title: Peroxisome Proliferator-Activated Receptor γ Level Contributes to Structural Integrity and Component Production of Elastic Fibers in the Aorta.
abstract: Loss of integrity and massive disruption of elastic fibers are key features of abdominal aortic aneurysm (AAA). Peroxisome proliferator-activated receptor γ (PPARγ) has been shown to attenuate AAA through inhibition of inflammation and proteolytic degradation. However, its involvement in elastogenesis during AAA remains unclear. PPARγ was highly expressed in human AAA within all vascular cells, including inflammatory cells and fibroblasts. In the aortas of transgenic mice expressing PPARγ at 25% normal levels (Pparg(C) (/-) mice), we observed the fragmentation of elastic fibers and reduced expression of vital elastic fiber components of elastin and fibulin-5. These were not observed in mice with 50% normal PPARγ expression (Pparg(+/-) mice). Infusion of a moderate dose of angiotensin II (500 ng/kg per minute) did not induce AAA but Pparg(+/-) aorta developed flattened elastic lamellae, whereas Pparg(C/-) aorta showed severe destruction of elastic fibers. After infusion of angiotensin II at 1000 ng/kg per minute, 73% of Pparg(C/-) mice developed atypical suprarenal aortic aneurysms: superior mesenteric arteries were dilated with extensive collagen deposition in adventitia and infiltrations of inflammatory cells. Although matrix metalloproteinase inhibition by doxycycline somewhat attenuated the dilation of aneurysm, it did not reduce the incidence nor elastic lamella deterioration in angiotensin II-infused Pparg(C/-) mice. Furthermore, PPARγ antagonism downregulated elastin and fibulin-5 in fibroblasts, but not in vascular smooth muscle cells. Chromatin immunoprecipitation assay demonstrated PPARγ binding in the genomic sequence of fibulin-5 in fibroblasts. Our results underscore the importance of PPARγ in AAA development though orchestrating proper elastogenesis and preserving elastic fiber integrity.
authors.affiliation: From the Institute of Clinical Medicine (H.-C.T., J.-Y.C., C.-H.L., Y.-S.T.), Cardiovascular Research Center (H.-C.T., J.-Y.C., C.-H.L., K.-C.W., M.-J.J., Y.-H.L., H.-L.W., Y.-S.T.), Departments of Medical Laboratory Science and Biotechnology (P.-J.T.), Biochemistry and Molecular Biology (K.-C.W., H.-L.W.), Physiology (S.-C.L., A.Y.W.C.), Cell Biology and Anatomy (M.-J.J.), National Cheng Kung University, Tainan, Taiwan, Republic of China; Departments of Internal Medicine (J.-Y.C., Y.-H.L.), Surgery (C.-H.L.), and Research Center of Clinical Medicine (Y.-S.T.), National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China; Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan, Republic of China (S.-H.T.); and Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill (N.M.).
authors.forename: Haw-Chih
authors.initials: HC
authors.lastname: Tai
authors.affiliation: From the Institute of Clinical Medicine (H.-C.T., J.-Y.C., C.-H.L., Y.-S.T.), Cardiovascular Research Center (H.-C.T., J.-Y.C., C.-H.L., K.-C.W., M.-J.J., Y.-H.L., H.-L.W., Y.-S.T.), Departments of Medical Laboratory Science and Biotechnology (P.-J.T.), Biochemistry and Molecular Biology (K.-C.W., H.-L.W.), Physiology (S.-C.L., A.Y.W.C.), Cell Biology and Anatomy (M.-J.J.), National Cheng Kung University, Tainan, Taiwan, Republic of China; Departments of Internal Medicine (J.-Y.C., Y.-H.L.), Surgery (C.-H.L.), and Research Center of Clinical Medicine (Y.-S.T.), National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China; Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan, Republic of China (S.-H.T.); and Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill (N.M.).
authors.forename: Pei-Jane
authors.initials: PJ
authors.lastname: Tsai
authors.affiliation: From the Institute of Clinical Medicine (H.-C.T., J.-Y.C., C.-H.L., Y.-S.T.), Cardiovascular Research Center (H.-C.T., J.-Y.C., C.-H.L., K.-C.W., M.-J.J., Y.-H.L., H.-L.W., Y.-S.T.), Departments of Medical Laboratory Science and Biotechnology (P.-J.T.), Biochemistry and Molecular Biology (K.-C.W., H.-L.W.), Physiology (S.-C.L., A.Y.W.C.), Cell Biology and Anatomy (M.-J.J.), National Cheng Kung University, Tainan, Taiwan, Republic of China; Departments of Internal Medicine (J.-Y.C., Y.-H.L.), Surgery (C.-H.L.), and Research Center of Clinical Medicine (Y.-S.T.), National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China; Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan, Republic of China (S.-H.T.); and Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill (N.M.).
authors.forename: Ju-Yi
authors.initials: JY
authors.lastname: Chen
authors.affiliation: From the Institute of Clinical Medicine (H.-C.T., J.-Y.C., C.-H.L., Y.-S.T.), Cardiovascular Research Center (H.-C.T., J.-Y.C., C.-H.L., K.-C.W., M.-J.J., Y.-H.L., H.-L.W., Y.-S.T.), Departments of Medical Laboratory Science and Biotechnology (P.-J.T.), Biochemistry and Molecular Biology (K.-C.W., H.-L.W.), Physiology (S.-C.L., A.Y.W.C.), Cell Biology and Anatomy (M.-J.J.), National Cheng Kung University, Tainan, Taiwan, Republic of China; Departments of Internal Medicine (J.-Y.C., Y.-H.L.), Surgery (C.-H.L.), and Research Center of Clinical Medicine (Y.-S.T.), National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China; Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan, Republic of China (S.-H.T.); and Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill (N.M.).
authors.forename: Chao-Han
authors.initials: CH
authors.lastname: Lai
authors.affiliation: From the Institute of Clinical Medicine (H.-C.T., J.-Y.C., C.-H.L., Y.-S.T.), Cardiovascular Research Center (H.-C.T., J.-Y.C., C.-H.L., K.-C.W., M.-J.J., Y.-H.L., H.-L.W., Y.-S.T.), Departments of Medical Laboratory Science and Biotechnology (P.-J.T.), Biochemistry and Molecular Biology (K.-C.W., H.-L.W.), Physiology (S.-C.L., A.Y.W.C.), Cell Biology and Anatomy (M.-J.J.), National Cheng Kung University, Tainan, Taiwan, Republic of China; Departments of Internal Medicine (J.-Y.C., Y.-H.L.), Surgery (C.-H.L.), and Research Center of Clinical Medicine (Y.-S.T.), National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China; Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan, Republic of China (S.-H.T.); and Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill (N.M.).
authors.forename: Kuan-Chieh
authors.initials: KC
authors.lastname: Wang
authors.affiliation: From the Institute of Clinical Medicine (H.-C.T., J.-Y.C., C.-H.L., Y.-S.T.), Cardiovascular Research Center (H.-C.T., J.-Y.C., C.-H.L., K.-C.W., M.-J.J., Y.-H.L., H.-L.W., Y.-S.T.), Departments of Medical Laboratory Science and Biotechnology (P.-J.T.), Biochemistry and Molecular Biology (K.-C.W., H.-L.W.), Physiology (S.-C.L., A.Y.W.C.), Cell Biology and Anatomy (M.-J.J.), National Cheng Kung University, Tainan, Taiwan, Republic of China; Departments of Internal Medicine (J.-Y.C., Y.-H.L.), Surgery (C.-H.L.), and Research Center of Clinical Medicine (Y.-S.T.), National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China; Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan, Republic of China (S.-H.T.); and Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill (N.M.).
authors.forename: Shih-Hua
authors.initials: SH
authors.lastname: Teng
authors.affiliation: From the Institute of Clinical Medicine (H.-C.T., J.-Y.C., C.-H.L., Y.-S.T.), Cardiovascular Research Center (H.-C.T., J.-Y.C., C.-H.L., K.-C.W., M.-J.J., Y.-H.L., H.-L.W., Y.-S.T.), Departments of Medical Laboratory Science and Biotechnology (P.-J.T.), Biochemistry and Molecular Biology (K.-C.W., H.-L.W.), Physiology (S.-C.L., A.Y.W.C.), Cell Biology and Anatomy (M.-J.J.), National Cheng Kung University, Tainan, Taiwan, Republic of China; Departments of Internal Medicine (J.-Y.C., Y.-H.L.), Surgery (C.-H.L.), and Research Center of Clinical Medicine (Y.-S.T.), National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China; Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan, Republic of China (S.-H.T.); and Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill (N.M.).
authors.forename: Shih-Chieh
authors.initials: SC
authors.lastname: Lin
authors.affiliation: From the Institute of Clinical Medicine (H.-C.T., J.-Y.C., C.-H.L., Y.-S.T.), Cardiovascular Research Center (H.-C.T., J.-Y.C., C.-H.L., K.-C.W., M.-J.J., Y.-H.L., H.-L.W., Y.-S.T.), Departments of Medical Laboratory Science and Biotechnology (P.-J.T.), Biochemistry and Molecular Biology (K.-C.W., H.-L.W.), Physiology (S.-C.L., A.Y.W.C.), Cell Biology and Anatomy (M.-J.J.), National Cheng Kung University, Tainan, Taiwan, Republic of China; Departments of Internal Medicine (J.-Y.C., Y.-H.L.), Surgery (C.-H.L.), and Research Center of Clinical Medicine (Y.-S.T.), National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China; Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan, Republic of China (S.-H.T.); and Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill (N.M.).
authors.forename: Alice Y W
authors.initials: AY
authors.lastname: Chang
authors.affiliation: From the Institute of Clinical Medicine (H.-C.T., J.-Y.C., C.-H.L., Y.-S.T.), Cardiovascular Research Center (H.-C.T., J.-Y.C., C.-H.L., K.-C.W., M.-J.J., Y.-H.L., H.-L.W., Y.-S.T.), Departments of Medical Laboratory Science and Biotechnology (P.-J.T.), Biochemistry and Molecular Biology (K.-C.W., H.-L.W.), Physiology (S.-C.L., A.Y.W.C.), Cell Biology and Anatomy (M.-J.J.), National Cheng Kung University, Tainan, Taiwan, Republic of China; Departments of Internal Medicine (J.-Y.C., Y.-H.L.), Surgery (C.-H.L.), and Research Center of Clinical Medicine (Y.-S.T.), National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China; Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan, Republic of China (S.-H.T.); and Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill (N.M.).
authors.forename: Meei-Jyh
authors.initials: MJ
authors.lastname: Jiang
authors.affiliation: From the Institute of Clinical Medicine (H.-C.T., J.-Y.C., C.-H.L., Y.-S.T.), Cardiovascular Research Center (H.-C.T., J.-Y.C., C.-H.L., K.-C.W., M.-J.J., Y.-H.L., H.-L.W., Y.-S.T.), Departments of Medical Laboratory Science and Biotechnology (P.-J.T.), Biochemistry and Molecular Biology (K.-C.W., H.-L.W.), Physiology (S.-C.L., A.Y.W.C.), Cell Biology and Anatomy (M.-J.J.), National Cheng Kung University, Tainan, Taiwan, Republic of China; Departments of Internal Medicine (J.-Y.C., Y.-H.L.), Surgery (C.-H.L.), and Research Center of Clinical Medicine (Y.-S.T.), National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China; Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan, Republic of China (S.-H.T.); and Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill (N.M.).
authors.forename: Yi-Heng
authors.initials: YH
authors.lastname: Li
authors.affiliation: From the Institute of Clinical Medicine (H.-C.T., J.-Y.C., C.-H.L., Y.-S.T.), Cardiovascular Research Center (H.-C.T., J.-Y.C., C.-H.L., K.-C.W., M.-J.J., Y.-H.L., H.-L.W., Y.-S.T.), Departments of Medical Laboratory Science and Biotechnology (P.-J.T.), Biochemistry and Molecular Biology (K.-C.W., H.-L.W.), Physiology (S.-C.L., A.Y.W.C.), Cell Biology and Anatomy (M.-J.J.), National Cheng Kung University, Tainan, Taiwan, Republic of China; Departments of Internal Medicine (J.-Y.C., Y.-H.L.), Surgery (C.-H.L.), and Research Center of Clinical Medicine (Y.-S.T.), National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China; Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan, Republic of China (S.-H.T.); and Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill (N.M.).
authors.forename: Hua-Lin
authors.initials: HL
authors.lastname: Wu
authors.affiliation: From the Institute of Clinical Medicine (H.-C.T., J.-Y.C., C.-H.L., Y.-S.T.), Cardiovascular Research Center (H.-C.T., J.-Y.C., C.-H.L., K.-C.W., M.-J.J., Y.-H.L., H.-L.W., Y.-S.T.), Departments of Medical Laboratory Science and Biotechnology (P.-J.T.), Biochemistry and Molecular Biology (K.-C.W., H.-L.W.), Physiology (S.-C.L., A.Y.W.C.), Cell Biology and Anatomy (M.-J.J.), National Cheng Kung University, Tainan, Taiwan, Republic of China; Departments of Internal Medicine (J.-Y.C., Y.-H.L.), Surgery (C.-H.L.), and Research Center of Clinical Medicine (Y.-S.T.), National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China; Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan, Republic of China (S.-H.T.); and Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill (N.M.).
authors.forename: Nobuyo
authors.initials: N
authors.lastname: Maeda
authors.affiliation: From the Institute of Clinical Medicine (H.-C.T., J.-Y.C., C.-H.L., Y.-S.T.), Cardiovascular Research Center (H.-C.T., J.-Y.C., C.-H.L., K.-C.W., M.-J.J., Y.-H.L., H.-L.W., Y.-S.T.), Departments of Medical Laboratory Science and Biotechnology (P.-J.T.), Biochemistry and Molecular Biology (K.-C.W., H.-L.W.), Physiology (S.-C.L., A.Y.W.C.), Cell Biology and Anatomy (M.-J.J.), National Cheng Kung University, Tainan, Taiwan, Republic of China; Departments of Internal Medicine (J.-Y.C., Y.-H.L.), Surgery (C.-H.L.), and Research Center of Clinical Medicine (Y.-S.T.), National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China; Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan, Republic of China (S.-H.T.); and Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill (N.M.). yaustsai@mail.ncku.edu.tw.
authors.forename: Yau-Sheng
authors.initials: YS
authors.lastname: Tsai
mesh_terms: D000704:Analysis of Variance; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000235:genetics*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004549:Elastin / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics*
chemical_list: D047495:PPAR gamma; D000804:Angiotensin II; D004549:Elastin; D020782:Matrix Metalloproteinases
keywords: aneurysm; angiotensin II; collagen; doxycycline; fibroblasts