Protective Role of Peroxisome Proliferator-Activated Receptor-γ in the Development of Intracranial Aneurysm Rupture.
OBJECTIVE
Inflammation is emerging as a key component of the pathophysiology of intracranial aneurysms. Peroxisome proliferator-activated receptor-γ (PPARγ) is a nuclear hormone receptor of which activation modulates various aspects of inflammation.


METHODS
Using a mouse model of intracranial aneurysm, we examined the potential roles of PPARγ in the development of rupture of intracranial aneurysm.


RESULTS
A PPARγ agonist, pioglitazone, significantly reduced the incidence of ruptured aneurysms and the rupture rate without affecting the total incidence aneurysm (unruptured aneurysms and ruptured aneurysms). PPARγ antagonist (GW9662) abolished the protective effect of pioglitazone. The protective effect of pioglitazone was absent in mice lacking macrophage PPARγ. Pioglitazone treatment reduced the mRNA levels of inflammatory cytokines (monocyte chemoattractant factor-1, interleukin-1, and interleukin-6) that are primarily produced by macrophages in the cerebral arteries. Pioglitazone treatment reduced the infiltration of M1 macrophage into the cerebral arteries and the macrophage M1/M2 ratio. Depletion of macrophages significantly reduced the rupture rate.


CONCLUSIONS
Our data showed that the activation of macrophage PPARγ protects against the development of aneurysmal rupture. PPARγ in inflammatory cells may be a potential therapeutic target for the prevention of aneurysmal rupture.
From the Departments of Anesthesia and Perioperative Care (K.S., H.F., K.W., M.K., Y.W., A.K., F.S., T.H.) and Neurological Surgery (M.T.L.), University of California, San Francisco; and Department of Neurosurgery (K.S., M.K., Y.T., K.T.K., S.N.), School of Medicine, The University of Tokushima, Tokushima City, Japan.
Kenji
K
Shimada
From the Departments of Anesthesia and Perioperative Care (K.S., H.F., K.W., M.K., Y.W., A.K., F.S., T.H.) and Neurological Surgery (M.T.L.), University of California, San Francisco; and Department of Neurosurgery (K.S., M.K., Y.T., K.T.K., S.N.), School of Medicine, The University of Tokushima, Tokushima City, Japan.
Hajime
H
Furukawa
From the Departments of Anesthesia and Perioperative Care (K.S., H.F., K.W., M.K., Y.W., A.K., F.S., T.H.) and Neurological Surgery (M.T.L.), University of California, San Francisco; and Department of Neurosurgery (K.S., M.K., Y.T., K.T.K., S.N.), School of Medicine, The University of Tokushima, Tokushima City, Japan.
Kosuke
K
Wada
From the Departments of Anesthesia and Perioperative Care (K.S., H.F., K.W., M.K., Y.W., A.K., F.S., T.H.) and Neurological Surgery (M.T.L.), University of California, San Francisco; and Department of Neurosurgery (K.S., M.K., Y.T., K.T.K., S.N.), School of Medicine, The University of Tokushima, Tokushima City, Japan.
Masaaki
M
Korai
From the Departments of Anesthesia and Perioperative Care (K.S., H.F., K.W., M.K., Y.W., A.K., F.S., T.H.) and Neurological Surgery (M.T.L.), University of California, San Francisco; and Department of Neurosurgery (K.S., M.K., Y.T., K.T.K., S.N.), School of Medicine, The University of Tokushima, Tokushima City, Japan.
Yuan
Y
Wei
From the Departments of Anesthesia and Perioperative Care (K.S., H.F., K.W., M.K., Y.W., A.K., F.S., T.H.) and Neurological Surgery (M.T.L.), University of California, San Francisco; and Department of Neurosurgery (K.S., M.K., Y.T., K.T.K., S.N.), School of Medicine, The University of Tokushima, Tokushima City, Japan.
Yoshiteru
Y
Tada
From the Departments of Anesthesia and Perioperative Care (K.S., H.F., K.W., M.K., Y.W., A.K., F.S., T.H.) and Neurological Surgery (M.T.L.), University of California, San Francisco; and Department of Neurosurgery (K.S., M.K., Y.T., K.T.K., S.N.), School of Medicine, The University of Tokushima, Tokushima City, Japan.
Atsushi
A
Kuwabara
From the Departments of Anesthesia and Perioperative Care (K.S., H.F., K.W., M.K., Y.W., A.K., F.S., T.H.) and Neurological Surgery (M.T.L.), University of California, San Francisco; and Department of Neurosurgery (K.S., M.K., Y.T., K.T.K., S.N.), School of Medicine, The University of Tokushima, Tokushima City, Japan.
Fumiaki
F
Shikata
From the Departments of Anesthesia and Perioperative Care (K.S., H.F., K.W., M.K., Y.W., A.K., F.S., T.H.) and Neurological Surgery (M.T.L.), University of California, San Francisco; and Department of Neurosurgery (K.S., M.K., Y.T., K.T.K., S.N.), School of Medicine, The University of Tokushima, Tokushima City, Japan.
Keiko T
KT
Kitazato
From the Departments of Anesthesia and Perioperative Care (K.S., H.F., K.W., M.K., Y.W., A.K., F.S., T.H.) and Neurological Surgery (M.T.L.), University of California, San Francisco; and Department of Neurosurgery (K.S., M.K., Y.T., K.T.K., S.N.), School of Medicine, The University of Tokushima, Tokushima City, Japan.
Shinji
S
Nagahiro
From the Departments of Anesthesia and Perioperative Care (K.S., H.F., K.W., M.K., Y.W., A.K., F.S., T.H.) and Neurological Surgery (M.T.L.), University of California, San Francisco; and Department of Neurosurgery (K.S., M.K., Y.T., K.T.K., S.N.), School of Medicine, The University of Tokushima, Tokushima City, Japan.
Michael T
MT
Lawton
From the Departments of Anesthesia and Perioperative Care (K.S., H.F., K.W., M.K., Y.W., A.K., F.S., T.H.) and Neurological Surgery (M.T.L.), University of California, San Francisco; and Department of Neurosurgery (K.S., M.K., Y.T., K.T.K., S.N.), School of Medicine, The University of Tokushima, Tokushima City, Japan. hashimot@anesthesia.ucsf.edu.
Tomoki
T
Hashimoto
D017542:Aneurysm, Ruptured / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D002536:Cerebral Arteries / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D002532:Intracranial Aneurysm / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D047495:PPAR gamma / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*
C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D016207:Cytokines; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077205:Pioglitazone
inflammation; intracranial aneurysm; subarachnoid hemorrhage