Dapagliflozin counteracts the pro-apoptotic effects of the secretome of visceral adipose cells from obese subjects in human cardiac progenitor cells via the SGLT2 co-transporter

Abstract

Aim: Dapagliflozin (DAPA), an SGLT2 inhibitor, has been shown to counteract heart failure outcomes in subjects with obesity and diabetes. We investigated the protective mechanisms of DAPA in human cardiac progenitor cells (hCPC) exposed to the conditioned medium (CM) from abdominal visceral (AV) and epicardial (E) adipose stem cells (ASC) and from AV mature adipocytes from obese subjects. Methods: ASC and mature adipocytes were isolated from AV adipose tissue biopsies of 27 obese (Ob) and 19 non-Ob subjects (n-Ob), and from E adipose tissue biopsies of 9 Ob and 10 non-Ob subjects, respectively. hCPC were isolated from right auricle biopsies of 10 healthy non-Ob donors. Results: Exposure of hCPC to the CM of adipose cells from Ob, but not from non-Ob subjects, induced apoptosis, c-Jun phosphorylation, and impairment of actin filaments, while these effects were not observed when hCPC were pretreated with DAPA. The CM of adipose cells from Ob compared to n-Ob subjects displayed a different pattern of cytokines. The levels of pro-inflammatory cytokines RANTES and MIP1β were increased in the CM from AV-ASC with higher BMI (p<0.05), while the levels of the cardioprotective factor GCSF in the CM of E-ASC were inversely correlated with BMI (p<0.05). SGLT2 was found to be expressed as both mRNA and protein in hCPC, and silencing of SGLT2 with a specific siRNA abrogated the capacity of DAPA to counteract the pro-apoptotic effects of the CM. Conclusions: In human obesity, the CM of both AV- and E-ASC and mature adipocytes is characterized by pro-inflammatory cytokines that induce stress kinase activation and apoptosis in hCPC. DAPA prevents the hCPC damage induced by the CM through an SGLT2-dependent mechanism.