Vascular smooth muscle cell peroxisome proliferator-activated receptor-γ deletion promotes abdominal aortic aneurysms.
OBJECTIVE
Peroxisome proliferator-activated receptor-γ (PPARγ) plays an important role in the vasculature; however, the role of PPARγ in abdominal aortic aneurysms (AAA) is not well understood. We hypothesized that PPARγ in smooth muscle cells (SMCs) attenuates the development of AAA. We also investigated PPARγ-mediated signaling pathways that may prevent the development of AAA.


METHODS
We determined whether periaortic application of CaCl(2) renders vascular SMC-selective PPARγ knockout (SMPG KO) mice more susceptible to destruction of normal aortic wall architecture.


RESULTS
There is evidence of increased vessel dilatation in the abdominal aorta 6 weeks after 0.25M periaortic CaCl(2) application in SMPG KO mice compared with littermate controls (1.4 ± 0.3 mm [n = 8] vs 1.1 ± 0.2 mm [n = 7]; P = .000119). Results from SMPG KO mice indicate medial layer elastin degradation was greater 6 weeks after abluminal application of CaCl(2) to the abdominal aorta (P < .01). Activated cathepsin S, a potent elastin-degrading enzyme, was increased in SMPG KO mice vs wild-type controls. To further identify a role of PPARγ signaling in reducing the development of AAA, we demonstrated that adenoviral-mediated PPARγ overexpression in cultured rat aortic SMCs decreases (P = .022) the messenger RNA levels of cathepsin S. In addition, a chromatin immunoprecipitation assay detected PPARγ bound to a peroxisome proliferator-activated receptor response element (PPRE) -141 to -159 bp upstream of the cathepsin S gene sequence in mouse aortic SMCs. Also, adenoviral-mediated PPARγ overexpression and knockdown in cultured rat aortic SMCs decreases (P = .013) and increases (P = .018) expression of activated cathepsin S. Finally, immunohistochemistry demonstrated a greater inflammatory infiltrate in SMPG KO mouse aortas, as evidenced by elevations in F4/80 and tumor necrosis factor-α expression.


CONCLUSIONS
In this study, we identify PPARγ as an important contributor in attenuating the development of aortic aneurysms by demonstrating that loss of PPARγ in vascular SMCs promotes aortic dilatation and elastin degradation. Thus, PPARγ activation may be potentially promising medical therapy in reducing the risk of AAA progression and rupture.
Hamblin
Milton
M
Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Mich, USA.
Chang
Lin
L
Zhang
Hengmin
H
Yang
Kun
K
Zhang
Jifeng
J
Chen
Y Eugene
YE
D000818:Animals; D001012:Aorta, Abdominal / Q000378:metabolism / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D001665:Binding Sites; D002122:Calcium Chloride; D002403:Cathepsins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004108:Dilatation, Pathologic; D004195:Disease Models, Animal; D004549:Elastin / Q000378:metabolism; D004789:Enzyme Activation; D007249:Inflammation / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D047495:PPAR gamma / Q000172:deficiency* / Q000235:genetics; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection
D047495:PPAR gamma; D012333:RNA, Messenger; D004549:Elastin; D002403:Cathepsins; C028217:cathepsin S; D002122:Calcium Chloride