Network-based predictions of in vivo cardiac hypertrophy

Journal of Molecular and Cellular Cardiology
Deborah U FrankJeffrey J Saucerman

Abstract

Cardiac hypertrophy is a common response of cardiac myocytes to stress and a predictor of heart failure. While in vitro cell culture studies have identified numerous molecular mechanisms driving hypertrophy, it is unclear to what extent these mechanisms can be integrated into a consistent framework predictive of in vivo phenotypes. To address this question, we investigate the degree to which an in vitro-based, manually curated computational model of the hypertrophy signaling network is able to predict in vivo hypertrophy of 52 cardiac-specific transgenic mice. After minor revisions motivated by in vivo literature, the model concordantly predicts the qualitative responses of 78% of output species and 69% of signaling intermediates within the network model. Analysis of four double-transgenic mouse models reveals that the computational model robustly predicts hypertrophic responses in mice subjected to multiple, simultaneous perturbations. Thus the model provides a framework with which to mechanistically integrate data from multiple laboratories and experimental systems to predict molecular regulation of cardiac hypertrophy.

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Citations

May 30, 2019·Journal of Biomechanical Engineering·Colleen Witzenburg, Jeffrey W Holmes
Sep 25, 2020·Biomechanics and Modeling in Mechanobiology·Ana C EstradaJeffrey W Holmes
Jan 27, 2019·Nature Reviews. Cardiology·Jeffrey J SaucermanJeffrey H Omens
Dec 19, 2020·PLoS Computational Biology·Ali KhalilimeybodiJeffrey J Saucerman
Jul 24, 2020·Progress in Biophysics and Molecular Biology·Kyoko Yoshida, Jeffrey W Holmes
Feb 12, 2021·CPT: Pharmacometrics & Systems Pharmacology·Angela C ZeiglerJeffrey J Saucerman
Mar 6, 2021·Journal of Molecular and Cellular Cardiology·Monika E GrabowskaJeffrey J Saucerman
Jan 26, 2022·Expert Opinion on Therapeutic Targets·Alexander J WinkleThomas J Hund

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