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Systemic delivery of IL-10 by an AAV vector prevents vascular remodeling and end-organ damage in stroke-prone spontaneously hypertensive rat

Gene Therapy volume 16, pages 383–391 (2009)Cite this article

Abstract

Interleukin-10 (IL-10) ameliorates various T-helper type 1 cell-mediated chronic inflammatory diseases. Although the therapeutic benefits of IL-10 include antiatherosclerotic effects, pathophysiological effects of IL-10 on vascular remodeling in hypertension have not yet been elucidated. These studies were designed to determine whether sustained IL-10 expression, mediated by an adeno-associated virus (AAV) vector, prevents vascular remodeling and target-organ damage in the stroke-prone spontaneously hypertensive rat (SHR-SP)—an animal model of malignant hypertension. A single intramuscular injection of an AAV1 vector encoding rat IL-10 introduced long-term IL-10 expression. These IL-10-transduced rats had decreased stroke episodes and proteinuria, resulting in improved survival. Histological examination revealed a reduced level of deleterious vascular remodeling of resistance vessels in the brain and kidney of these rats. Immunohistochemical analysis indicated that IL-10 inhibited the enhanced renal transforming growth factor-β expression and perivascular infiltration of monocytes/macrophages and nuclear factor-κB-positive cells normally observed in the SHR-SP. Four weeks after IL-10 vector injection, systolic blood pressure significantly decreased and this effect persisted for several months. Overall, AAV vector-mediated systemic IL-10 expression prevented vascular remodeling and inflammatory lesions of target organs in the SHR-SP. This approach provides significant insights into the prevention strategy of disease onset with unknown genetic predisposition or intractable polygenic disorders.

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Acknowledgements

We thank Dr James M Wilson for providing p1RepCap (identical to p5E18RXCI). We thank Avigen Inc. (Alamada, CA, USA) for providing pAAVLacZ and pAdeno. We thank Dr Thomas Hope for providing WPRE DNA. We also thank Ms Miyoko Mitsu and Ms Naomi Inaba for their encouragement and technical support. This work was supported in part by grants from the Ministry of Health, Labour and Welfare of Japan: grants-in-aid for Scientific Research; grant for twenty-first century COE program; and ‘High-Tech Research Center’ Project for Private Universities, matching fund subsidy, from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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Authors and Affiliations

  1. Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan

    T Nomoto, T Okada, T Yoshioka, M Nonaka-Sarukawa, T Ito, H Mizukami, A Kume & K Ozawa

  2. Second Department of Internal Medicine, Nippon Medical School, Tokyo, Japan

    T Nomoto, K-i Katsura & Y Katayama

  3. Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan

    T Okada

  4. Department of Physiology, Jichi Medical University, Tochigi, Japan

    K Shimazaki

  5. Department of Anatomy, Jichi Medical University, Tochigi, Japan

    K Takeuchi & S Ookawara

  6. Department of Cardiovascular Medicine, Shinshu University Graduate School of Medicine, Nagano, Japan

    U Ikeda

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  1. T Nomoto
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Correspondence to T Okada or K Ozawa.

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Nomoto, T., Okada, T., Shimazaki, K. et al. Systemic delivery of IL-10 by an AAV vector prevents vascular remodeling and end-organ damage in stroke-prone spontaneously hypertensive rat. Gene Ther 16, 383–391 (2009). https://doi.org/10.1038/gt.2008.151

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