Abstract 128: Network-based Approaches to Identify Novel Regulators of Heart Failure
Heart failure is a highly heterogeneous disorder characterized by the interactions of multiple environmental and genetic factors. While reductionistic approaches have made significant inroads into characterizing the pathophysiology of the syndrome, they are unable to properly dissect the complex interactions between sets of genes and pathways which result in the emergent phenotypes . Systems genetics offers a means by which these interactions may be identified and explored. We have developed a resource, the Hybrid Mouse Diversity Panel (HMDP) to perform systems-level analyses in mice. Nine week old female mice from 93 unique inbred lines of the HMDP were give 30 ug/g/day of isoproterenol through an abdominally implanted Alzet micropump. After three weeks, mice were sacrificed along with age-matched controls. A portion of the left ventricle was arrayed on an Illumina Mouse Ref 8.0 platform.
Maximal Information Component Analysis was used to construct gene networks, and a module of 41 genes was identified which shows strong correlation to a number of important phenotypic traits, including heart weight and cardiac fibrosis. This module contains a number of genes of interest, including Lgals3, a diagnostic marker for heart failure. Through the use of structural equation modeling, we identified several key genes within the module for further analysis, the most important of which is the metalloprotease Adamts2.
We have performed a series of in vitro analyses demonstrating the important role of Adamts2 in this module using neonatal rat ventricular myocytes. Knockout of Adamts2 results in an amelioration of the hypertrophic response to catecholamine stimulation as well as a reduction of hypertrophic markers such as Nppa and Nppb. Furthermore, we observe that other genes in the module no longer respond to catecholamine stimulation after knockdown of Adamts2.
Author Disclosures: C.D. Rau: None. M.C. Romay: None. J. Wang: None. S. Ren: None. Y. Wang: None. A.J. Lusis: None.
- © 2015 by American Heart Association, Inc.