MicroRNA-100 protects against ischemia-reperfusion injury

Franziska Pankratz (Freiburg im Breisgau)1, C. Smolka (Freiburg im Breisgau)1, D. Westermann (Freiburg im Breisgau)1

1Universitäts-Herzzentrum Freiburg - Bad Krozingen Klinik für Kardiologie und Angiologie Freiburg im Breisgau, Deutschland


Introduction: Ischemia reperfusion injury (IRI) describes a harmful response following re-oxygenation by restoration of the blood flow after a significant time of ischemia. Several studies implicate small non-coding RNAs (miRNAs) as regulator in IRI and we now aim to characterize the role of miR-100.

Methods and results:

For visualization of leukocyte-endothelial interaction and vascular leakage under different miR-100 expression conditions in vivo, we used the model of intravital imaging of postcapillary venules in the cremaster following IRI. A transgenic miR-100 mouse strain allowed the investigation of either ubiquitous or cell-specific miR-100 overexpression. Ubiquitous genetic overexpression of miR-100 resulted in reduced leukocyte adhesion accompanied with an attenuated vascular leakage, whereas a pharmacological inhibition of miR-100 by i.v. injection of a cholesterol-conjugated antisense oligonucleotide specific for miR-100 (AntagomiR-100) had the opposite effect. We next postulated that the observed effects were dependent on an intact miR-100 function in endothelial cells and indeed, endothelial-specific overexpression of miR-100 (Tie2Cre-miR-100 mice) revealed comparable results to the ubiquitous miR-100 overexpression approach. This was supported by a decrease in necrotic tissue in Tie2Cre-miR-100 mice following temporal occlusion of the LAD.  Pharmacologically overexpression of miR-100 resulted in a reduction of adherent leukocytes but not the vascular leakage in the murine cremaster model. Mechanistically, we suggest that miR-100 regulates vascular barrier function by direct suppression of mTOR.

Conclusion: Our data suggest a protective function of miR-100 in IRI and can contribute to the development of miRNA-based therapies of IRI in the future.

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