58th EASD Annual Meeting of the European Association for the Study of Diabetes : Stockholm, Sweden, 19 - 23 September 2022

Background and aims: Dysfunction of visceral and epicardial adipose tissue may alter heart performance and promote adverse cardiovascular outcomes in obesity and diabetes. The aim of this study is to assess whether the secretome from abdominal visceral (AV) and epicardial (E) adipose stem cells (ASC) and from AV mature adipocytes might affect the viability of human cardiac progenitor cells (CPC) in human obesity, as well as to evaluate the effects of dapagliflozin (DAPA), a selective SGLT-2 inhibitor. Materials and methods: ASC and mature adipocytes were isolated from AV adipose tissue biopsies of 27 obese (Ob) and 13 non-Ob subjects undergoing abdominal surgery, and from E adipose tissue biopsies of 8 Ob and 8 non-Ob subjects undergoing cardiac surgery. Human CPC were isolated fromright auricle biopsies of non-Ob, non-diabetic donors undergoing cardiac surgery. Human CPC were pretreated with 10 uM DAPA for 24 h or left untreated, and then exposed to the conditioned media (CM) of AV-ASC, E-ASC, and AV mature adipocytes. Apoptosis was evaluated by ELISA assay for cytoplasmic oligonucleosomes. Impairment of organization of actin filaments was assessed by indirect immunofluorescence. JNK activation was studied by immunoblotting of c-Jun phosphorylation. Results: The CM of AV-ASC, E-ASC, and AV mature adipocytes from Ob subjects induced apoptosis in human CPC after 24 h (p<0.05). Exposure of human CPC to the CMof AV-ASC, E-ASC, and AVmature adipocytes for 24 h also resulted in impaired organization of the human CPC actin filaments. In addition, the CM of AV-ASC, E-ASC, and AV mature adipocytes induced c-Jun phosphorylation after 4 h and 8 h (p<0.05). Importantly, these effects were not observed when the human CPC were exposed to the CM of AV-ASC, E-ASC, and AV mature adipocytes from non-Ob subjects. Pretreatment of human CPC with DAPA resulted in reduced apoptosis (p<0.05), and less impairment of actin filaments following exposure to the CM of AV-ASC, E-ASC, and AV mature adipocytes, as well as in reduced c-Jun phosphorylation (p<0.05). Conclusion: In human obesity, the secretome of both AVand E ASC and mature adipocytes induces stress kinase activation in human CPC and impairs their viability and functionality, and these effects can be counteracted by SGLT-2 inhibitors directly acting on the human CPC.