Systemic delivery of IL-10 by an AAV vector prevents vascular remodeling and end-organ damage in stroke-prone spontaneously hypertensive rat.
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-beta expression and perivascular infiltration of monocytes/macrophages and nuclear factor-kappaB-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.
Nomoto
T
T
Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan.
Okada
T
T
Shimazaki
K
K
Yoshioka
T
T
Nonaka-Sarukawa
M
M
Ito
T
T
Takeuchi
K
K
Katsura
K-I
KI
Mizukami
H
H
Kume
A
A
Ookawara
S
S
Ikeda
U
U
Katayama
Y
Y
Ozawa
K
K
D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D001921:Brain / Q000098:blood supply / Q000473:pathology; D002339:Carotid Arteries / Q000473:pathology; D000229:Dependovirus / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006973:Hypertension / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000235:genetics; D007674:Kidney Diseases / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D020521:Stroke / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D016019:Survival Analysis; D014161:Transduction, Genetic
D016753:Interleukin-10