Hypoxia inhibits cardiomyocyte proliferation in fetal rat hearts via upregulating TIMP-4.

Abstract

Maternal hypoxia inhibits cardiomyocyte proliferation in the heart of fetal and neonatal rats. The present study tested the hypothesis that hypoxia has a direct effect inhibiting cardiomyocyte proliferation via upregulating tissue inhibitors of metalloproteinases (TIMP) in fetal rat hearts. Isolated fetal rat hearts and rat embryonic ventricular myocyte H9c2 cells were treated ex vivo with 20% or 1% O(2) for 48 or 24 h, respectively. Hypoxia caused a significant reduction in cardiomyocyte Ki-67 expression and bromodeoxyuridine incorporation in fetal hearts and H9c2 cells. In both fetal hearts and H9c2 cells, hypoxia resulted in a significant decrease in a cell division marker cyclin D2 but an increase in a cell division inhibitor p27. Additionally, hypoxia caused an upregulation of TIMP-3 and TIMP-4 in fetal hearts and H9c2 cells. Knockdown of TIMP-3 in H9c2 cells significantly increased cyclin D2 and Ki-67 and partially blocked the hypoxia-induced inhibition of cyclin D2 and Ki-67 in H9c2 cells. Unlike TIMP-3, TIMP-4 knockdown had no significant effects on the basal levels of cell proliferation but completely abrogated the hypoxia-mediated effects. These findings provide evidence of a novel causal role of TIMP-4 and TIMP-3 in the direct inhibitory effect of hypoxia on cardiomyocyte proliferation in the developing heart.

• Authors: Wenni Tong, Fuxia Xiong, Yong Li, Lubo Zhang
• Journal: American journal of physiology. Regulatory, integrative and comparative physiology (Am J Physiol Regul Integr Comp Physiol) Vol. 304 Issue 8 Pg. R613-20 (Apr 15 2013) ISSN: 1522-1490 [Electronic] United States
• PMID: 23427085 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antimetabolites
• Cyclin D2
• Ki-67 Antigen
• RNA, Small Interfering
• Tissue Inhibitor of Metalloproteinase-3
• Tissue Inhibitor of Metalloproteinases
• tissue inhibitor of metalloproteinase-4
• Cyclin-Dependent Kinase Inhibitor p27
• Bromodeoxyuridine

Topics

• Animals
• Antimetabolites
• Blotting, Western
• Bromodeoxyuridine
• Cell Line
• Cell Proliferation
• Cell Size
• Cyclin D2 (biosynthesis, physiology)
• Cyclin-Dependent Kinase Inhibitor p27 (biosynthesis)
• Female
• Fetal Heart (physiology)
• Fetal Hypoxia (pathology)
• Fluorescent Antibody Technique
• Ki-67 Antigen (biosynthesis)
• Myocytes, Cardiac (physiology)
• Pregnancy
• RNA, Small Interfering (genetics)
• Rats
• Rats, Sprague-Dawley
• Tissue Inhibitor of Metalloproteinase-3 (genetics, physiology)
• Tissue Inhibitor of Metalloproteinases (genetics, physiology)
• Transfection
• Up-Regulation (physiology)