Abstract:
Chronic hyperglycaemia is a major risk factor for diabetes-induced cardiovascular
dysfunction. In a hyperglycaemic state, excess production of reactive oxygen species (ROS), coupled
with decreased levels of glutathione, contribute to increased lipid peroxidation and subsequent
myocardial apoptosis. N-acetylcysteine (NAC) is a thiol-containing antioxidant known to protect
against hyperglycaemic-induced oxidative stress by promoting the production of glutathione. While
the role of NAC against oxidative stress-related cardiac dysfunction has been documented, to date
data is lacking on its beneficial e ect when used with glucose lowering therapies, such as metformin
(MET). Thus, the aim of the study was to better understand the cardioprotective e ect of NAC plus
MET against hyperglycaemia-induced cardiac damage in an H9c2 cardiomyoblast model. H9c2
cardiomyoblasts were exposed to chronic high glucose concentrations for 24 h. Thereafter, cells were
treated with MET, NAC or a combination of MET and NAC for an additional 24 h. The combination
treatment mitigated high glucose-induced oxidative stress by improving metabolic activity i.e. ATP
activity, glucose uptake (GU) and reducing lipid accumulation. The combination treatment was as
e ective as MET in diminishing oxidative stress, lipid peroxidation and apoptosis. We observed
that the combination treatment prevented hyperglycaemic-induced cardiac damage by increasing
GLUT4 expression and mitigating lipid accumulation via phosphorylation of both AMPK and AKT,
while decreasing nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), as well as
protein kinase C (PKC), a known activator of insulin receptor substrate-1 (IRS-1), via phosphorylation
at Ser307. On this basis, the current results support the notion that the combination of NAC and
MET can shield the diabetic heart against impaired glucose utilization and therefore its long-term
protective e ect warrants further investigation.
