Novel oral edaravone attenuates diastolic dysfunction of diabetic cardiomyopathy by activating the Nrf2 signaling pathway

Eur J Pharmacol. 2022 Apr 5:920:174846. doi: 10.1016/j.ejphar.2022.174846. Epub 2022 Feb 22.

Abstract

Oxidative stress plays a crucial role in the pathophysiology of diastolic dysfunction associated with diabetic cardiomyopathy. Novel oral edaravone (OED) alleviates oxidative stress by scavenging free radicals and may be suitable for the treatment of chronic diseases such as diabetic cardiomyopathy. Oral administration of OED to type 2 diabetic rats (induced by high-sugar/high-fat diet and intraperitoneal injection of streptozotocin) for 4 w decreased malondialdehyde and increased superoxide dismutase. Moreover, it significantly improved ratios of early to late diastolic peak velocity, myocardium hypertrophy accompanied by decreased cross-sectional areas of cardiomyocytes, the proportion of apoptotic cells, collagen volume fractions, and deposition of collagen I/III. In H9c2 cells, OED reduced reactive oxygen species, cell surface area, and numbers of terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling-positive cells induced by glucolipotoxicity. OED remarkably upregulated expression of the nuclear factor E2-related factor (Nrf2) signaling pathway both in vivo and in vitro. In addition, OED promoted Nrf2 nuclear translocation and upregulated nicotinamide adenine dinucleotide phosphate quinone oxidoreductase and heme oxygenase. Silencing of Nrf2 abolished the protective effect of OED in H9c2 cells. Our findings demonstrate that OED has the therapeutic potential to ameliorate diastolic dysfunction associated with diabetic cardiomyopathy. Its effect was mainly achieved by attenuating hyperglycemia and hyperlipidemia-induced cardiomyocyte hypertrophy, apoptosis, and fibrosis by activating the Nrf2 signaling pathway.

Keywords: Diabetic cardiomyopathy; Diastolic dysfunction; Novel oral edaravone; Nrf2 signaling pathway; Oxidative stress.

MeSH terms

  • Animals
  • Apoptosis
  • Diabetes Mellitus, Experimental* / complications
  • Diabetes Mellitus, Experimental* / drug therapy
  • Diabetic Cardiomyopathies* / drug therapy
  • Edaravone / pharmacology
  • Edaravone / therapeutic use
  • NF-E2-Related Factor 2 / metabolism
  • Oxidative Stress
  • Rats
  • Signal Transduction

Substances

  • NF-E2-Related Factor 2
  • Edaravone