, non-coding, regulatory RNA, in the pathogenesis and signaling of DMCM. Therefore, inhibiting deleterious miRNAs and mimicking cardioprotective miRNAs could provide a potential therapeutic intervention for DMCM. miRNA-133a (miR-133a) is a highly abundant miRNA in the human heart. It is a cardioprotective miRNA, which is downregulated in the DM heart. It has anti-hypertrophic and anti-fibrotic effects. miR-133a mimic treatment after the onset of early DMCM can reverse histological and clinical signs of the disease in mice. We hypothesized that overexpression of cardiac-specific miR-133a in Ins2+/− Akita (T1DM) mice can prevent progression of DMCM. Here, we describe a method to create and validate cardiac-specific Ins2+/−/miR-133aTg mice to determine whether cardiac-specific miR-133a overexpression prevents development of DMCM. These strategies demonstrate the value of genetic modeling of human disease such as DMCM and evaluate the potential of miRNA as a therapeutic intervention.

Original languageEnglish (US)
Title of host publicationMethods in Molecular Biology
PublisherHumana Press Inc.
Pages113-121
Number of pages9
DOIs
StatePublished - 2021

Publication series

NameMethods in Molecular Biology
Volume2224
ISSN (Print)1064-3745
ISSN (Electronic)1940-6029

Keywords

  • Akita
  • Cardiac physiology
  • Diabetes models
  • Tissue-specific transgenic mice

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics

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