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rAAV9-Mediated MEK1 Gene Expression Restores Post-conditioning Protection Against Ischemia Injury in Hypertrophic Myocardium

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Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusion

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.

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Funding

This work was supported by a key project of Xinjiang jointed program (U1903212) from the National Science Technology Ministry of China, an open project (No. 2018D04030) of Key Laboratory from Science and Technology Department of Xinjiang Uygur Autonomous Region, a project grant (No. 81870272) from National Nature Science Foundation of China and a “973” Preliminary program grant (ID 2010CB535013) from the National Science Technology Ministry of China.

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Author notes

  1. You Chen and Fen Liu contributed equally to this work.

Authors and Affiliations

  1. 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

    You Chen, Fen Liu, Bang-Dang Chen, Xiao-Mei Li, Ying Huang, Zi-Xiang Yu, Chun-Hui He, Yi-Ning Yang, Yi-Tong Ma & Xiao-Ming Gao

  2. Xinjiang Key Laboratory of Cardiovascular Disease Research, Urumqi, 830054, China

    You Chen, Fen Liu, Bang-Dang Chen, Xiao-Mei Li, Ying Huang, Zi-Xiang Yu, Chun-Hui He, Yi-Ning Yang, Yi-Tong Ma & Xiao-Ming Gao

  3. Clinical Medical Research Institute, Xinjiang Medical University, Urumqi, 830054, China

    Fen Liu, Bang-Dang Chen & Xiao-Ming Gao

  4. College of Pharmacy, Xinjiang Medical University, Urumqi, China

    Xiao-Li Gao

  5. Xinjiang Key Laboratory of Medical Animal Model Research, Urumqi, 830054, China

    Xiao-Ming Gao

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  1. You Chen
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Contributions

Conceived and designed the experiments and obtained funding support: X.M.G., Y.T.M. and Y.N.Y.; Performed the experiment: Y.C., F.L., X.M.G., B.D.C. and Z.X.Y.; Contributed reagents/materials/analysis: F.L., X.M.L., X.L.G., Y.H., Z.X.Y. and X.M.G.; Wrote the manuscript: Y.C., C.H.H. and X.M.G.; Revised manuscript for submission: Y.C. and X.M.G.

Corresponding authors

Correspondence to Yi-Ning Yang, Yi-Tong Ma or Xiao-Ming Gao.

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Chen, Y., Liu, F., Chen, BD. et al. rAAV9-Mediated MEK1 Gene Expression Restores Post-conditioning Protection Against Ischemia Injury in Hypertrophic Myocardium. Cardiovasc Drugs Ther 34, 3–14 (2020). https://doi.org/10.1007/s10557-020-06936-8

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