Adeno-associated viral transfer of glyoxalase-1 blunts carbonyl and oxidative stresses in hearts of type 1 diabetic rats

Fadhel A. Alomar, Abdullah Al-Rubaish, Fahad Al-Muhanna, Amein K. Al-Ali, Joellyn McMillan, Jaipaul Singh, Keshore R. Bidasee

Research output: Contribution to journalArticle

Abstract

Accumulation of methylglyoxal (MG) arising from downregulation of its primary degrading enzyme glyoxalase-1 (Glo1) is an underlying cause of diabetic cardiomyopathy (DC). This study investigated if expressing Glo1 in rat hearts shortly after the onset of Type 1 diabetes mellitus (T1DM) would blunt the development of DC employing the streptozotocin-induced T1DM rat model, an adeno-associated virus containing Glo1 driven by the endothelin-1 promoter (AAV2/9-Endo-Glo1), echocardiography, video edge, confocal imaging, and biochemical/histopathological assays. After eight weeks of T1DM, rats developed DC characterized by a decreased E:A ratio, fractional shortening, and ejection fraction, and increased isovolumetric relaxation time, E: e’ ratio, and circumferential and longitudinal strains. Evoked Ca2+ transients and contractile kinetics were also impaired in ventricular myocytes. Hearts from eight weeks T1DM rats had lower Glo1 and GSH levels, elevated carbonyl/oxidative stress, microvascular leakage, inflammation, and fibrosis. A single injection of AAV2/9 Endo-Glo1 (1.7 × 1012 viron particles/kg) one week after onset of T1DM, potentiated GSH, and blunted MG accumulation, carbonyl/oxidative stress, microvascular leakage, inflammation, fibrosis, and impairments in cardiac and myocyte functions that develop after eight weeks of T1DM. These new data indicate that preventing Glo1 downregulation by administering AAV2/9-Endo-Glo1 to rats one week after the onset of T1DM, blunted the DC that develops after eight weeks of diabetes by attenuating carbonyl/oxidative stresses, microvascular leakage, inflammation, and fibrosis.

Original languageEnglish (US)
Article number592
Pages (from-to)1-22
Number of pages22
JournalAntioxidants
Volume9
Issue number7
DOIs
StatePublished - Jul 2020

Keywords

  • Adeno-associated virus
  • Carbonyl stress
  • Cardiomyopathy
  • Diabetes mellitus
  • Glyoxalase-1
  • Methylglyoxal
  • Oxidative stress

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

Fingerprint Dive into the research topics of 'Adeno-associated viral transfer of glyoxalase-1 blunts carbonyl and oxidative stresses in hearts of type 1 diabetic rats'. Together they form a unique fingerprint.

  • Cite this