Abnormal accumulation of saturated fatty acids in the heart results in insulin resistance, stress kinase activation, and increased cardiovascular risk in humans. The viability of human cardiac progenitor cells (CPC) is essential for myocardium homeostasis. This study investigates the ability of palmitate, a saturated fatty acid, to induce apoptosis, autophagy, and stress kinase activation in human CPC isolated from right auricle biopsies of nondiabetic, non-obese subjects, and the potential protective effects of insulin on palmitate-induced abnormalities. Human CPC expressed both IR-A and IR-B, and IR-A was more expressed than IR-B, as assessed by quantitative RT-PCR and immunoblotting. Exposure of human CPC to 100 nM insulin for 15 minutes resulted in increased Akt (S473) and p44/p42 MAPK (T202/Y204) phosphorylation (p<0.05), as evidenced by immunoblotting. Treatment of human CPC with palmitate 0.25 mM for 16 h induced apoptosis (p<0.05), as assessed by caspase-3 cleavage and ELISA assay, and increased S63-phosphorylation of c-Jun (p<0.05), a downstream transcription factor of JNK 1/2, as assessed by immunoblotting. Exposure of human CPC to 0.25 mM palmitate for 16 h resulted also in increased autophagy, evidenced by light chain 3-II immunoblotting (p<0.05). Pretreatment with 20 µM SP600125, a JNK inhibitor, for 1 h inhibited palmitate-induced apoptosis (p<0.05), but not autophagy. Similarly, pretreatment with 10 mM 3-methyladenine, an autophagy inhibitor, for 1 h decreased palmitate-induced apoptosis (p<0.05). Interestingly, palmitate effects on apoptosis, autophagy, and on stress kinase activation, were prevented when human CPC were pretreated with 100 nM insulin for 1 h (p<0.05). In conclusion, insulin prevents palmitate-induced apoptosis by inhibition of JNK signaling and autophagy in human CPC. Hence, preserving insulin signaling in human CPC might protect from lipotoxicity-induced metabolic alterations in the heart.


I. Calderoni: None. R. Doria: None. C. Caccioppoli: None. V. Genchi: None. G. Palma: None. G. Santarpino: None. A.D. Milano: None. A. Leonardini: None. A. Natalicchio: Other Relationship; AstraZeneca, Novo Nordisk, Sanofi, Boehringer-Ingelheim, Lilly. S. Perrini: None. A. Cignarelli: Speaker's Bureau; Eli Lilly and Company, Novo Nordisk, Sanofi. F. Giorgino: Research Support; Lilly, Roche Diabetes Care. Consultant; Novo Nordisk, Lilly. Speaker's Bureau; Abbott, Boehringer-Ingelheim, Lilly. Advisory Panel; Boehringer-Ingelheim, Amarin Corporation, Medtronic, Roche Diabetes Care, Sanofi. Speaker's Bureau; Sanofi. Advisory Panel; Bayer Inc., Novo Nordisk. Research Support; AlfaSigma. Speaker's Bureau; Medscape. L. Laviola: Speaker's Bureau; Abbott. Advisory Panel; A. Menarini Diagnostics, Boehringer Ingelheim Inc., Eli Lilly and Company, Novo Nordisk, Roche Diabetes Care. Speaker's Bureau; Terumo Corporation. Other Relationship; Medtronic. Advisory Panel; Sanofi.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.