Metformin alleviates bevacizumab-induced vascular endothelial injury in mice through growth differentiation factor ۱۵ upregulation

Objective(s): Bevacizumab is a commonly used anticancer drug in clinical practice, but it often leads to adverse reactions such as vascular endothelial damage, hypertension, arterial and venous thrombosis, and bleeding. This study investigated the protective effects of metformin against bevacizumab-induced vascular injury in a mouse model and examined the possible involvement of GDF۱۵/PI۳K/AKT/FOXO/PPARγ signaling in the effects.Materials and Methods: C۵۷ male mice were purchased. To investigate metformin, the mice were assigned to the saline, bevacizumab (۱۵ mg every ۳ days), metformin (۱۲۰۰ mg/day), and bevacizumab+metformin groups. To investigate GDF۱۵, the mice were assigned to the siNC+bevacizumab, siNC+bevacizumab+metformin, siGDF۱۵+bevacizumab, and siGDF۱۵+bevacizumab+metformin groups. Histological staining was used to evaluate vascular injury. Flow cytometry was used to evaluate apoptosis. ELISA was used to measure plasma endothelial injury markers and proinflammatory cytokines. qRT-PCR and western blot were used to determine the expression of GDF۱۵ and PI۳K/AKT/FOXO/PPARγ in aortic tissues.Results: Metformin alleviated bevacizumab-induced abdominal aortic injury, endothelial cell apoptosis, and systemic inflammation in mice (all P<۰.۰۵). Metformin up-regulated GDF۱۵ expression and PI۳K/AKT/FOXO/PPARγ signaling in the abdominal aorta of mice treated with bevacizumab (all P<۰.۰۵). siGDF۱۵ abolished the vascular protective and anti-inflammatory effects of metformin (all P<۰.۰۵). siGDF۱۵ suppressed PI۳K/AKT/FOXO/PPARγ signaling in the abdominal aorta of mice treated with bevacizumab (all P<۰.۰۵).Conclusion: Metformin attenuates bevacizumab-induced vascular endothelial injury, apoptosis, and systemic inflammation by activating GDF۱۵/PI۳K/AKT/FOXO/PPARγ signaling.

Keywords:

Bevacizumab , Growth differentiation-factor ۱۵ , Metformin , Mouse , PI۳K/AKT/FOXO/PPARγ- , Signaling pathway , Vascular injuries