PERK-Mediated Suppression of microRNAs by Sildenafil Improves Mitochondrial Dysfunction in Heart Failure

Takashi Shimizu; Akashi Taguchi; Yoshiki Higashijima; Naoko Takubo; Yasuharu Kanki; Yoshihiro Urade; Youichiro Wada

doi:10.1016/j.isci.2020.101410

PERK-Mediated Suppression of microRNAs by Sildenafil Improves Mitochondrial Dysfunction in Heart Failure

iScience. 2020 Aug 21;23(8):101410. doi: 10.1016/j.isci.2020.101410. Epub 2020 Jul 24.

Authors

Takashi Shimizu¹, Akashi Taguchi², Yoshiki Higashijima³, Naoko Takubo², Yasuharu Kanki², Yoshihiro Urade², Youichiro Wada²

Affiliations

¹ Isotope Science Center, The University of Tokyo, Tokyo 113-0032, Japan; Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan. Electronic address: tshimizu227-tky@umin.ac.jp.
² Isotope Science Center, The University of Tokyo, Tokyo 113-0032, Japan.
³ Isotope Science Center, The University of Tokyo, Tokyo 113-0032, Japan; Department of Bioinformational Pharmacology, Tokyo Medical and Dental University, Tokyo 113-8510, Japan; Department of Proteomics, The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, Copenhagen 2200, Denmark.

Abstract

Oxidative/nitrosative stress is a major trigger of cardiac dysfunction, involving the unfolded protein response and mitochondrial dysfunction. Activation of nitric oxide-cyclic guanosine monophosphate-protein kinase G signaling by sildenafil improves cardiac mal-remodeling during pressure-overload-induced heart failure. Transcriptome analysis was conducted in failing hearts with or without sildenafil treatment. Protein kinase R-like endoplasmic reticulum (ER) kinase (PERK) downstream signaling pathways, EIF2 and NRF2, were significantly altered. Although EIF2 signaling was suppressed, NRF2 signaling was upregulated, inhibiting the maturation of miR 24-3p through EGFR-mediated Ago2 phosphorylation. To study the effect of sildenafil on these pathways, we generated cardiac-specific PERK knockout mice. In these mice, sildenafil could not inhibit the maturations, the nuclear translocation of NRF2 was suppressed, and mitochondrial dysfunction advanced. Altogether, these results show that PERK-mediated suppression of miRNAs by sildenafil is vital for maintaining mitochondrial homeostasis through NRF2-mediated oxidative stress response.

Keywords: Biological Sciences; Cell Biology; Molecular Biology.