This study aimed to assess whether the secretome from abdominal visceral (AV) and epicardial (E) adipose stem cells (ASC), ASC-derived mature adipocytes, and isolated AV mature adipocytes may affect the viability of cardiac progenitor cells (CPC) in human obesity, and whether dapagliflozin (DAPA) may reduce the proapoptotic effects in injured CPC. ASC were isolated from AV and E adipose tissue biopsies of nondiabetic subjects with varying levels of BMI and used before and after differentiation into adipocytes in vitro. CPC were isolated from right auricle biopsies of non-obese (Ob) subjects, preincubated in the presence or absence of 10 uM DAPA, and exposed or not to conditioned media (CM) of AV-ASC, E-ASC, AV-ASC-derived adipocytes and isolated AV mature adipocytes. The CM of AV-ASC and differentiated adipocytes from Ob subjects induced CPC apoptosis after 4-8-24 h (p<0.05). In addition, exposure of CPC to CM of Ob AV-ASC and mature adipocytes resulted in marked inhibition of insulin-stimulated Akt phosphorylation (Akt-Ph) (p<0.05). In contrast, the CM of AV-ASC and differentiated adipocytes from non-Ob subjects did not induce apoptosis nor impaired insulin signaling. Similarly, the CM of AV mature adipocytes isolated from Ob subjects induced a marked apoptosis of CPC (p<0.05) and inhibited insulin-stimulated Akt-Ph, whereas no effects were observed when CPC were exposed to CM of mature adipocytes isolated from non-Ob subjects. Of note, the CM of E-ASC isolated from Ob subjects also induced CPC apoptosis and impaired insulin-stimulated Akt-Ph (p<0.05), while these effects were not observed when CPC were exposed to CM of E-ASC from non-Ob subjects. The proapoptotic effects of the CM in the CPC were inhibited when these cells were pretreated with DAPA (p<0.05).
In conclusion, the secretome of adipose cells from Ob subjects impairs insulin action and viability of the CPC, and these effects can be counteracted by DAPA.
S. Porro: None. S. Perrini: None. C. Caccioppoli: None. R. Doria: None. V. Genchi: None. R. Schipani: None. A. Cignarelli: None. A. Natalicchio: Consultant; Self; AstraZeneca, Novo Nordisk Inc., Sanofi-Aventis. L. Laviola: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk Inc., Roche Diabetes Care, Sanofi-Aventis. Speaker’s Bureau; Self; Abbott, Medtronic. F. Giorgino: Advisory Panel; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk Inc., Roche Diabetes Care, Sanofi. Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., LifeScan, Inc., MedImmune, Merck Sharp & Dohme Corp., Roche Diabetes Care, Sanofi. Research Support; Self; Eli Lilly and Company, LifeScan, Inc., Takeda Development Centre Europe Ltd.