Systems Genetics Approach Identifies Gene Pathways and Adamts2 as Drivers of Isoproterenol-Induced Cardiac Hypertrophy and Cardiomyopathy in Mice
By Christoph D. Rau, Milagros C. Romay, Mary Tuteryan, Jessica J Wang, Marc Santolini, Shuxun Ren, Alain Karma, J. Weiss, Yibin Wang, Aldons J. Lusis. 2016
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SUMMARY 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.
Subfields: Cardiology and Cardiovascular Medicine, Molecular Biology, Physiology
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Citations in the corpus
- A Disintegrin and Metalloproteinase (ADAM) and ADAM with Thrombospondin Motifs (ADAMTS) Family in Vascular Biology and Disease (2019, background): “ADAMTS-2 has been implicated in the pathogenesis of cardiac hypertrophy and cardiomyopathy [166].”