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Updated: Dec 18, 2025
09:43
Measurement of Heme Synthesis Levels in Mammalian Cells
Published on: July 9, 2015
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Heme induces rapid endothelial barrier dysfunction via the MKK3/p38MAPK axis
Joel James1, Anup Srivastava1, Mathews Valuparampil Varghese1
1Division of Endocrinology, Department of Medicine, College of Medicine, University of Arizona, Tucson, AZ.
Blood
|June 18, 2020
Summary
Free heme damages endothelial barrier integrity by reducing key proteins and activating the p38MAPK/HSP27 pathway. Targeting this pathway may treat heme-induced diseases.
Area of Science:
- Endothelial Biology
- Molecular Pathology
- Cardiovascular Research
Background:
- Hemolysis and circulating free heme are linked to severe conditions like ARDS, ACS, and sepsis.
- The molecular mechanisms of heme-induced endothelial barrier disruption are not fully understood.
Purpose of the Study:
- To investigate the impact of free heme on endothelial barrier integrity.
- To elucidate the intracellular signaling mechanisms of heme-mediated endothelial dysfunction in human lung microvascular endothelial cells (HLMVECs).
Main Methods:
- HLMVECs were exposed to varying doses of heme to assess barrier integrity.
- Expression levels of tight junction proteins (zona occludens-1, claudin-1, claudin-5) were analyzed.
- The p38MAPK/HSP27 signaling pathway was investigated in HLMVECs and mice.
- Mice with MKK3 knockout (KO) were used to evaluate the role of the p38MAPK pathway.
Main Results:
- Heme dose-dependently decreased endothelial barrier integrity in HLMVECs.
- Heme exposure significantly reduced tight junction proteins zona occludens-1, claudin-1, and claudin-5.
- The p38MAPK/HSP27 pathway was significantly altered by heme treatment in cells and mice.
- MKK3 KO mice showed reduced heme-induced endothelial barrier dysfunction.
Conclusions:
- Free heme disrupts endothelial barrier integrity by affecting tight junction proteins.
- The p38MAPK/HSP27 pathway plays a critical role in heme-mediated endothelial barrier dysfunction.
- Targeting the p38MAPK pathway could be a therapeutic strategy for hemolytic diseases.
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