Martinka P, Lai E Y, Fähling M, Jankowski V, Jankowski J, Schubert R, Gaestel M, Persson A E G, Persson P B, Patzak A
Institut für Vegetative Physiologie, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Acta Physiol (Oxf). 2008 May;193(1):37-46. doi: 10.1111/j.1748-1716.2007.01800.x. Epub 2007 Nov 14.
Adenosine (Ado) restores desensitized angiotensin II-induced contractions in the renal arterioles via an intracellular, receptor-independent mechanisms including the p38 mitogen-activated protein kinase (MAPK). In the present study we test the hypothesis that MAPK-activated protein kinase 2 (MK2) mediates the Ado effect downstream from p38 MAPK resulting in an increased phosphorylation of the regulatory unit of the myosin light chain (MLC(20)).
Contraction experiments were performed in rings of mesenteric arteries under isometric conditions in C57BL6 and MK2 knock out mice (MK2-/-). Ado pretreatment (10(-5) mol L(-1)) strongly increased Ang II sensitivity, calcium sensitivity and the phosphorylation of MLC(20). Treatment with Ado (3 x 10(-6) or 10(-5) mol L(-1) in between successive Ang II applications) enhanced the desensitized Ang II responses (second to fifth application). Ca(2+) transients were not effected by Ado. Further, blockade of type 1 and type 2 Ado receptors during treatment did not influence the effect. Type 3 receptor activation by inosine instead of Ado had no effect. Conversely, inhibition of nitrobenzylthioinosine-sensitive Ado transporters prevented the effects of Ado. Inhibition of p38 MAPK as well as use of MK2-/- mice prevented contractile Ado effects on the mesenteric arteries and the phosphorylation of MLC(20).
The study shows that Ado activates the p38 MAPK/MK2 pathway in vascular smooth muscle via an intracellular action, which results in an increased MLC(20) phosphorylation in concert with increased calcium sensitivity of the contractile apparatus. This mechanism can significantly contribute to the regulation of vascular tone, e.g. under post-ischaemic conditions.
腺苷（Ado）通过包括p38丝裂原活化蛋白激酶（MAPK）在内的细胞内、受体非依赖性机制恢复肾小动脉中脱敏的血管紧张素II诱导的收缩。在本研究中，我们检验以下假设：MAPK活化蛋白激酶2（MK2）介导Ado在p38 MAPK下游的效应，导致肌球蛋白轻链调节单位（MLC(20)）磷酸化增加。
在等长条件下，对C57BL6和MK2基因敲除小鼠（MK2-/-）的肠系膜动脉环进行收缩实验。Ado预处理（10(-5) mol L(-1)）强烈增加了血管紧张素II敏感性、钙敏感性以及MLC(20)的磷酸化。在连续应用血管紧张素II之间用Ado（3 x 10(-6)或10(-5) mol L(-1)）处理增强了脱敏的血管紧张素II反应（第二次至第五次应用）。Ca(2+)瞬变不受Ado影响。此外，在处理过程中阻断1型和2型Ado受体不影响该效应。用肌苷而非Ado激活3型受体没有作用。相反，抑制对硝基苄硫基肌苷敏感的Ado转运体可阻止Ado的效应。抑制p38 MAPK以及使用MK2-/-小鼠可阻止Ado对肠系膜动脉的收缩效应以及MLC(20)的磷酸化。
该研究表明，Ado通过细胞内作用激活血管平滑肌中的p38 MAPK/MK2途径，这与收缩装置的钙敏感性增加协同导致MLC(20)磷酸化增加。这种机制可显著有助于血管张力的调节，例如在缺血后条件下。
