Palmitate-induced apoptosis in cardiomyocytes

G Arunachalam1, K Machaca2, H Ding1,3, CR Triggle1,3. 1Department of Pharmacology, Weill Cornell Medical College in Qatar, Doha, Qatar, 2Department of Physiology ad Biophysics, Weill Cornell Medical College in Qatar, Doha, Qatar, 3Medical Education, Weill Cornell Medical College in Qatar, Doha, Qatar

Saturated free fatty acids (FFA) overload is an important causative factor critically implicated in diabetes and obesity-associated heart failure. Palmitate (a circulating FFA)-induced cardiomyocyte apoptosis has been implicated during the development of endothelial dysfunction and diabetic cardiomyopathy (1). Metformin, an oral anti-diabetic drug, has been reported to attenuate hyperglycaemia-induced vascular senescence and apoptosis in mouse micro vascular endothelial cells (2). The purpose of the current study was to evaluate whether metformin can protect against palmitate-induced apoptosis in rat cardiomyocyte cultured in high glucose. Rat cardiomyocytes were cultured under either normoglycaemic (NG, 5.5 mM glucose) or hyperglycaemic (HG, 25 mM) conditions in the presence of palmitate (250μM) and in the absence or presence of metformin (100μM). Cell survival and apoptotic markers were analysed by immuno-blotting. Data is given as Mean±SEM and analyses performed using one-way analysis of variance (ANOVA) with p<0.05 to indicate statistical significance. Post-hoc comparisons between the groups were performed by Tukey Multiple Comparisons Test. The immuno-blotting results reveal that palmitate combined with HG results in a significant (p<0.05) induction of the transcription factor E2F1 (1.50±0.05 fold increase vs NG) and this induction paralleled a significant (p<0.05) reduction in expression of cell survival and anti-apoptotic sirtuin-1 (0.5±0.04 fold decrease vs NG), Bcl-2 family proteins and an increase in pro-apoptotic Bim (2.50±0.07 fold increase vs NG) expression. The presence of metformin attenuates palmitate-induced cardiomyocyte apoptosis in hyperglycaemic conditions.

Conclusion: These results suggest that in a hyperglycaemic environment palmitate-induced apoptosis is mediated through E2F1 activation and down-regulation of sirtuin-1 and Bcl-2 family proteins. Interestingly, treatment with metformin attenuated the detrimental effects of palmitate in cardiomyocytes.

(1) Sparagna GC et al (2001). Antioxid redox Signal 3:71-79.

(2) Arunachalam G et al (2014). Brit J Pharmacol 171:523-535