Adeno-associated virus vector-mediated systemic interleukin-10 expression ameliorates hypertensive organ damage in Dahl salt-sensitive rats

✍ Scribed by Mutsuko Nonaka-Sarukawa; Takashi Okada; Takayuki Ito; Keiji Yamamoto; Toru Yoshioka; Tatsuya Nomoto; Yukihiro Hojo; Masahisa Shimpo; Masashi Urabe; Hiroaki Mizukami; Akihiro Kume; Uichi Ikeda; Kazuyuki Shimada; Keiya Ozawa

• Publisher: John Wiley and Sons
• Year: 2008
• Tongue: English
• Weight: 823 KB
• Volume: 10
• Category: Article
• ISSN: 1099-498X
• DOI: 10.1002/jgm.1166

✦ Synopsis

Abstract

Background

Inflammation plays an important role in the pathogenesis of hypertension and hypertensive organ damage. Interleukin (IL)‐10, a pleiotropic anti‐inflammatory cytokine, exerts vasculoprotective effects in many animal models. In the present study, we examined the preventive effects of adeno‐associated virus (AAV) vector‐mediated sustained IL‐10 expression against hypertensive heart disease and renal dysfunction in Dahl salt‐sensitive rats.

Methods

We injected the rats intramuscularly with an AAV type 1‐based vector encoding rat IL‐10 or enhanced green fluorescent protein (EGFP) at 5 weeks of age; subsequently, the rats were fed a high‐sodium diet from 6 weeks of age.

Results

Sustained IL‐10 expression significantly improved survival rate of Dahl salt‐sensitive rats compared with EGFP expression (62.5% versus 0%, p < 0.001); it also caused 26.0% reduction in systolic blood pressure at 15 weeks (p < 0.0001). Echocardiography exhibited a 22.0% reduction in hypertrophy (p < 0.0001) and a 26.3% improvement in fractional shortening (p < 0.0001) of the rat left ventricle in the IL‐10 group compared to the EGFP group. IL‐10 expression also caused a 21.7% decrease in the heart weight/body weight index and cardiac atrial natriuretic peptide levels. Histopathological studies revealed that IL‐10 decreased inflammatory cell infiltration, fibrosis, and transforming growth factor‐β~1~ levels in the failing heart. Furthermore, IL‐10 expression significantly reduced urine protein excretion with increased glomerular filtration rates.

Conclusions

This is the first study to demonstrate that the anti‐inflammatory cytokine IL‐10 has a significant anti‐hypertensive effect. AAV vector‐mediated IL‐10 expression potentially prevents the progression of refractory hypertension and hypertensive organ damage in humans. Copyright © 2008 John Wiley & Sons, Ltd.