Abstract:
BACKGROUND: Hyperglycemia-induced cardiovascular dysfunction has been linked to oxidative stress and accelerated apoptosis in the diabetic myocardium. While there is currently no treatment for diabetic cardiomyopathy
(DCM), studies suggest that the combinational use of anti-hyperglycemic agents and triterpenes could be
effective in alleviating DCM.
HYPOTHESIS: To investigate the therapeutic effect of methyl-3β-hydroxylanosta-9,24-dien-21-oate (RA3), in the
absence or presence of the anti-diabetic drug, metformin (MET), against hyperglycemia-induced cardiac injury
using an in vitro H9c2 cell model.
METHODS: To mimic a hyperglycemic state, H9c2 cells were exposed to high glucose (HG, 33 mM) for 24 h.
Thereafter, the cells were treated with RA3 (1 μM), MET (1 μM) and the combination of MET (1 μM) plus RA3 (1
μM) for 24 h, to assess the treatments therapeutic effect.
RESULTS: Biochemical analysis revealed that RA3, with or without MET, improves glucose uptake via insulindependent (IRS-1/PI3K/Akt signaling) and independent (AMPK) pathways whilst ameliorating the activity of
antioxidant enzymes in the H9c2 cells. Mechanistically, RA3 was able to alleviate HG-stimulated oxidative stress
through the inhibition of reactive oxygen species (ROS) and lipid peroxidation as well as the reduced expression
of the PKC/NF-кB cascade through decreased intracellular lipid content. Subsequently, RA3 was able to mitigate
HG-induced apoptosis by decreasing the activity of caspase 3/7 and DNA fragmentation in the cardiomyoblasts.
CONCLUSION: RA3, in the absence or presence of MET, demonstrated potent therapeutic properties against
hyperglycemia-mediated cardiac damage and could be a suitable candidate in the prevention of DCM.
