Interleukin-10 Fails to Modulate Low Shear Stress–Induced Neointimal Hyperplasia

• Published in: The Journal of surgical research 2002-02, Vol.102 (2), p.110-118
• Main Authors: Rectenwald, John E., Minter, Rebecca M., Moldawer, Lyle L., Abouhamze, Zaher, La Face, Drake, Hutchins, Elizabeth, Huber, Thomas S., Seeger, James M., Ozaki, C.Keith
• Format: Article
• Language: English
• Subjects: Adenoviridae - genetics; adenovirus gene therapy, arterial remodeling; Animals; atherosclerosis; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Carotid Artery Diseases - drug therapy; Carotid Artery Diseases - pathology; Carotid Artery, Common - pathology; Female; Genetic Therapy; Green Fluorescent Proteins; Hyperplasia; Indicators and Reagents - metabolism; interleukin 10; Interleukin-10 - genetics; Interleukin-10 - pharmacology; Ligation; Luminescent Proteins - genetics; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; neointimal hyperplasia; Stress, Mechanical; Tunica Intima - pathology
• ISSN: 0022-4804; 1095-8673
• DOI: 10.1006/jsre.2001.6283

Introduction. Overexpression of the anti-inflammatory cytokine interleukin-10 (IL-10) blocks atherosclerotic events in vivo, and IL-10 has been recently hailed as an “immunologic scalpel” for atherosclerosis. Alternatively, mice lacking IL-10 receiving atherogenic diets have increased occlusive lesions. It remains unclear whether such IL-10 modulation broadly applies to other forms of occlusive arterial remodeling. We hypothesized that lack of IL-10 would exacerbate, and exogenous or overexpression of IL-10 would abrogate low shear stress–induced neointimal hyperplasia (NIH). Methods. Wild-type (WT) and IL-10-deficient (IL-10−/−) mice underwent unilateral common carotid artery (CCA) ligation. Low shear stress in the patent ligated artery results in remodeling and formation of neointima containing BrdU and SMC α-actin-positive cells. Additional groups of WT mice underwent CCA ligation and were treated daily with intraperitoneal saline or 1 μg of human IL-10. Chronic delivery gene therapy approaches were also utilized to define the role of IL-10 signaling. WT mice were treated adventitially with 1 × 1010 adenovirus/green fluorescent protein (Ad/gfp) and an Ad/empty control to confirm the veracity of adventitial delivery. Then, Ad viral IL-10 (vIL-10), Ad/empty, and virus buffer alone were applied directly to the adventitia of the CAA immediately following ligation. In separate experiments, 1 × 1010 Ad/empty or Ad/vIL-10 was injected intramuscularly. CCAs were perfusion fixed 28 days postligation, the time at which NIH is near maximum. Results. IL-10−/− mice developed identical NIH areas compared to WT controls. Mice receiving IL-10 demonstrated NIH equivalent to saline controls. Mice receiving intramuscular or adventitial Ad/IL-10 developed high serum levels of IL-10 yet formed NIH areas similar to those of controls. Serum IL-10 levels were significantly higher (P = 0.04) with adventitial delivery. Mice treated adventitially with Ad/gfp showed reliable transfection of cells within the adventitia of CAA. No antibody to human IL-10 was found in the sera of intraperitoneal IL-10-treated mice, which failed to attenuate NIH. Conclusion. Under the conditions of this experiment, lack of IL-10 does not exacerbate low shear stress–induced NIH, nor does exogenous administration or overexpression of IL-10 attenuate it. Despite high serum levels of vIL-10 in mice treated with ad/vIL-10 adventitially, there appears to be no therapeutic effect despite the confirmed transf