Factors involved in extracellular matrix turnover in human derived cardiomyocytes.

Abstract

BACKGROUND:

The molecular mechanisms by which myocardial ischemia translates into ventricular remodeling remain unclear.

METHODS:

We investigated whether hypoxia and proinflammatory cytokines are specific inducers of remodeling signals in an in vitro model of cultured adult human ventricular myocytes (AC16 cells).

RESULTS:

Hypoxia modified the ratio of matrix remodeling factors by increasing the aminoterminal propeptide of type III procollagen (PIIINP) and reducing tissue inhibitor of matrix metalloproteinase type 1 (TIMP-1) secretion in AC16 cells. These effects, however, were not associated with either modifications in expression of matrix metalloproteinase type 2, collagen-I or metalloproteinase activity. Hypoxia does, actually increase the production of the cardiac antifibrogenic growth factors, Apelin and VEGF, through an Hypoxia Inducible Factor type 1-dependent mechanism. Concerning proinflammatory signaling pathways, IL1β emerged as a powerful inducer of matrix turnover, since it significantly enhanced PIIINP, TIMP-1 and hyaluronic acid production and increased metalloproteinase activity. In contrast, TNFα did not modify matrix turnover but markedly induced the production of Apelin and VEGF.

CONCLUSION:

Hypoxia and increased TNFα activity likely exert cardioprotective actions by activating the cardiac antifibrogenic factors Apelin and VEGF. In contrast, IL1β is a strong promoter of interstitial collagen remodeling that may contribute to ventricular dilation and heart failure in the ischemic myocardium.

• Authors: Gregori Casals, Guillermo Fernández-Varo, Pedro Melgar-Lesmes, Santi Marfà, Vedrana Reichenbach, Manuel Morales-Ruiz, Wladimiro Jiménez
• Journal: Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology (Cell Physiol Biochem) Vol. 32 Issue 5 Pg. 1125-36 ( 2013) ISSN: 1421-9778 [Electronic] Germany
• PMID: 24247107 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 S. Karger AG, Basel.

Chemical References

• APLN protein, human
• Apelin
• Collagen Type III
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Intercellular Signaling Peptides and Proteins
• Interleukin-1beta
• TIMP1 protein, human
• Tissue Inhibitor of Metalloproteinase-1
• Tumor Necrosis Factor-alpha
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• Matrix Metalloproteinase 2

Topics

• Apelin
• Cell Hypoxia (physiology)
• Cells, Cultured
• Collagen Type III (genetics, metabolism)
• Extracellular Matrix (metabolism)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Intercellular Signaling Peptides and Proteins (genetics, metabolism)
• Interleukin-1beta (metabolism)
• Matrix Metalloproteinase 2 (genetics, metabolism)
• Myocytes, Cardiac (metabolism, pathology)
• Tissue Inhibitor of Metalloproteinase-1 (genetics, metabolism)
• Tumor Necrosis Factor-alpha (metabolism)
• Vascular Endothelial Growth Factor A (genetics, metabolism)
• Ventricular Remodeling (physiology)