DUSP5 Protects against Diabetes-Related Heart Failure via Inhibiting PPARα-Mediated Fatty Acid Oxidation

Abstract

Background: Heart failure (HF) is one of the most common complications of diabetes mellitus. This study aimed to investigate the potential roles of dual specificity phosphatase 5 (DUSP5), a negative regulator of mitogen-activated protein kinase signaling, in diabetes-related HF. Methods: Sprague dawley rats were randomly divided into the sham group, streptozotocin (STZ) group, STZ + vector group, STZ + Ad-DUSP5 group and vehicle group, and a group that was intravenously administered DUSP5-nanoparticle (NP) that carried the peroxisome proliferator-activated receptor alpha (PPARα) antagonist GW-6471. Triphenyl tetrazolium chloride staining was used to analyze the infarct area. The apoptosis of cardiomyocytes was determined using the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling assay. For in vitro assays, mRNA expression was determined using quantitative reverse transcription-PCR; protein expression was detected using western blotting; protein localization was determined using immunofluorescence assay; and cell apoptosis was analyzed using flow cytometry. Results: DUSP5 expression was decreased in patients with diabetes-related HF, as well as in the in vitro model (p < 0.05). However, overexpression of DUSP5 inhibited the apoptosis of cardiomyocytes and fatty acid oxidation (p < 0.05). Moreover, DUSP5 mediated the nuclear translocation of PPARα (p < 0.05). By contrast, overexpression of PPARα promoted fatty acid oxidation and the apoptosis of cardiomyocytes (p < 0.05). The in vivo assay showed that DUSP5 overexpression inhibited the infarct area and death of cardiomyocytes (p < 0.05). Additionally, DUSP5-NP that delivered GW-6471 markedly alleviated heart damage induced by diabetes mellitus (p < 0.05). Conclusions: Our findings suggest that DUSP5 exerts a protective effect on diabetes-related HF by suppressing PPARα-dependent fatty acid oxidation. Therefore, DUSP5 may be a potential target for diabetes-related HF.