Systems Genetics Approach Identifies Gene Pathways and Adamts2 as Drivers of Isoproterenol-Induced Cardiac Hypertrophy and Cardiomyopathy in Mice.

Journal Article (Journal Article)

We previously reported a genetic analysis of heart failure traits in a population of inbred mouse strains treated with isoproterenol to mimic catecholamine-driven cardiac hypertrophy. Here, we apply a co-expression network algorithm, wMICA, to perform a systems-level analysis of left ventricular transcriptomes from these mice. We describe the features of the overall network but focus on a module identified in treated hearts that is strongly related to cardiac hypertrophy and pathological remodeling. Using the causal modeling algorithm NEO, we identified the gene Adamts2 as a putative regulator of this module and validated the predictive value of NEO using small interfering RNA-mediated knockdown in neonatal rat ventricular myocytes. Adamts2 silencing regulated the expression of the genes residing within the module and impaired isoproterenol-induced cellular hypertrophy. Our results provide a view of higher order interactions in heart failure with potential for diagnostic and therapeutic insights.

Full Text

Duke Authors

Cited Authors

  • Rau, CD; Romay, MC; Tuteryan, M; Wang, JJ-C; Santolini, M; Ren, S; Karma, A; Weiss, JN; Wang, Y; Lusis, AJ

Published Date

  • January 25, 2017

Published In

Volume / Issue

  • 4 / 1

Start / End Page

  • 121 - 128.e4

PubMed ID

  • 27866946

Pubmed Central ID

  • PMC5338604

International Standard Serial Number (ISSN)

  • 2405-4712

Digital Object Identifier (DOI)

  • 10.1016/j.cels.2016.10.016

Language

  • eng

Conference Location

  • United States