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

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Mitochondrial Medicine

Background:

• Oxidative/nitrosative stress and unfolded protein response (UPR) are key contributors to cardiac dysfunction and heart failure.
• Sildenafil activates nitric oxide-cyclic guanosine monophosphate-protein kinase G (NO-cGMP-PKG) signaling, improving cardiac remodeling in pressure-overload-induced heart failure.

Purpose of the Study:

• To investigate the molecular mechanisms by which sildenafil mitigates cardiac dysfunction.
• To elucidate the role of the Protein kinase R-like endoplasmic reticulum (ER) kinase (PERK) pathway in sildenafil's cardioprotective effects.

Main Methods:

• Transcriptome analysis of failing hearts with and without sildenafil treatment.
• Generation of cardiac-specific PERK knockout mice to assess sildenafil's effects in vivo.
• Analysis of downstream signaling pathways including EIF2, NRF2, and microRNA (miRNA) maturation.

Main Results:

• Sildenafil treatment altered PERK downstream signaling, suppressing EIF2 and upregulating NRF2 pathways.
• Upregulated NRF2 signaling inhibited miR-24-3p maturation via EGFR-mediated Ago2 phosphorylation.
• In cardiac-specific PERK knockout mice, sildenafil failed to inhibit miRNA maturation, leading to suppressed NRF2 nuclear translocation and exacerbated mitochondrial dysfunction.

Conclusions:

• PERK-mediated suppression of miRNAs by sildenafil is crucial for maintaining mitochondrial homeostasis.
• This pathway is vital for the NRF2-mediated oxidative stress response in the heart.
• Sildenafil's cardioprotective effects are dependent on the PERK signaling pathway's ability to regulate miRNA maturation and oxidative stress.