Alogliptin and Pioglitazone, Alone or in Combination, Prevent Palmitate-Induced Apoptosis and Autophagy in Human Cardiac Progenitor Cells

Abstract

Physiological tissue turnover in the heart requires proper activation and viability of multipotent cardiac progenitor cells (CPCs). A defective CPC compartment, in terms of CPC number and maturation capacity, contributes to diabetes- and hyperglycemia-related heart failure in humans. GLP-1-based therapies, including the DPP-4 inhibitors, improve cardiac function in vivo and ameliorate myocardial and endothelial dysfunction in vitro. Pioglitazone has also demonstrated pleiotropic anti-oxidant and anti-atherogenic effects. The aim of this study was to evaluate the effects of alogliptin and pioglitazone, alone or in combination, on the viability of human CPCs exposed to 0.25 mM palmitate for 16 h. Human CPCs were obtained from patients undergoing cardiac surgery for coronary artery bypass grafting and/or valve surgery. Exposure of human CPCs to both alogliptin (10 µM) and pioglitazone (10 µM) for 16 h resulted in Akt, but not Erk, activation. Exposure to palmitate was associated with increased human CPC apoptosis and autophagy evaluated by ELISA assay and LC3-II immunoblotting, respectively (p<0.05). Pretreatment with alogliptin, alone or in combination with pioglitazone for 1 h before exposure to palmitate, reduced palmitate-induced apoptosis and autophagy (p<0.05). In conclusion, palmitate induces apoptosis and autophagy in human CPCs, and alogliptin and pioglitazone, as well as their combination, prevent the effects of palmitate, likely through enhancement of pro-survival pathways. Hence, DPP-4 inhibitors and thiazolidinediones, alone or in combination, may limit the lipotoxic damage of the human heart by preserving the viability of myocardial progenitor cells. Disclosure M. Incalza: None. R. D'Oria: None. C. Caccioppoli: None. A. Leonardini: None. R. Schipani: None. A. Cignarelli: Advisory Panel; Self; Aegerion Pharmaceuticals. Consultant; Self; Roche Diagnostics Corporation, Eli Lilly and Company. A. Natalicchio: None. S. Perrini: None. V. Margari: None. D. Paparella: None. L. Laviola: Advisory Panel; Self; AstraZeneca, Animas Corporation. Speaker's Bureau; Self; A. Menarini Diagnostics. Advisory Panel; Self; Boehringer Ingelheim GmbH, Eli Lilly and Company. Speaker's Bureau; Self; Medtronic, Merck Sharp & Dohme Corp.. Advisory Panel; Self; Novo Nordisk Inc., Roche Diabetes Care Health and Digital Solutions, Sanofi-Aventis, Takeda Development Centre Europe Ltd. F. Giorgino: Consultant; Self; Abbott, AstraZeneca, Boehringer Ingelheim GmbH. Research Support; Self; Eli Lilly and Company, Johnson & Johnson Services, Inc.. Consultant; Self; MedImmune, Merck Sharp & Dohme Corp., Roche Diabetes Care Health and Digital Solutions, Sanofi. Research Support; Self; Takeda Development Centre Europe Ltd..