| First Author | Shimizu T | Year | 2020 |
| Journal | iScience | Volume | 23 |
| Issue | 8 | Pages | 101410 |
| PubMed ID | 32768667 | Mgi Jnum | J:306918 |
| Mgi Id | MGI:6705723 | Doi | 10.1016/j.isci.2020.101410 |
| Citation | Shimizu T, et al. (2020) PERK-Mediated Suppression of microRNAs by Sildenafil Improves Mitochondrial Dysfunction in Heart Failure. iScience 23(8):101410 |
| abstractText | 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. |
