Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Montréal, Québec, Canada.
Hypertension. 2011 Feb;57(2):245-54. doi: 10.1161/HYPERTENSIONAHA.110.159889. Epub 2010 Dec 20.
Vascular oxidative stress and inflammation play an important role in angiotensin II-induced hypertension, and mitogen-activated protein kinases participate in these processes. We questioned whether mitogen-activated protein kinase-activated protein kinase 2 (MK2), a downstream target of p38 mitogen-activated protein kinase, is involved in angiotensin II-induced vascular responses. In vivo experiments were performed in wild-type and Mk2 knockout mice infused intravenously with angiotensin II. Angiotensin II induced a 30 mm Hg increase in mean blood pressure in wild-type that was delayed in Mk2 knockout mice. Angiotensin II increased superoxide production and vascular cell adhesion molecule-1 in blood vessels of wild-type but not in Mk2 knockout mice. Mk2 knockdown by small interfering RNA in mouse mesenteric vascular smooth muscle cells caused a 42% reduction in MK2 protein and blunted the angiotensin II-induced 40% increase of MK2 expression. Mk2 knockdown blunted angiotensin II-induced doubling of intracellular adhesion molecule-1 expression, 2.4-fold increase of nuclear p65, and 1.4-fold increase in Ets-1. Mk2 knockdown abrogated the angiotensin II-induced 4.7-fold and 1.3-fold increase of monocyte chemoattractant protein-1 mRNA and protein. Angiotensin II enhanced reactive oxygen species levels (by 29%) and nicotinamide adenine dinucleotide phosphate oxidase activity (by 48%), both abolished by Mk2 knockdown. Reduction of MK2 blocked angiotensin II-induced p47phox translocation to the membrane, associated with a 53% enhanced catalase expression. Angiotensin II-induced increase of MK2 was prevented by the nicotinamide adenine dinucleotide phosphate oxidase inhibitor Nox2ds-tat. Mk2 small interfering RNA prevented the angiotensin II-induced 30% increase of proliferation. In conclusion, MK2 plays a critical role in angiotensin II signaling, leading to hypertension, oxidative stress via activation of p47phox and inhibition of antioxidants, and vascular inflammation and proliferation.
血管氧化应激和炎症在血管紧张素 II 诱导的高血压中起重要作用，丝裂原活化蛋白激酶参与这些过程。我们质疑丝裂原活化蛋白激酶激活的蛋白激酶 2（MK2），p38 丝裂原活化蛋白激酶的下游靶点，是否参与血管紧张素 II 诱导的血管反应。在静脉内输注血管紧张素 II 的野生型和 Mk2 敲除小鼠中进行体内实验。血管紧张素 II 使野生型小鼠的平均血压升高 30mmHg，而 Mk2 敲除小鼠的血压升高延迟。血管紧张素 II 增加了野生型小鼠血管中的超氧化物产生和血管细胞黏附分子-1，但在 Mk2 敲除小鼠中则没有。在小鼠肠系膜血管平滑肌细胞中用小干扰 RNA 敲低 Mk2 导致 MK2 蛋白减少 42%，并减弱了血管紧张素 II 诱导的 MK2 表达增加 40%。Mk2 敲低减弱了血管紧张素 II 诱导的细胞间黏附分子-1 表达增加 40%，核 p65 增加 2.4 倍，Ets-1 增加 1.4 倍。Mk2 敲低阻断了血管紧张素 II 诱导的单核细胞趋化蛋白-1 mRNA 和蛋白增加 4.7 倍和 1.3 倍。血管紧张素 II 增强了活性氧水平（增加 29%）和烟酰胺腺嘌呤二核苷酸磷酸氧化酶活性（增加 48%），这两种作用都被 Mk2 敲低所消除。MK2 的减少阻断了血管紧张素 II 诱导的 p47phox 向膜的易位，与过氧化氢酶表达增加 53%相关。烟酰胺腺嘌呤二核苷酸磷酸氧化酶抑制剂 Nox2ds-tat 阻止了血管紧张素 II 诱导的 MK2 增加。Mk2 小干扰 RNA 阻止了血管紧张素 II 诱导的 30%的增殖增加。总之，MK2 在血管紧张素 II 信号转导中起关键作用，导致高血压、通过激活 p47phox 和抑制抗氧化剂引起的氧化应激，以及血管炎症和增殖。
