Endothelin-1-mediated vasoconstriction alters cerebral gene expression in iron homeostasis and eicosanoid metabolism

Justin S. Bickford, Department of Neuroscience, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL 32610, USA; Departments of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
Narjis F. Ali, Department of Neurology, McKnight Brain Institute, College of Medicine, University of Florida, PO Box 100296 Gainesville, FL 32610, USA.
Jerelyn A. Nick, Department of Neurology, McKnight Brain Institute, College of Medicine, University of Florida, PO Box 100296 Gainesville, FL 32610, USA.
Musab Al-Yahia, Department of Neurology, McKnight Brain Institute, College of Medicine, University of Florida, PO Box 100296 Gainesville, FL 32610, USA.
Dawn E. Beachy, Department of Neuroscience, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
Sylvain Doré, Department of Neuroscience, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL 32610, USA; Anesthesiology, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
Harry S. Nick, Department of Neuroscience, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL 32610, USA; Departments of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
Michael F. Waters, Department of Neuroscience, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL 32610, USA; Department of Neurology, McKnight Brain Institute, College of Medicine, University of Florida, PO Box 100296 Gainesville, FL 32610, USA. Electronic address: mwaters@neurology.ufl.edu.

Document Type

Article

Abstract

Endothelins are potent vasoconstrictors and signaling molecules. Their effects are broad, impacting processes ranging from neurovascular and cardiovascular health to cell migration and survival. In stroke, traumatic brain injury or subarachnoid hemorrhage, endothelin-1 (ET-1) is induced resulting in cerebral vasospasm, ischemia, reperfusion and the activation of various pathways. Given the central role that ET-1 plays in these patients and to identify the downstream molecular events specific to transient vasoconstriction, we studied the consequences of ET-1-mediated vasoconstriction of the middle cerebral artery in a rat model. Our observations demonstrate that ET-1 can lead to increases in gene expression, including genes associated with the inflammatory response (Ifnb, Il6, Tnf) and oxidative stress (Hif1a, Myc, Sod2). We also observed inductions (>2 fold) of genes involved in eicosanoid biosynthesis (Pla2g4a, Pla2g4b, Ptgs2, Ptgis, Alox12, Alox15), heme metabolism (Hpx, Hmox1, Prdx1) and iron homeostasis (Hamp, Tf). Our findings demonstrate that mRNA levels for the hormone hepcidin (Hamp) are induced in the brain in response to ET-1, providing a novel target in the treatment of multiple conditions. These changes on the ipsilateral side were also accompanied by corresponding changes in a subset of genes in the contralateral hemisphere. Understanding ET-1-mediated events at the molecular level may lead to better treatments for neurological diseases and provide significant impact on neurological function, morbidity and mortality.

Keywords

Eicosanoid, Focal ischemia, Gene expression, Iron homeostasis

Medical Subject Headings

Animals; Apoptosis (physiology); Brain (pathology, physiopathology); Brain Ischemia (pathology, physiopathology); Disease Models, Animal; Eicosanoids (biosynthesis); Endothelin-1 (administration & dosage); Gene Expression (drug effects); Homeostasis (physiology); Iron (metabolism); Iron-Sulfur Proteins (metabolism); Male; Middle Cerebral Artery (drug effects, physiopathology); Neuroimmunomodulation (physiology); Oxidative Stress (physiology); RNA, Messenger (metabolism); Random Allocation; Rats, Sprague-Dawley; Vasoconstriction (drug effects, physiology); Vasoconstrictor Agents (administration & dosage)

Publication Date

11-7-2014

Publication Title

Brain research

E-ISSN

1872-6240

Volume

1588

First Page

25

Last Page

36

PubMed ID

25230250

Digital Object Identifier (DOI)

10.1016/j.brainres.2014.09.022

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