Dataset Information

Deficiency of Adipocyte IKK? Affects Atherosclerotic Plaque Vulnerability in Obese LDLR Deficient Mice.

ABSTRACT: Background Obesity-associated chronic inflammation has been known to contribute to atherosclerosis development, but the underlying mechanisms remain elusive. Recent studies have revealed novel functions of IKK ? (inhibitor of NF -?B [nuclear factor ?B] kinase ?), a key coordinator of inflammation through activation of NF -?B, in atherosclerosis and adipose tissue development. However, it is not clear whether IKK ? signaling in adipocytes can also affect atherogenesis. This study aims to investigate the impact of adipocyte IKK ? expression on atherosclerosis development in lean and obese LDLR (low-density lipoprotein receptor)-deficient ( LDLR ^-/-) mice. Methods and Results To define the role of adipocyte IKK ? in atherogenesis, we generated adipocyte-specific IKK ?-deficient LDLR ^-/- ( IKK ?^?Ad LDLR ^-/-) mice. Targeted deletion of IKK ? in adipocytes did not affect adiposity and atherosclerosis in lean LDLR ^-/- mice when fed a low-fat diet. In response to high-fat feeding, however, IKK ?^?Ad LDLR ^-/- mice had defective adipose remodeling and increased adipose tissue and systemic inflammation. Deficiency of adipocyte IKK ? did not affect atherosclerotic lesion sizes but resulted in enhanced lesional inflammation and increased plaque vulnerability in obese IKK ?^?Ad LDLR ^-/- mice. Conclusions These data demonstrate that adipocyte IKK ? signaling affects the evolution of atherosclerosis plaque vulnerability in obese LDLR ^-/- mice. This study suggests that the functions of IKK ? signaling in atherogenesis are complex, and IKK ? in different cell types or tissues may have different effects on atherosclerosis development.

SUBMITTER: Lu W

PROVIDER: S-EPMC6645619 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Publications

Deficiency of Adipocyte IKKβ Affects Atherosclerotic Plaque Vulnerability in Obese LDLR Deficient Mice.

Lu Weiwei W Park Se-Hyung SH Meng Zhaojie Z Wang Fang F Zhou Changcheng C

Journal of the American Heart Association 20190615 12

Background Obesity-associated chronic inflammation has been known to contribute to atherosclerosis development, but the underlying mechanisms remain elusive. Recent studies have revealed novel functions of IKK β (inhibitor of NF -κB [nuclear factor κB] kinase β), a key coordinator of inflammation through activation of NF -κB, in atherosclerosis and adipose tissue development. However, it is not clear whether IKK β signaling in adipocytes can also affect atherogenesis. This study aims to investig ...[more]

PMID: 31203708

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Project description:Atherosclerosis is a major cause of heart attack and stroke. Inflammation plays a critical role in the development of atherosclerosis. Since the cytoplasmic adaptor molecule TRAF3IP2 (TRAF3-Interacting Protein 2) plays a causal role in various autoimmune and inflammatory diseases, we hypothesized that TRAF3IP2 mediates atherosclerotic plaque development.TRAF3IP2/ApoE double knockout (DKO) mice were generated by crossing TRAF3IP2(-/-) and ApoE(-/-) mice. ApoE(-/-) mice served as controls. Both DKO and control mice were fed a high-fat diet for 12 weeks. Plasma lipids were measured by ELISA, atherosclerosis by en face analysis of aorta and plaque cross-section measurements at the aortic valve region, plaque necrotic core area, collagen and smooth muscle cell (SMC) content by histomorphometry, and aortic gene expression by RT-qPCR.The plasma lipoprotein profile was not altered by TRAF3IP2 gene deletion in ApoE(-/-) mice. While total aortic plaque area was decreased in DKO female, but not male mice, the plaque necrotic area was significantly decreased in DKO mice of both genders. Plaque collagen and SMC contents were increased significantly in both female and male DKO mice compared to respective controls. Aortic expression of proinflammatory cytokine (Tumor necrosis factor ?, TNF?), chemokine (Chemokine (C-X-C motif) Ligand 1, CXCL1) and adhesion molecule (Vascular cell adhesion molecule 1, VCAM1; and Intercellular adhesion molecule 1, ICAM1) gene expression were decreased in both male and female DKO mice. In addition, the male DKO mice expressed markedly reduced levels of extracellular matrix (ECM)-related genes, including TIMP1 (Tissue inhibitor of metalloproteinase 1), RECK (Reversion-Inducing-Cysteine-Rich Protein with Kazal Motifs) and ADAM17 (A Disintegrin And Metalloproteinase 17).TRAF3IP2 plays a causal role in atherosclerotic plaque development and vulnerability, possibly by inducing the expression of multiple proinflammatory mediators. TRAF3IP2 could be a potential therapeutic target in atherosclerotic vascular diseases.

Dataset Information

Deficiency of Adipocyte IKK? Affects Atherosclerotic Plaque Vulnerability in Obese LDLR Deficient Mice.

Publications

Deficiency of Adipocyte IKKβ Affects Atherosclerotic Plaque Vulnerability in Obese LDLR Deficient Mice.

Similar Datasets

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