Systemic Delivery of MicroRNA-181b Inhibits Nuclear Factor-κB Activation, Vascular Inflammation, and Atherosclerosis in Apolipoprotein E–Deficient Mice

Abstract Background: The activated nuclear factor (NF)-κB pathway in atherosclerotic plaques promotes the progression of atherosclerosis. Targeting of plaque NF-κB may provide a novel strategy for limiting chronic inflammation. This study was conducted to examine the effect of NF-κB inhibition by using recombinant adeno-associated virus 9 (AAV9) to deliver IκBα (AAV9‐IκBα) which can be overexpressed to influence atherosclerosis.Methods and Results: Systemic delivery of AAV9‐IκBα resulted in ~2-fold overexpression of IκBα protein in the atherosclerotic plaques of apolipoprotein E-/- mice fed a high-fat diet. AAV9‐IκBα delivery did not affect the body weight or lipid deposition and plaque size in the mice. During plaque formation, overexpression of IκBα suppressed intra-plaque macrophage infiltration, inhibited the expression of pro-inflammatory genes including interleukin-6, monocyte chemoattractant protein-1, tumor necrosis factor-α and matrix metalloproteinase, enhanced the contents of collagen and vascular smooth muscle cells, and decreased the plaque vulnerability index by inhibiting the phosphorylation of NF-κB subunit p65 and its nuclear translocation. Conclusions: Systemic delivery of AAV9-IκBα promotes plaque stability by inhibiting NF-κB activation and suppressing intra-plaque inflammation, suggesting that inhibition of the NF-κB pathway in atherosclerotic plaques is a promising approach for treating atherosclerosis.

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Trimethylamine N‐Oxide Promotes Vascular Inflammation Through Signaling of Mitogen‐Activated Protein Kinase and Nuclear Factor‐κB

Journal of the American Heart Association ◽

10.1161/jaha.115.002767 ◽

2016 ◽

Vol 5 (2) ◽

Cited By ~ 229

Author(s):

Marcus M. Seldin ◽

Yonghong Meng ◽

Hongxiu Qi ◽

WeiFei Zhu ◽

Zeneng Wang ◽

...

Keyword(s):

Protein Kinase ◽

Vascular Inflammation ◽

Nuclear Factor Κb ◽

Mitogen Activated Protein Kinase ◽

Nuclear Factor ◽

Mitogen Activated Protein

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Abstract 276: Systemic Delivery of Microrna-146a Improves Endothelial Function and Ameliorates Atherosclerosis in Apolipoprotein E-deficient Mice

Circulation Research ◽

10.1161/res.117.suppl_1.276 ◽

2015 ◽

Vol 117 (suppl_1) ◽

Author(s):

Shuangtao Ma ◽

Xiao Yu Tian ◽

Chaofeng Mu ◽

Haifa Shen ◽

Yunrong Zhang ◽

...

Keyword(s):

Endothelial Function ◽

Apolipoprotein E ◽

Carotid Arteries ◽

Treated Group ◽

Vehicle Group ◽

Early Event ◽

Aortic Tissue ◽

Systemic Delivery ◽

Plaque Area ◽

Deficient Mice

Rationale: Endothelial inflammation is an early event in the development of atherosclerosis. The microRNA (miR)-146a showed anti-inflammatory effects in cultured endothelial cells. In this study, we investigated the therapeutic role of miR-146a in endothelial function and atherosclerosis in apolipoprotein E (ApoE)-deficient mice. Methods and Results: The miR-146a was packaged into a multistage vector (MSV) that was conjugated with an E-selectin-targeting thioaptamer (ESTA) to form an ESTA-MSV microparticle. The ApoE-deficient mice were fed with Western diet and injected through tail vein with 15μg of miR-146a loaded ESTA-MSV microparticles or vehicle vectors biweekly for 12 weeks. The expressions of miR-146a in aortic tissue was increased by five times at two weeks after injection. However, the expressions of miR-146a in heart, lung, liver, spleen, kidney, and skeletal muscle were not increased. The acetylcholine-induced endothelium-dependent relaxations in both carotid arteries and aortas were significantly improved in mice from miR-146a treated group compared with vehicle group. In addition, the endothelium-dependent contractions of carotid arteries were also improved by miR-146a treatment. The en face oil red O staining of whole aortas showed the plaque area was decreased in miR-146a-treated mice. Application of miR-146a also decreased the plaque size, macrophages, and T-lymphocytes, but increased the collagen deposition and vascular smooth muscle cells in the sections of aortic roots. The PCR results showed that expressions of chemokine (C-C motif) ligand (CCL)-2, CCL-5, and CCL-8 were decreased by miR-146a. Conclusions: E-selectin-targeting delivery of miR-146a improves endothelial function and inhibits atherosclerosis.

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Cilostazol Protects Diabetic Rats from Vascular Inflammation via Nuclear Factor-κB-Dependent Down-Regulation of Vascular Cell Adhesion Molecule-1 Expression

Journal of Pharmacology and Experimental Therapeutics ◽

10.1124/jpet.106.101444 ◽

2006 ◽

Vol 318 (1) ◽

pp. 53-58 ◽

Cited By ~ 29

Author(s):

Ling Gao ◽

Furong Wang ◽

Bo Wang ◽

Bendi Gong ◽

Jie Zhang ◽

...

Keyword(s):

Cell Adhesion ◽

Adhesion Molecule ◽

Cell Adhesion Molecule ◽

Vascular Inflammation ◽

Nuclear Factor Κb ◽

Diabetic Rats ◽

Nuclear Factor ◽

Vascular Cell Adhesion ◽

Vascular Cell ◽

Cell Adhesion Molecule 1

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Protease-Activated Receptor-2 Plays a Critical Role in Vascular Inflammation and Atherosclerosis in Apolipoprotein E–Deficient Mice

Circulation ◽

10.1161/circulationaha.118.033544 ◽

2018 ◽

Vol 138 (16) ◽

pp. 1706-1719 ◽

Cited By ~ 22

Author(s):

Tomoya Hara ◽

Pham Tran Phuong ◽

Daiju Fukuda ◽

Koji Yamaguchi ◽

Chie Murata ◽

...

Keyword(s):

Apolipoprotein E ◽

Vascular Inflammation ◽

Critical Role ◽

Protease Activated Receptor 2 ◽

Deficient Mice

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Muscle weakness and selective muscle atrophy in osteoprotegerin-deficient mice

Human Molecular Genetics ◽

10.1093/hmg/ddz312 ◽

2020 ◽

Vol 29 (3) ◽

pp. 483-494 ◽

Cited By ~ 3

Author(s):

Dounia Hamoudi ◽

Zineb Bouredji ◽

Laetitia Marcadet ◽

Hideo Yagita ◽

Louis-Bénédict Landry ◽

...

Keyword(s):

Muscle Weakness ◽

Ex Vivo ◽

Elevated Serum ◽

Biomechanical Properties ◽

Nuclear Factor Κb ◽

C2c12 Myotubes ◽

Nuclear Factor ◽

Receptor Activator ◽

Fast Twitch ◽

Deficient Mice

Abstract Bone and muscle are tightly coupled and form a functional unit under normal conditions. The receptor-activator of nuclear factor κB/receptor-activator of nuclear factor κB ligand/osteoprotegerin (RANK/RANKL/OPG) triad plays a crucial role in bone remodeling. RANKL inhibition by OPG prevents osteoporosis. In contrast, the absence of OPG results in elevated serum RANKL and early onset osteoporosis. However, the impacts of OPG deletion on muscle structure and function are unknown. Our results showed that 1-, 3- and 5-month-old Opg−/− mice have reduced tibial and femoral bone biomechanical properties and higher levels of circulating RANKL. OPG-deficient mice displayed reduced locomotor activity and signs of muscle weakness at 5 months of age. Furthermore, OPG deficiency did not affect the skeletal muscles in 1- and 3-month-old mice. However, it impaired fast-twitch EDL but not slow-twitch Sol muscles in 5-month-old Opg−/− mice. Moreover, 5-month-old Opg−/− mice exhibited selective atrophy of fast-twitch-type IIb myofibers, with increased expression of atrophic proteins such as NF-kB, atrogin-1 and MuRF-1. We used an in vitro model to show that RANKL-stimulated C2C12 myotubes significantly increased the expression of NF-kB, atrogin-1 and MuRF-1. A 2-month anti-RANKL treatment starting at 3 months of age in Opg−/− mice improved voluntary activity, the ex vivo maximum specific force (sP0) of EDL muscles, and whole limb grip force performance and rescued the biomechanical properties of bone. In conclusion, the deletion of OPG and the disruption of the RANKL/OPG balance induced osteoporosis as well as the selective weakness and atrophy of the powerful fast-twitch IIb myofibers, which was partly alleviated by an anti-RANKL treatment.

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