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

Christoph D Rau; Milagros C Romay; Mary Tuteryan; Jessica J-C Wang; Marc Santolini; Shuxun Ren; Alain Karma; James N Weiss; Yibin Wang; Aldons J Lusis

doi:10.1016/j.cels.2016.10.016

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

Cell Syst. 2017 Jan 25;4(1):121-128.e4. doi: 10.1016/j.cels.2016.10.016. Epub 2016 Nov 17.

Authors

Affiliations

¹ Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Departments of Anesthesiology, Physiology, and Medicine, Cardiovascular Research Laboratories, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
² Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
³ Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁴ Center for Interdisciplinary Research on Complex Systems, Department of Physics, Northeastern University, Boston, MA 02115, USA.
⁵ Departments of Anesthesiology, Physiology, and Medicine, Cardiovascular Research Laboratories, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁶ Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: jlusis@mednet.ucla.edu.

Abstract

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.

Keywords: MICA; causal modeling; gene network; siRNA mediated knockdown; ventricular myocytes.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

ADAMTS Proteins / genetics*
ADAMTS Proteins / physiology
Animals
Cardiomegaly / chemically induced
Cardiomegaly / genetics*
Cardiomyopathies / genetics
Cardiomyopathies / metabolism
Cardiomyopathies / physiopathology
Cardiotonic Agents / adverse effects
Catecholamines / adverse effects
Gene Expression Regulation / drug effects
Gene Regulatory Networks / genetics
Heart Failure / genetics
Heart Ventricles / metabolism
Isoproterenol / pharmacology
Mice
Mice, Inbred Strains / genetics
Myocardium / metabolism
Myocytes, Cardiac / metabolism
Signal Transduction / drug effects
Systems Biology / methods*
Ventricular Remodeling / genetics

Substances

Cardiotonic Agents
Catecholamines
ADAMTS Proteins
Adamts2 protein, mouse
Isoproterenol

Abstract

Publication types

MeSH terms

Substances

Grants and funding