Elevated circulating levels of saturated fatty acids (SFA; e.g., palmitate) are associated with increased cardiovascular risk in diabetes. In contrast, monounsaturated fatty acids (e.g., oleate) prevent the toxic effects of SFA in multiple cell types. The viability of cardiac progenitor cells (CPC) is essential for myocardial tissue homeostasis. In this study, the ability of palmitate and oleate to induce apoptosis and autophagy, as well as the effects of oleate on the palmitate-induced damage, were investigated in human CPC isolated from right auricle biopsies. Palmitate, but not oleate, induced apoptosis in a dose- and time-dependent manner in human CPC, as assessed by caspase-3 cleavage and ELISA assay for cytoplasmic oligonucleosomes (p<0.05). Exposure of CPC to 0.25 mM palmitate for 16 h also resulted in increased autophagy, evidenced by autophagosome labeling with monodansyl cadaverine and light chain 3 (LC3)-II immunoblotting (p<0.05). In contrast, oleate did not induce autophagy. Palmitate, but not oleate, also induced phosphorylation of both p38 MAPK and the JNK substrate, c-Jun (p<0.05). Pretreatment with the p38 MAPK inhibitors, SB202190 and SB203580, significantly inhibited palmitate-induced apoptosis and autophagy (p<0.05), whereas the JNK inhibitor SP600125 was able to prevent palmitate-induced apoptosis, but not autophagy (p<0.05). Interestingly, palmitate-induced apoptosis and autophagy were prevented when human CPC were co-treated with 0.1 mM oleate for 16 h (p<0.05). Co-incubation with oleate also abolished the ability of palmitate to induce p38 MAPK and c-Jun phosphorylation.
In conclusion, oleate prevents the palmitate-induced increase in apoptosis and autophagy of human CPC by counteracting the activation of p38 MAPK and JNK. Hence, oleate supplementation might limit the lipotoxic damage of human heart by preserving the viability of myocardial progenitors.
R. Doria: None. R. Schipani: None. C. Caccioppoli: None. M. Incalza: None. A. Leonardini: None. A. Natalicchio: Other Relationship; Self; Novo Nordisk Inc., Sanofi-Aventis. S. Perrini: None. A. Cignarelli: Consultant; Self; Eli Lilly and Company. Speaker's Bureau; Self; Merck Sharp & Dohme Corp., Novo Nordisk A/S. L. Laviola: Advisory Panel; Self; Abbott, Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Novo Nordisk Inc. Board Member; Self; AstraZeneca, Roche Diabetes Care, Sanofi-Aventis. Speaker's Bureau; Self; Medtronic, Mundipharma, Takeda Pharmaceutical Company Limited. F. Giorgino: Advisory Panel; Self; Aegerion Pharmaceuticals, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, MedImmune, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Roche Diabetes Care, Sanofi. Consultant; Self; Roche Diabetes Care, Sanofi. Research Support; Self; Eli Lilly and Company, LifeScan, Inc., Takeda Pharmaceutical Company Limited. Other Relationship; Self; AstraZeneca, Eli Lilly and Company, Sanofi.