Systemic delivery of IL-10 by an AAV vector prevents vascular remodeling and end-organ damage in stroke-prone spontaneously hypertensive rat
Systemic delivery of IL-10 by an AAV vector prevents vascular remodeling and end-organ damage in stroke-prone spontaneously hypertensive rat
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DOI：
10.1038/gt.2008.151
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发表时间：
2009-03-01
期刊：
影响因子：
5.1
通讯作者：
Ozawa, K.
中科院分区：
文献类型：
--
作者：
Nomoto, T.;Okada, T.;Ozawa, K.
白细胞介素-10（IL-10）可改善多种1型辅助性T细胞介导的慢性炎性疾病。虽然IL-10的治疗益处包括抗动脉粥样硬化作用，但IL-10对高血压中血管重塑的病理生理学作用尚未阐明。这些研究的目的是确定是否持续的IL-10表达，介导的腺相关病毒（AAV）载体，防止血管重塑和靶器官损伤的中风倾向的自发性高血压大鼠（SHR-SP）-恶性高血压的动物模型。编码大鼠IL-10的AAV 1载体的单次肌内注射引入长期IL-10表达。这些IL-10转导的大鼠减少了中风发作和蛋白尿，从而提高了生存率。组织学检查显示这些大鼠的脑和肾中阻力血管的有害血管重塑水平降低。免疫组织化学分析表明，IL-10抑制了SHR-SP中正常观察到的肾转化生长因子-β表达增强和单核细胞/巨噬细胞和核因子-κ B阳性细胞的血管周围浸润。IL-10载体注射后4周，收缩压显著降低，这种作用持续数月。总体而言，AAV载体介导的系统性IL-10表达预防了SHR-SP中靶器官的血管重塑和炎性病变。这种方法为未知遗传易感性疾病或难治性多基因疾病的预防策略提供了重要的见解。
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-kappa B-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.