Department of Internal Medicine, Eastern Virginia Medical School, Norfolk, VA, USA.
Hypertension. 2010 Mar;55(3):715-21. doi: 10.1161/HYPERTENSIONAHA.109.148049. Epub 2010 Jan 25.
Obesity, hypertension, cardiovascular disease, and inflammation are closely associated with the rising incidence of diabetes mellitus. One pharmacological target that may have significant potential to lower the risk of obesity-related diseases is the angiotensin type 1 receptor (AT1R). We examined the hypothesis that the AT1R blocker valsartan reduces the metabolic consequences and inflammatory effects of a high-fat (Western) diet in mice. C57BL/6J mice were treated by oral gavage with 10 mg/kg per day of valsartan or vehicle and placed on either a standard chow or Western diet for 12 weeks. Western diet-fed mice given valsartan had improved glucose tolerance, reduced fasting blood glucose levels, and reduced serum insulin levels compared with mice fed a Western diet alone. Valsartan treatment also blocked Western diet-induced increases in serum levels of the proinflammatory cytokines interferon-gamma and monocyte chemotactic protein 1. In the pancreatic islets, valsartan enhanced mitochondrial function and prevented Western diet-induced decreases in glucose-stimulated insulin secretion. In adipose tissue, valsartan reduced Western diet-induced macrophage infiltration and expression of macrophage-derived monocyte chemotactic protein 1. In isolated adipocytes, valsartan treatment blocked or attenuated Western diet-induced changes in expression of several key inflammatory signals: interleukin 12p40, interleukin 12p35, tumor necrosis factor-alpha, interferon-gamma, adiponectin, platelet 12-lipoxygenase, collagen 6, inducible NO synthase, and AT1R. Our findings indicate that AT1R blockade with valsartan attenuated several deleterious effects of the Western diet at the systemic and local levels in islets and adipose tissue. This study suggests that AT1R blockers provide additional therapeutic benefits in the metabolic syndrome and other obesity-related disorders beyond lowering blood pressure.
肥胖症、高血压、心血管疾病和炎症与糖尿病发病率的上升密切相关。血管紧张素 1 型受体（AT1R）可能是降低肥胖相关疾病风险的有前途的药物靶点之一。我们检验了这样一个假设，即 AT1R 阻断剂缬沙坦可降低高脂肪（西式）饮食对小鼠的代谢后果和炎症作用。通过口服灌胃，用 10mg/kg/天的缬沙坦或载体处理 C57BL/6J 小鼠，并将其置于标准饲料或西式饮食中 12 周。与单独给予西式饮食的小鼠相比，给予缬沙坦的西式饮食喂养的小鼠具有改善的葡萄糖耐量、降低的空腹血糖水平和降低的血清胰岛素水平。缬沙坦治疗还阻断了西式饮食诱导的促炎细胞因子干扰素-γ和单核细胞趋化蛋白 1 的血清水平升高。在胰岛中，缬沙坦增强了线粒体功能并防止了西式饮食诱导的葡萄糖刺激的胰岛素分泌减少。在脂肪组织中，缬沙坦减少了西式饮食诱导的巨噬细胞浸润和巨噬细胞衍生的单核细胞趋化蛋白 1 的表达。在分离的脂肪细胞中，缬沙坦处理阻断或减弱了西式饮食诱导的几种关键炎症信号的表达变化：白细胞介素 12p40、白细胞介素 12p35、肿瘤坏死因子-α、干扰素-γ、脂联素、血小板 12-脂加氧酶、胶原 6、诱导型一氧化氮合酶和 AT1R。我们的研究结果表明，缬沙坦阻断 AT1R 减轻了系统性和局部水平在胰岛和脂肪组织中西式饮食的几种有害影响。这项研究表明，AT1R 阻断剂除了降低血压外，还为代谢综合征和其他肥胖相关疾病提供了额外的治疗益处。
