Combining experimental and mathematical modeling to reveal mechanisms of macrophage-dependent left ventricular remodeling

Yu Fang Jin, Hai Chao Han, Jamie Berger, Qiuxia Dai, Merry L. Lindsey

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Background: Progressive remodeling of the left ventricle (LV) following myocardial infarction (MI) can lead to congestive heart failure, but the underlying initiation factors remain poorly defined. The objective of this study, accordingly, was to determine the key factors and elucidate the regulatory mechanisms of LV remodeling using integrated computational and experimental approaches.Results: By examining the extracellular matrix (ECM) gene expression and plasma analyte levels in C57/BL6J mice LV post-MI and ECM gene responses to transforming growth factor (TGF-β1) in cultured cardiac fibroblasts, we found that key factors in LV remodeling included macrophages, fibroblasts, transforming growth factor-β1, matrix metalloproteinase-9 (MMP-9), and specific collagen subtypes. We established a mathematical model to study LV remodeling post-MI by quantifying the dynamic balance between ECM construction and destruction. The mathematical model incorporated the key factors and demonstrated that TGF-β1 stimuli and MMP-9 interventions with different strengths and intervention times lead to different LV remodeling outcomes. The predictions of the mathematical model fell within the range of experimental measurements for these interventions, providing validation for the model.Conclusions: In conclusion, our results demonstrated that the balance between ECM synthesis and degradation, controlled by interactions of specific key factors, determines the LV remodeling outcomes. Our mathematical model, based on the balance between ECM construction and destruction, provides a useful tool for studying the regulatory mechanisms and for predicting LV remodeling outcomes.

Original languageEnglish (US)
Article number60
JournalBMC systems biology
Volume5
DOIs
StatePublished - May 5 2011

Fingerprint

Remodeling
Macrophage
Ventricular Remodeling
Left Ventricle
Macrophages
Mathematical Modeling
Extracellular Matrix
Dependent
Myocardial Infarction
Theoretical Models
Mathematical models
Mathematical Model
Matrix Metalloproteinase 9
Transforming Growth Factors
Fibroblasts
Growth Factors
Fibroblast Growth Factor 1
Peptide Initiation Factors
Congestive Heart Failure
Collagen

ASJC Scopus subject areas

  • Structural Biology
  • Modeling and Simulation
  • Molecular Biology
  • Computer Science Applications
  • Applied Mathematics

Cite this

Combining experimental and mathematical modeling to reveal mechanisms of macrophage-dependent left ventricular remodeling. / Jin, Yu Fang; Han, Hai Chao; Berger, Jamie; Dai, Qiuxia; Lindsey, Merry L.

In: BMC systems biology, Vol. 5, 60, 05.05.2011.

Research output: Contribution to journalArticle

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