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

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

doi:10.1016/j.isci.2020.101410

Abstract

SummaryOxidative/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.

Highlights

Death due to heart failure (HF) is steadily increasing worldwide
Chronic inflammation related to obesity and hypertension induces excessive production of reactive oxygen species (ROS) in mitochondria, leading to mitochondrial DNA damage, impairment of sarcomere contraction, and activation of various signaling pathways related to cardiac hypertrophy and apoptosis (Tsutsui et al, 2011)
The activity of the IRE1a-XBP1 arm was not suppressed in the chronic phase when compared with that in the acute phase

Summary

Introduction

Death due to heart failure (HF) is steadily increasing worldwide. Chronic inflammation related to obesity and hypertension induces excessive production of reactive oxygen species (ROS) in mitochondria, leading to mitochondrial DNA (mtDNA) damage, impairment of sarcomere contraction, and activation of various signaling pathways related to cardiac hypertrophy and apoptosis (Tsutsui et al, 2011). ROS overproduction causes the misfolding of proteins in the ER, which leads to ER stress (Fujii et al, 2018). Three ER stress sensors, inositol-requiring protein-1 (IRE1) a, activating transcription factor-6 (ATF6), and protein kinase RNA (PKR)-like ER kinase (PERK) initiate the unfolded protein response (UPR). Each of the three arms of the UPR, IRE1a (Steiger et al, 2018), ATF6 (Blackwood et al, 2019), and PERK (Liu et al, 2014), is known to be protective for hearts exposed to pressure overload (PO)

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