246-OR: Dapagliflozin Counteracts the Proapoptotic Effects of the Secretome of Visceral Adipose Cells from Obese Subjects in Human Cardiac Progenitor Cells via the SGLT2 Cotransporter
Authors: PALMA GIUSEPPE , CACCIOPPOLI CRISTINA , DORIA ROSSELLA , ANNAMARIA GENCHI VALENTINA , CALDERONI ISABELLA , BRAUN ANTONIO , SANTARPINO GIUSEPPE , MILANO ALDO D. , CIGNARELLI ANGELO , NATALICCHIO ANNALISA , LAVIOLA LUIGI , PEZZOLLA ANGELA , GIORGINO FRANCESCO , PERRINI SEBASTIO 
Published: June 2023

Dapagliflozin (DAPA), an SGLT2 inhibitor, has been shown to counteract heart failure outcomes in subjects with obesity and diabetes. We investigated the mechanisms of the protective action 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. ASC and mature adipocytes were isolated from AV and E adipose tissue biopsies of 15 obese (Ob) and 13 non-Ob subjects (n-Ob), respectively. hCPC were isolated from right auricle biopsies of healthy non-Ob donors. 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, as assessed by ELISA assay and immunofluorescence, respectively, while these effects were not observed when the hCPC were pretreated with DAPA. The CM of adipose cells from Ob compared to n-Ob subjects displayed a different pattern of pro-inflammatory and anti-inflammatory cytokines. The levels of pro-inflammatory cytokines such as RANTES and MIP1β were increased in the CM from AV-ASC with higher BMI (p&lt;0.05), while the levels of anti-inflammatory factors such as GCSF in the CM of E-ASC were inversely correlated with BMI (p&lt;0.05). SGLT2 was found to be expressed as both mRNA and protein in the hCPC, and silencing of SGLT2 with a specific siRNA attenuated the capacity of DAPA to counteract the pro-apoptotic effects of the CM. In conclusion, we show that: i) 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 the hCPC; ii) hCPC express SGLT2 mRNA and protein; iii) DAPA prevents the hCPC damage induced by the CM through an SGLT2-dependent mechanism.

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