Smooth Muscle Peroxisome Proliferator-Activated Receptor γ Plays a Critical Role in Formation and Rupture of Cerebral Aneurysms in Mice In Vivo.
Vascular inflammation plays a critical role in the pathogenesis of cerebral aneurysms. Peroxisome proliferator-activated receptor γ (PPARγ) protects against vascular inflammation and atherosclerosis, whereas dominant-negative mutations in PPARγ promote atherosclerosis and vascular dysfunction. We tested the role of PPARγ in aneurysm formation and rupture. Aneurysms were induced with a combination of systemic infusion of angiotensin-II and local injection of elastase in (1) mice that received the PPARγ antagonist GW9662 or the PPARγ agonist pioglitazone, (2) mice carrying dominant-negative PPARγ mutations in endothelial or smooth muscle cells, and (3) mice that received the Cullin inhibitor MLN4924. Incidence of aneurysm formation, rupture, and mortality was quantified. Cerebral arteries were analyzed for expression of Cullin3, Kelch-like ECH-associated protein 1, nuclear factor (erythroid-derived 2)-like 2, NAD(P)H dehydrogenase (quinone)1 (NQO1), and inflammatory marker mRNAs. Neither pioglitazone nor GW9662 altered the incidence of aneurysm formation. GW9662 significantly increased the incidence of aneurysm rupture, whereas pioglitazone tended to decrease the incidence of rupture. Dominant-negative endothelial-specific PPARγ did not alter the incidence of aneurysm formation or rupture. In contrast, dominant-negative smooth muscle-specific PPARγ resulted in an increase in aneurysm formation (P<0.05) and rupture (P=0.05). Dominant-negative smooth muscle-specific PPARγ, but not dominant-negative endothelial-specific PPARγ, resulted in significant decreases in expression of genes encoding Cullin3, Kelch-like ECH-associated protein 1, and nuclear factor (erythroid-derived 2)-like 2, along with significant increases in tumor necrosis factor-α, monocyte chemoattractant protein-1, chemokine (C-X-C motif) ligand 1, CD68, matrix metalloproteinase-3, -9, and -13. MLN4924 did not alter incidence of aneurysm formation, but increased the incidence of rupture (P<0.05). In summary, endogenous PPARγ, specifically smooth muscle PPARγ, plays an important role in protecting from formation and rupture of experimental cerebral aneurysms in mice.
From the Department of Neurological Surgery (D.M.H., H.G., K.W., Y.C.) and Departments of Pharmacology and Internal Medicine, Carver College of Medicine (Y.C., D.D.H., F.M.F., C.D.S.), University of Department of Internal Medicine, Iowa; Department of Neurological Surgery, University of Virginia, Charlottesville (R.M.S.); Department of Neurological Surgery, Thomas Jefferson University, Philadelphia, PA (N.C.); and Department of Internal Medicine, Iowa City Veterans Affairs Healthcare System (F.M.F.).
David M
DM
Hasan
From the Department of Neurological Surgery (D.M.H., H.G., K.W., Y.C.) and Departments of Pharmacology and Internal Medicine, Carver College of Medicine (Y.C., D.D.H., F.M.F., C.D.S.), University of Department of Internal Medicine, Iowa; Department of Neurological Surgery, University of Virginia, Charlottesville (R.M.S.); Department of Neurological Surgery, Thomas Jefferson University, Philadelphia, PA (N.C.); and Department of Internal Medicine, Iowa City Veterans Affairs Healthcare System (F.M.F.).
Robert M
RM
Starke
From the Department of Neurological Surgery (D.M.H., H.G., K.W., Y.C.) and Departments of Pharmacology and Internal Medicine, Carver College of Medicine (Y.C., D.D.H., F.M.F., C.D.S.), University of Department of Internal Medicine, Iowa; Department of Neurological Surgery, University of Virginia, Charlottesville (R.M.S.); Department of Neurological Surgery, Thomas Jefferson University, Philadelphia, PA (N.C.); and Department of Internal Medicine, Iowa City Veterans Affairs Healthcare System (F.M.F.).
He
H
Gu
From the Department of Neurological Surgery (D.M.H., H.G., K.W., Y.C.) and Departments of Pharmacology and Internal Medicine, Carver College of Medicine (Y.C., D.D.H., F.M.F., C.D.S.), University of Department of Internal Medicine, Iowa; Department of Neurological Surgery, University of Virginia, Charlottesville (R.M.S.); Department of Neurological Surgery, Thomas Jefferson University, Philadelphia, PA (N.C.); and Department of Internal Medicine, Iowa City Veterans Affairs Healthcare System (F.M.F.).
Katina
K
Wilson
From the Department of Neurological Surgery (D.M.H., H.G., K.W., Y.C.) and Departments of Pharmacology and Internal Medicine, Carver College of Medicine (Y.C., D.D.H., F.M.F., C.D.S.), University of Department of Internal Medicine, Iowa; Department of Neurological Surgery, University of Virginia, Charlottesville (R.M.S.); Department of Neurological Surgery, Thomas Jefferson University, Philadelphia, PA (N.C.); and Department of Internal Medicine, Iowa City Veterans Affairs Healthcare System (F.M.F.).
Yi
Y
Chu
From the Department of Neurological Surgery (D.M.H., H.G., K.W., Y.C.) and Departments of Pharmacology and Internal Medicine, Carver College of Medicine (Y.C., D.D.H., F.M.F., C.D.S.), University of Department of Internal Medicine, Iowa; Department of Neurological Surgery, University of Virginia, Charlottesville (R.M.S.); Department of Neurological Surgery, Thomas Jefferson University, Philadelphia, PA (N.C.); and Department of Internal Medicine, Iowa City Veterans Affairs Healthcare System (F.M.F.).
Nohra
N
Chalouhi
From the Department of Neurological Surgery (D.M.H., H.G., K.W., Y.C.) and Departments of Pharmacology and Internal Medicine, Carver College of Medicine (Y.C., D.D.H., F.M.F., C.D.S.), University of Department of Internal Medicine, Iowa; Department of Neurological Surgery, University of Virginia, Charlottesville (R.M.S.); Department of Neurological Surgery, Thomas Jefferson University, Philadelphia, PA (N.C.); and Department of Internal Medicine, Iowa City Veterans Affairs Healthcare System (F.M.F.).
Donald D
DD
Heistad
From the Department of Neurological Surgery (D.M.H., H.G., K.W., Y.C.) and Departments of Pharmacology and Internal Medicine, Carver College of Medicine (Y.C., D.D.H., F.M.F., C.D.S.), University of Department of Internal Medicine, Iowa; Department of Neurological Surgery, University of Virginia, Charlottesville (R.M.S.); Department of Neurological Surgery, Thomas Jefferson University, Philadelphia, PA (N.C.); and Department of Internal Medicine, Iowa City Veterans Affairs Healthcare System (F.M.F.).
Frank M
FM
Faraci
From the Department of Neurological Surgery (D.M.H., H.G., K.W., Y.C.) and Departments of Pharmacology and Internal Medicine, Carver College of Medicine (Y.C., D.D.H., F.M.F., C.D.S.), University of Department of Internal Medicine, Iowa; Department of Neurological Surgery, University of Virginia, Charlottesville (R.M.S.); Department of Neurological Surgery, Thomas Jefferson University, Philadelphia, PA (N.C.); and Department of Internal Medicine, Iowa City Veterans Affairs Healthcare System (F.M.F.). curt-sigmund@uiowa.edu.
Curt D
CD
Sigmund
D017542:Aneurysm, Ruptured / Q000235:genetics / Q000503:physiopathology*; D000804:Angiotensin II / Q000633:toxicity; D000813:Anilides / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D002536:Cerebral Arteries / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D005799:Genes, Dominant; D006973:Hypertension / Q000139:chemically induced / Q000150:complications; D018836:Inflammation Mediators / Q000378:metabolism; D002532:Intracranial Aneurysm / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology*; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D009928:Organ Specificity; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D010196:Pancreatic Elastase / Q000633:toxicity; D000077205:Pioglitazone; D013345:Subarachnoid Hemorrhage / Q000209:etiology / Q000517:prevention & control; D045162:Thiazolidinediones / Q000494:pharmacology; D015854:Up-Regulation; D014657:Vasculitis / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000473:pathology
C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D018836:Inflammation Mediators; D047495:PPAR gamma; D045162:Thiazolidinediones; D000804:Angiotensin II; D010196:Pancreatic Elastase; D000077205:Pioglitazone
aneurysm; inflammation; myocytes, smooth muscle; pioglitazone; subarachnoid hemorrhage