3 years ago

MicroRNA-142-3p improves vascular relaxation in uremia

Máté Kétszeri, Andrijana Kirsch, Bianca Frauscher, Foteini Moschovaki-filippidou, Agnes A. Mooslechner, Alexander H. Kirsch, Corinna Schabhuettl, Ida Aringer, Katharina Artinger, Gudrun Pregartner, Robert Ekart, Silva Breznik, Radovan Hojs, Walter Goessler, Irene Schilcher, Helmut Müller, Barbara Obermayer-pietsch, Saša Frank, Alexander R. Rosenkranz, Philipp Eller

Publication date: Available online 10 November 2018

Source: Atherosclerosis

Author(s): Máté Kétszeri, Andrijana Kirsch, Bianca Frauscher, Foteini Moschovaki-Filippidou, Agnes A. Mooslechner, Alexander H. Kirsch, Corinna Schabhuettl, Ida Aringer, Katharina Artinger, Gudrun Pregartner, Robert Ekart, Silva Breznik, Radovan Hojs, Walter Goessler, Irene Schilcher, Helmut Müller, Barbara Obermayer-Pietsch, Saša Frank, Alexander R. Rosenkranz, Philipp Eller

Abstract
Background and aims

Chronic kidney disease (CKD) is strongly associated with a high burden of cardiovascular morbidity and mortality. Therefore, we aimed to characterize the putative role of microRNAs (miR)s in uremic vascular remodelling and endothelial dysfunction.

Methods

We investigated the expression pattern of miRs in two independent end-stage renal disease (ESRD) cohorts and in the animal model of uremic DBA/2 mice via quantitative RT-PCR. Moreover, DBA/2 mice were treated with intravenous injections of synthetic miR-142-3p mimic and were analysed for functional and morphological vascular changes by mass spectrometry and wire myography.

Results

The expression pattern of miRs was regulated in ESRD patients and was reversible after kidney transplantation. Out of tested miRs, only blood miR-142-3p was negatively associated with carotid-femoral pulse-wave velocity in CKD 5D patients. We validated these findings in a murine uremic model and found similar suppression of miR-142-3p as well as decreased acetylcholine-mediated vascular relaxation of the aorta. Therefore, we designed experiments to restore bioavailability of aortic miR-142-3p in vivo via intravenous injection of synthetic miR-142-3p mimic. This intervention restored acetylcholine-mediated vascular relaxation.

Conclusions

Taken together, we provide compelling evidence, both in humans and in mice, that miR-142-3p constitutes a potential pharmacological agent to prevent endothelial dysfunction and increased arterial stiffness in ESRD.

Graphical abstract

Image 1

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