| First Author | Hasan DM | Year | 2015 |
| Journal | Hypertension | Volume | 66 |
| Issue | 1 | Pages | 211-20 |
| PubMed ID | 25916724 | Mgi Jnum | J:280623 |
| Mgi Id | MGI:6368932 | Doi | 10.1161/HYPERTENSIONAHA.115.05332 |
| Citation | Hasan DM, et al. (2015) Smooth Muscle Peroxisome Proliferator-Activated Receptor gamma Plays a Critical Role in Formation and Rupture of Cerebral Aneurysms in Mice In Vivo. Hypertension 66(1):211-20 |
| abstractText | Vascular inflammation plays a critical role in the pathogenesis of cerebral aneurysms. Peroxisome proliferator-activated receptor gamma (PPARgamma) protects against vascular inflammation and atherosclerosis, whereas dominant-negative mutations in PPARgamma promote atherosclerosis and vascular dysfunction. We tested the role of PPARgamma 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 PPARgamma antagonist GW9662 or the PPARgamma agonist pioglitazone, (2) mice carrying dominant-negative PPARgamma 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 PPARgamma did not alter the incidence of aneurysm formation or rupture. In contrast, dominant-negative smooth muscle-specific PPARgamma resulted in an increase in aneurysm formation (P<0.05) and rupture (P=0.05). Dominant-negative smooth muscle-specific PPARgamma, but not dominant-negative endothelial-specific PPARgamma, 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-alpha, 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 PPARgamma, specifically smooth muscle PPARgamma, plays an important role in protecting from formation and rupture of experimental cerebral aneurysms in mice. |
