Myeloperoxidase is increased in human cerebral aneurysms and increases formation and rupture of cerebral aneurysms in mice.
OBJECTIVE
Cerebral aneurysm (CA) affects 3% of the population and is associated with hemodynamic stress and inflammation. Myeloperoxidase, a major oxidative enzyme associated with inflammation, is increased in patients with CA, but whether myeloperoxidase contributes to CA is not known. We tested the hypotheses that myeloperoxidase is increased within human CA and is critical for formation and rupture of CA in mice.


METHODS
Blood was drawn from the lumen of CAs and femoral arteries of 25 patients who underwent endovascular coiling of CA, and plasma myeloperoxidase concentrations were measured with ELISA. Effects of endogenous myeloperoxidase on CA formation and rupture were studied in myeloperoxidase knockout mice and wild-type (WT) mice using an angiotensin II-elastase induction model of CA. In addition, effects of myeloperoxidase on inflammatory gene expression in endothelial cells were analyzed.


RESULTS
Plasma concentrations of myeloperoxidase were 2.7-fold higher within CA than in femoral arterial blood in patients with CA. myeloperoxidase-positive cells were increased in aneurysm tissue compared with superficial temporal artery of patients with CA. Incidence of aneurysms and subarachnoid hemorrhage was significantly lower in myeloperoxidase knockout than in WT mice. In cerebral arteries, proinflammatory molecules, including tumor necrosis factor-α, cyclooxygenase-2 (COX2), chemokine (C-X-C motif) ligand 1 (CXCL1), chemokine (C motif) ligand (XCL1), matrix metalloproteinase (MMP) 8, cluster of differentiation 68 (CD68), and matrix metalloproteinase 13, and leukocytes were increased, and α-smooth muscle actin was decreased, in WT but not in myeloperoxidase knockout mice after induction of CA. Myeloperoxidase per se increased expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 in endothelial cells.


CONCLUSIONS
These findings suggest that myeloperoxidase may contribute importantly to formation and rupture of CA.
From the Departments of Neurosurgery (Y.C., K.W., H.G., S.A.D., D.H.), Internal Medicine (Y.C., K.W., D.D.H.), Anesthesiology (H.G.), and Health and Human Physiology (L.W.-P., G.L.P.), University of Iowa Carver College of Medicine; Department of Internal Medicine, University of Alabama School of Medicine, Birmingham (G.C.); and Departments of Pharmacology and Neurosurgery, Medical School, Universidad de los Andes, Bogota, Colombia (R.A.P.S.).
Yi
Y
Chu
From the Departments of Neurosurgery (Y.C., K.W., H.G., S.A.D., D.H.), Internal Medicine (Y.C., K.W., D.D.H.), Anesthesiology (H.G.), and Health and Human Physiology (L.W.-P., G.L.P.), University of Iowa Carver College of Medicine; Department of Internal Medicine, University of Alabama School of Medicine, Birmingham (G.C.); and Departments of Pharmacology and Neurosurgery, Medical School, Universidad de los Andes, Bogota, Colombia (R.A.P.S.).
Katina
K
Wilson
From the Departments of Neurosurgery (Y.C., K.W., H.G., S.A.D., D.H.), Internal Medicine (Y.C., K.W., D.D.H.), Anesthesiology (H.G.), and Health and Human Physiology (L.W.-P., G.L.P.), University of Iowa Carver College of Medicine; Department of Internal Medicine, University of Alabama School of Medicine, Birmingham (G.C.); and Departments of Pharmacology and Neurosurgery, Medical School, Universidad de los Andes, Bogota, Colombia (R.A.P.S.).
He
H
Gu
From the Departments of Neurosurgery (Y.C., K.W., H.G., S.A.D., D.H.), Internal Medicine (Y.C., K.W., D.D.H.), Anesthesiology (H.G.), and Health and Human Physiology (L.W.-P., G.L.P.), University of Iowa Carver College of Medicine; Department of Internal Medicine, University of Alabama School of Medicine, Birmingham (G.C.); and Departments of Pharmacology and Neurosurgery, Medical School, Universidad de los Andes, Bogota, Colombia (R.A.P.S.).
Lauren
L
Wegman-Points
From the Departments of Neurosurgery (Y.C., K.W., H.G., S.A.D., D.H.), Internal Medicine (Y.C., K.W., D.D.H.), Anesthesiology (H.G.), and Health and Human Physiology (L.W.-P., G.L.P.), University of Iowa Carver College of Medicine; Department of Internal Medicine, University of Alabama School of Medicine, Birmingham (G.C.); and Departments of Pharmacology and Neurosurgery, Medical School, Universidad de los Andes, Bogota, Colombia (R.A.P.S.).
Sarah A
SA
Dooley
From the Departments of Neurosurgery (Y.C., K.W., H.G., S.A.D., D.H.), Internal Medicine (Y.C., K.W., D.D.H.), Anesthesiology (H.G.), and Health and Human Physiology (L.W.-P., G.L.P.), University of Iowa Carver College of Medicine; Department of Internal Medicine, University of Alabama School of Medicine, Birmingham (G.C.); and Departments of Pharmacology and Neurosurgery, Medical School, Universidad de los Andes, Bogota, Colombia (R.A.P.S.).
Gary L
GL
Pierce
From the Departments of Neurosurgery (Y.C., K.W., H.G., S.A.D., D.H.), Internal Medicine (Y.C., K.W., D.D.H.), Anesthesiology (H.G.), and Health and Human Physiology (L.W.-P., G.L.P.), University of Iowa Carver College of Medicine; Department of Internal Medicine, University of Alabama School of Medicine, Birmingham (G.C.); and Departments of Pharmacology and Neurosurgery, Medical School, Universidad de los Andes, Bogota, Colombia (R.A.P.S.).
Guangjie
G
Cheng
From the Departments of Neurosurgery (Y.C., K.W., H.G., S.A.D., D.H.), Internal Medicine (Y.C., K.W., D.D.H.), Anesthesiology (H.G.), and Health and Human Physiology (L.W.-P., G.L.P.), University of Iowa Carver College of Medicine; Department of Internal Medicine, University of Alabama School of Medicine, Birmingham (G.C.); and Departments of Pharmacology and Neurosurgery, Medical School, Universidad de los Andes, Bogota, Colombia (R.A.P.S.).
Ricardo A
RA
Pena Silva
From the Departments of Neurosurgery (Y.C., K.W., H.G., S.A.D., D.H.), Internal Medicine (Y.C., K.W., D.D.H.), Anesthesiology (H.G.), and Health and Human Physiology (L.W.-P., G.L.P.), University of Iowa Carver College of Medicine; Department of Internal Medicine, University of Alabama School of Medicine, Birmingham (G.C.); and Departments of Pharmacology and Neurosurgery, Medical School, Universidad de los Andes, Bogota, Colombia (R.A.P.S.).
Donald D
DD
Heistad
From the Departments of Neurosurgery (Y.C., K.W., H.G., S.A.D., D.H.), Internal Medicine (Y.C., K.W., D.D.H.), Anesthesiology (H.G.), and Health and Human Physiology (L.W.-P., G.L.P.), University of Iowa Carver College of Medicine; Department of Internal Medicine, University of Alabama School of Medicine, Birmingham (G.C.); and Departments of Pharmacology and Neurosurgery, Medical School, Universidad de los Andes, Bogota, Colombia (R.A.P.S.). david-hasan@uiowa.edu.
David
D
Hasan
D017542:Aneurysm, Ruptured / Q000097:blood* / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D000804:Angiotensin II / Q000009:adverse effects / Q000494:pharmacology; D000818:Animals; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood / Q000235:genetics; D002532:Intracranial Aneurysm / Q000097:blood* / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D007958:Leukocyte Count; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010196:Pancreatic Elastase / Q000633:toxicity; D009195:Peroxidase / Q000097:blood* / Q000235:genetics; D019010:Vascular Cell Adhesion Molecule-1 / Q000097:blood / Q000235:genetics; D014662:Vasoconstrictor Agents / Q000009:adverse effects / Q000494:pharmacology
C573420:ICAM1 protein, human; C090509:Icam1 protein, mouse; D018836:Inflammation Mediators; D019010:Vascular Cell Adhesion Molecule-1; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D018799:Intercellular Adhesion Molecule-1; D009195:Peroxidase; D010196:Pancreatic Elastase
inflammation; intercellular adhesion molecule-1; intracranial aneurysm; neutrophils; peroxidase subarachnoid hemorrhage; vascular cell adhesion molecule-1