Key result
A single injection of AAV2/9-Endo-Glo1 one week after T1DM onset blunted the development of diabetic cardiomyopathy, attenuating oxidative stress, inflammation, and fibrosis at eight weeks.
Why the study?
Downregulation of glyoxalase-1 and methylglyoxal accumulation underlie diabetic cardiomyopathy, but whether expressing Glo1 shortly after diabetes onset blunts disease development was unknown.
Does AAV2/9-Endo-Glo1 prevent diabetic cardiomyopathy in a streptozotocin-induced Type 1 diabetes mellitus rat model?
Does AAV2/9-Endo-Glo1 prevent diabetic cardiomyopathy in a streptozotocin-induced Type 1 diabetes mellitus rat model?
Gene transfer of Glo1 early in the course of Type 1 diabetes blunts the development of diabetic cardiomyopathy in a rat model by reducing oxidative stress, inflammation, and fibrosis.
Hypothesis-generating for Glo1 gene transfer in diabetic cardiomyopathy; leaves open translation to human prevention.
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.
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Alomar et al. (2020) studied Type 1 diabetes mellitus and diabetic cardiomyopathy. AAV2/9-Endo-Glo1 vs. Untreated T1DM rats was evaluated on Development of diabetic cardiomyopathy (cardiac/myocyte function, oxidative stress, inflammation, fibrosis). A single injection of AAV2/9-Endo-Glo1 one week after T1DM onset blunted the development of diabetic cardiomyopathy, attenuating oxidative stress, inflammation, and fibrosis at eight weeks.
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