Smooth Muscle Peroxisome Proliferator-Activated Receptor γ Plays a Critical Role in Formation and Rupture of Cerebral Aneurysms in Mice In Vivo

David M Hasan; Robert M Starke; He Gu; Katina Wilson; Yi Chu; Nohra Chalouhi; Donald D Heistad; Frank M Faraci; Curt D Sigmund

doi:10.1161/HYPERTENSIONAHA.115.05332

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Smooth Muscle Peroxisome Proliferator-Activated Receptor γ Plays a Critical Role in Formation and Rupture of Cerebral Aneurysms in Mice In Vivo

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Smooth Muscle Peroxisome Proliferator-Activated Receptor γ Plays a Critical Role in Formation and Rupture of Cerebral Aneurysms in Mice In Vivo

David M Hasan, Robert M Starke, He Gu, Katina Wilson, Yi Chu, Nohra Chalouhi, Donald D Heistad, Frank M Faraci and Curt D Sigmund

Hypertension (Dallas, Tex. 1979), Vol.66(1), pp.211-220

2015-07

DOI: https://doi.org/10.1161/HYPERTENSIONAHA.115.05332

PMID: 25916724

Abstract

Up-Regulation

Vasculitis - metabolism

Muscle, Smooth, Vascular - metabolism

Vasculitis - pathology

Vasculitis - complications

Subarachnoid Hemorrhage - prevention & control

Vasculitis - genetics

Aneurysm, Ruptured - physiopathology

Genes, Dominant

Hypertension - chemically induced

PPAR gamma - deficiency

Inflammation Mediators - metabolism

Pancreatic Elastase - toxicity

Angiotensin II - toxicity

Thiazolidinediones - pharmacology

Anilides - toxicity

Myocytes, Smooth Muscle - metabolism

PPAR gamma - genetics

Intracranial Aneurysm - genetics

Gene Expression Regulation - physiology

Mice, Transgenic

Organ Specificity

Muscle, Smooth, Vascular - pathology

PPAR gamma - physiology

Animals

PPAR gamma - antagonists & inhibitors

Cerebral Arteries - metabolism

Endothelium, Vascular - metabolism

Anilides - pharmacology

PPAR gamma - agonists

Hypertension - complications

Subarachnoid Hemorrhage - etiology

Mice

Mutation

Intracranial Aneurysm - physiopathology

Aneurysm, Ruptured - genetics

Intracranial Aneurysm - chemically induced

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.

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Collaboration types: Domestic collaboration
Citation topics: 1 Clinical & Life Sciences; 1.105 Strokes; 1.105.514 Subarachnoid Hemorrhage
Web Of Science research areas: Peripheral Vascular Disease
ESI research areas: Clinical Medicine

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Title: Smooth Muscle Peroxisome Proliferator-Activated Receptor γ Plays a Critical Role in Formation and Rupture of Cerebral Aneurysms in Mice In Vivo
Creators: David M 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 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 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 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 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 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 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 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 D Sigmund - 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
Publication Details: Hypertension (Dallas, Tex. 1979), Vol.66(1), pp.211-220
Grant note: HL084207 / NHLBI NIH HHS I01 BX001399 / BLRD VA HL113863 / NHLBI NIH HHS HL62984 / NHLBI NIH HHS K08 NS082363 / NINDS NIH HHS P01 HL062984 / NHLBI NIH HHS R37 HL048058 / NHLBI NIH HHS K08NS082363 / NINDS NIH HHS R01 HL125603 / NHLBI NIH HHS HL048058 / NHLBI NIH HHS NS72628 / NINDS NIH HHS R01 HL113863 / NHLBI NIH HHS R03 NS079227 / NINDS NIH HHS R01 HL048058 / NHLBI NIH HHS R01 NS072628 / NINDS NIH HHS P01 HL084207 / NHLBI NIH HHS R03NS079227 / NINDS NIH HHS HL062984 / NHLBI NIH HHS
Academic Unit: Miller School of Medicine; UMMG Dept of Neurological Surgery
Language: English
Resource Type: Journal article
PMID: 25916724
Record Identifier: 991031600597902976