Heme Oxygenase Gene Targeting to Adipocytes Attenuates Adiposity and Vascular Dysfunction in Mice Fed a High-Fat Diet

被引:106
作者
Cao, Jian [2 ]
Peterson, Stephen J. [3 ]
Sodhi, Komal [1 ]
Vanella, Luca [1 ]
Barbagallo, Ignazio [1 ]
Rodella, Luigi F. [4 ]
Schwartzman, Michal L. [5 ]
Abraham, Nader G. [1 ,3 ,5 ]
Kappas, Attallah [6 ]
机构
[1] Univ Toledo, Dept Physiol & Pharmacol, Coll Med, Toledo, OH 43614 USA
[2] Chinese Peoples Liberat Army Gen Hosp, Dept Geriatr Cardiol, Beijing, Peoples R China
[3] New York Med Coll, Dept Med, Valhalla, NY 10595 USA
[4] Univ Brescia, Dept Biomed Sci, Brescia, Italy
[5] New York Med Coll, Dept Pharmacol, Valhalla, NY 10595 USA
[6] Rockefeller Univ, New York, NY 10021 USA
基金
美国国家卫生研究院;
关键词
HO-1; adiposity; Wnt; 10b; Peg1/Mest; lentivirus; SnMP; IMPROVES INSULIN SENSITIVITY; INCREASES ADIPONECTIN LEVELS; MESENCHYMAL STEM-CELLS; OBESE MICE; PPAR-GAMMA; ADIPOGENESIS; HYPERTENSION; INDUCTION; HEDGEHOG; EXPRESSION;
D O I
10.1161/HYPERTENSIONAHA.112.193805
中图分类号
R6 [外科学];
学科分类号
100210 [外科学];
摘要
We examined the hypothesis that adipocyte dysfunction in mice fed a high-fat (HF) diet can be prevented by lentiviral-mediated and adipocyte specific-targeting delivery of the human heme oxygenase-1 (aP2-HO-1). A bolus intracardial injection of aP2-HO-1 resulted in expression of human HO-1 for up to 9.5 months. Transduction of aP2-HO-1 increased human HO-1 expression in fat tissues without affecting murine HO-1. In mice fed a HF diet, aP2-HO-1 transduction attenuated the increases in body weight, blood glucose, blood pressure, and inflammatory cytokines, as well as the content of both visceral and subcutaneous fat. Transduction of aP2-HO-1 increased the numbers of adipocytes of small cell size (P < 0.05), insulin sensitivity (P < 0.05), adiponectin levels, as well as vascular relaxation to acetylcholine compared with HF mice administered the aP2-green fluorescent protein. Adipocytes of mice fed a HF diet expressed high levels of peroxisome proliferator activator receptor, aP2, C/EBP, and Wnt5b proteins and displayed marked increases in Peg1/Mesoderm specific transcript (P < 0.03). Transduction of aP2-HO-1 lowered the elevated levels of these proteins and increased Sonic hedgehog, Wnt10b, and beta-catenin (P < 0.05). Inhibition of HO activity by administration of tin mesoporphyrin to HF-fed mice transduced with the aP2-HO-1 reversed the decrease in Peg1/Mesoderm-specific transcript, TNF alpha, and MCP-1 levels. Collectively, this novel study demonstrates that adipocyte-specific overexpression of HO-1 attenuates HF-mediated adiposity and vascular dysfunction; increases insulin sensitivity; and improves adipocyte function by increasing adiponectin, Shh, and WNT10b, and by decreasing inflammatory cytokines. These effects are reversed by the HO activity inhibitor, stannous mesoporphyrin. (Hypertension. 2012;60:467-475.) circle Online Data Supplement
引用
收藏
页码:467 / 475
页数:9
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