Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
Br J Pharmacol. 2011 Mar;162(5):1012-28. doi: 10.1111/j.1476-5381.2010.01043.x.
While maintaining cardiac performance, chronic β-adrenoceptor activation eventually exacerbates the progression of cardiac remodelling and failure. We examined the adverse signalling pathways mediated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and reactive oxygen species (ROS) after chronic β₂-adrenoceptor activation.
Mice with transgenic β₂-adrenoceptor overexpression (β₂-TG) and non-transgenic littermates were either untreated or treated with an antioxidant (N-acetylcysteine, NAC) or NADPH oxidase inhibitors (apocynin, diphenyliodonium). Levels of ROS, phosphorylated p38 mitogen-activated protein kinase (MAPK), pro-inflammatory cytokines and collagen content in the left ventricle (LV) and LV function were measured and compared.
β₂-TG mice showed increased ROS production, phosphorylation of p38 MAPK and heat shock protein 27 (HSP27), expression of pro-inflammatory cytokines and collagen, and progressive ventricular dysfunction. β₂-adrenoceptor stimulation similarly increased ROS production and phosphorylation of p38 MAPK and HSP27 in cultured cardiomyocytes. Treatment with apocynin, diphenyliodonium or NAC reduced phosphorylation of p38 MAPK and HSP27 in both cultured cardiomyocytes and the LV of β₂-TG mice. NAC treatment (500 mg·kg⁻¹ ·day⁻¹) for 2 weeks eliminated the up-regulated expression of pro-inflammatory cytokines and collagen in the LV of β₂-TG mice. Chronic NAC treatment to β₂-TG mice from 7 to 10 months of age largely prevented progression of ventricular dilatation, preserved contractile function (fractional shortening 37 ± 5% vs. 25 ± 3%, ejection fraction 52 ± 5% vs. 32 ± 4%, both P < 0.05), reduced cardiac fibrosis and suppressed matrix metalloproteinase activity.
β₂-adrenoceptor stimulation provoked NADPH oxidase-derived ROS production in the heart. Elevated ROS activated p38 MAPK and contributed significantly to cardiac inflammation, remodelling and failure.
在维持心脏功能的同时，慢性β肾上腺素受体激活最终会加剧心脏重构和衰竭的进展。我们研究了慢性β₂肾上腺素受体激活后烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶和活性氧（ROS）介导的不良信号通路。
过表达转基因β₂肾上腺素受体（β₂-TG）的小鼠及其非转基因同窝仔鼠，分别给予抗氧化剂（N-乙酰半胱氨酸，NAC）或 NADPH 氧化酶抑制剂（apocynin，二苯基碘鎓）处理或未处理。测量并比较左心室（LV）中 ROS、磷酸化 p38 丝裂原激活蛋白激酶（p38 MAPK）、促炎细胞因子和胶原蛋白含量以及 LV 功能。
β₂-TG 小鼠表现出 ROS 生成增加、p38 MAPK 和热休克蛋白 27（HSP27）磷酸化、促炎细胞因子和胶原蛋白表达以及心室功能进行性障碍。β₂肾上腺素受体刺激同样增加了培养的心肌细胞中 ROS 的产生以及 p38 MAPK 和 HSP27 的磷酸化。apocynin、二苯基碘鎓或 NAC 处理可降低培养的心肌细胞和β₂-TG 小鼠 LV 中 p38 MAPK 和 HSP27 的磷酸化。2 周的 NAC 治疗（500 mg·kg⁻¹·day⁻¹）消除了β₂-TG 小鼠 LV 中促炎细胞因子和胶原蛋白的上调表达。从 7 至 10 个月龄开始对β₂-TG 小鼠进行慢性 NAC 治疗在很大程度上阻止了心室扩张的进展，保留了收缩功能（缩短分数 37±5%比 25±3%，射血分数 52±5%比 32±4%，均 P<0.05），减少了心脏纤维化并抑制了基质金属蛋白酶活性。
β₂肾上腺素受体刺激引起心脏中 NADPH 氧化酶衍生的 ROS 生成。升高的 ROS 激活了 p38 MAPK，对心脏炎症、重构和衰竭有重要贡献。
