Adeno-associated virus vector-mediated systemic interleukin-10 expression ameliorates hypertensive organ damage in Dahl salt-sensitive rats.
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-beta(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.
Nonaka-Sarukawa
Mutsuko
M
Division of Genetic Therapeutics, Jichi Medical University, Tochigi, Japan.
Okada
Takashi
T
Ito
Takayuki
T
Yamamoto
Keiji
K
Yoshioka
Toru
T
Nomoto
Tatsuya
T
Hojo
Yukihiro
Y
Shimpo
Masahisa
M
Urabe
Masashi
M
Mizukami
Hiroaki
H
Kume
Akihiro
A
Ikeda
Uichi
U
Shimada
Kazuyuki
K
Ozawa
Keiya
K
D000818:Animals; D000229:Dependovirus; D015316:Genetic Therapy; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000235:genetics; D006973:Hypertension / Q000150:complications* / Q000473:pathology; D017379:Hypertrophy, Left Ventricular / Q000209:etiology / Q000473:pathology / Q000628:therapy*; D016753:Interleukin-10 / Q000235:genetics*; D008297:Male; D051381:Rats; D020303:Rats, Inbred Dahl; D020257:Ventricular Remodeling
D016753:Interleukin-10; D049452:Green Fluorescent Proteins