PPARδ reduces abdominal aortic aneurysm formation in angiotensin II-infused apolipoprotein E-deficient mice by regulating extracellular matrix homeostasis and inflammatory responses.
BACKGROUND
Abdominal aortic aneurysm (AAA) is an inflammatory disorder characterized by a localized degradation of connective tissue and apoptosis of vascular smooth muscle cells. This study examined whether the ligand-activated peroxisome proliferator-activated receptor (PPAR) δ can directly antagonize angiotensin II (Ang II)-induced AAA formation in apoE-deficient mice.


RESULTS
Six-month-old male apoE-deficient mice were infused with Ang II and/or GW501516 (1.44 and 3.3mg/kg/day, respectively) via osmotic mini-pumps. At day 28, aortic size was measured and tissues were collected for analyses. Co-infusion of GW501516, an activator of PPARδ, attenuated both the incidence and the severity of Ang II-induced AAA in apoE-deficient mice. Ligand-activated PPARδ also reduced infiltration of macrophages, resulting in significant decreases in chemotactic proteins such as monocyte chemoattractant protein-1, macrophage inflammatory protein-1β, and inducible nitric oxide synthase. The anti-inflammatory effect of GW501516 was associated with the suppression of apoptotic cell death, along with the inhibition of medial smooth muscle cell loss and focal elastin destruction, which leads to a medial dissection and aortic rupture. These ameliorative effects of GW501516 on Ang II-induced aneurysm were correlated with increased expression of extracellular matrix (ECM) proteins, such as types I and III collagen, fibronectin, and elastin, along with the up-regulation of transforming growth factor-β1. In addition, ligand-activated PPARδ also increased the expression of tissue inhibitor of metalloproteinase (TIMP)-2 and TIMP-3, while it strongly suppressed that of matrix metalloproteinase-2.


CONCLUSIONS
PPARδ attenuates Ang II-induced AAA formation by regulating ECM homeostasis and inflammatory responses, suggesting a novel strategy for the treatment of AAA.
Department of Animal Biotechnology, Konkuk University, Seoul 143-701, Republic of Korea.
Jung Seok
JS
Hwang
Department of Animal Biotechnology, Konkuk University, Seoul 143-701, Republic of Korea.
Hyo Jung
HJ
Kim
Department of Anatomy, Gyeongsang National University School of Medicine, Jinju 660-751, Republic of Korea.
Gyeongwha
G
Kim
Department of Animal Biotechnology, Konkuk University, Seoul 143-701, Republic of Korea.
Eun Sil
ES
Kang
Department of Animal Biotechnology, Konkuk University, Seoul 143-701, Republic of Korea.
Sun Ah
SA
Ham
Department of Animal Biotechnology, Konkuk University, Seoul 143-701, Republic of Korea.
Taesik
T
Yoo
Department of Nursing, Semyung University, Jecheon 390-711, Republic of Korea.
Kyung Shin
KS
Paek
Department of Pharmacology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
Chihiro
C
Yabe-Nishimura
Department of Anatomy, Gyeongsang National University School of Medicine, Jinju 660-751, Republic of Korea. Electronic address: kimhj@gnu.ac.kr.
Hyun Joon
HJ
Kim
Department of Animal Biotechnology, Konkuk University, Seoul 143-701, Republic of Korea. Electronic address: hgseo@konkuk.ac.kr.
Han Geuk
HG
Seo
D000804:Angiotensin II / Q000008:administration & dosage; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000517:prevention & control*; D001057:Apolipoproteins E / Q000172:deficiency; D005109:Extracellular Matrix / Q000187:drug effects*; D006706:Homeostasis / Q000187:drug effects* / Q000502:physiology*; D007249:Inflammation / Q000517:prevention & control*; D007260:Infusion Pumps; D008297:Male; D051379:Mice; D047494:PPAR delta / Q000494:pharmacology* / Q000627:therapeutic use*
D001057:Apolipoproteins E; D047494:PPAR delta; D000804:Angiotensin II
Abdominal aortic aneurysms; Angiotensin II; Extracellular matrix proteins; Gene expression; Peroxisome proliferator-activated receptor δ