State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Disease in Central Asia, Department of Cardiology, The First Affiliated Hospital of Xinjiang Medical University, 137 Liyushan South Road, Urumqi, 830054, China.
Xinjiang Key Laboratory of Cardiovascular Disease Research, Urumqi, 830054, China.
Cardiovasc Drugs Ther. 2020 Feb;34(1):3-14. doi: 10.1007/s10557-020-06936-8.
We investigated whether increased expression of activated mitogen-activated protein kinase (MAPK) kinases 1 (MEK1) restores ischemic post-conditioning (IPostC) protection in hypertrophic myocardium following ischemia/reperfusion (I/R) injury.
C57Bl/6 mice received recombinant adeno-associated virus type 9 (rAAV9)-mediated activated MEK1 gene delivery systemically, then following the induction of cardiac hypertrophy via transverse aortic constriction for 4 weeks. In a Langendorff model, hypertrophic hearts were subjected to 40 min/60 min I/R or with IPostC intervention consisting of 6 cycles of 10 s reperfusion and 10 s no-flow before a 60-min reperfusion. Hemodynamics, infarct size (IS), myocyte apoptosis and changes in expression of reperfusion injury salvage kinase (RISK) pathway were examined.
rAAV9-MEK1 gene delivery led to a 4.3-fold and 2.7-fold increase in MEK1 mRNA and protein expression in the heart versus their control values. I/R resulted in a larger IS in hypertrophic than in non-hypertrophic hearts (52.3 ± 4.7% vs. 40.0 ± 2.5%, P < 0.05). IPostC mediated IS reduction in non-hypertrophic hearts (27.6 ± 2.6%, P < 0.05), while it had no significant effect in hypertrophic hearts (46.5 ± 3.1%, P=NS) compared with the IS in non-hypertrophic or hypertrophic hearts subjected to I/R injury only, respectively. Hemodynamic decline induced by I/R was preserved by IPostC in non-hypertrophic hearts but not in hypertrophic hearts. rAAV9-MEK1 gene delivery restored IPostC protection in hypertrophic hearts evidenced by reduced IS (32.0 ± 2.8% vs. 46.5 ± 3.1%) and cardiac cell apoptosis and largely preserved hemodynamic parameters. These protective effects were associated with significantly increased phosphorylation of ERK1/2 and ribosomal protein S6 kinases (p70S6K), but it had no influence on Akt and glycogen synthase kinase-3β.
These results demonstrated that rAAV9-mediated activated MEK1 expression restores IPostC protection in the hypertrophic heart against I/R injury through the activation of ERK pathway.
我们研究了激活丝裂原活化蛋白激酶（MAPK）激酶 1（MEK1）的表达增加是否能恢复肥厚心肌缺血后处理（IPostC）对缺血/再灌注（I/R）损伤的保护作用。
C57Bl/6 小鼠接受重组腺相关病毒 9（rAAV9）介导的激活 MEK1 基因全身递送系统，然后通过横主动脉缩窄诱导心肌肥厚 4 周。在 Langendorff 模型中，肥厚的心脏经历 40min/60min 的 I/R，或用 IPostC 干预，包括 6 个循环的 10s 再灌注和 10s 无血流，然后再进行 60min 的再灌注。检测血流动力学、梗死面积（IS）、心肌细胞凋亡以及再灌注损伤挽救激酶（RISK）通路表达的变化。
rAAV9-MEK1 基因转导使心脏中 MEK1 mRNA 和蛋白的表达分别增加了 4.3 倍和 2.7 倍。与非肥厚心脏相比，肥厚心脏的 I/R 导致更大的 IS（52.3±4.7%比 40.0±2.5%，P<0.05）。IPostC 介导非肥厚心脏的 IS 减少（27.6±2.6%，P<0.05），而在肥厚心脏中则没有显著影响（46.5±3.1%，P=NS），分别与非肥厚或肥厚心脏仅接受 I/R 损伤相比。IPostC 在非肥厚心脏中保留了 I/R 引起的血流动力学下降，但在肥厚心脏中则没有。rAAV9-MEK1 基因转导恢复了肥厚心脏的 IPostC 保护作用，表现为 IS 减少（32.0±2.8%比 46.5±3.1%）和心肌细胞凋亡减少，并且很大程度上保留了血流动力学参数。这些保护作用与 ERK1/2 和核糖体蛋白 S6 激酶（p70S6K）的磷酸化显著增加有关，但对 Akt 和糖原合酶激酶-3β没有影响。
这些结果表明，rAAV9 介导的激活 MEK1 表达通过激活 ERK 通路恢复肥厚心肌对 I/R 损伤的 IPostC 保护作用。
