Forkhead box protein O1 as a novel player of diabetic vascular remodeling

Abstract

Diabetic vascular complications usually lead to a bleak medical prognosis, even after intensive treatment, thereby posing a major challenge for today’s healthcare practitioners. However, the precise molecular and cellular mechanisms underlying the pathogenesis for diabetic vascular complications are still not fully understood. Hyperactivation of Forkhead box protein O1 (FoxO1) plays a crucial part in regulating cell metabolism and is critical in the process of angiogenesis and maturation. The expression of FoxO1 alters in the diabetic circulation system and is associated with overt diabetes hallmarks, yet the character of FoxO1 in vascular complications in diabetes remains unclear. In type 1 diabetic rats induced by streptozotocin, FoxO1 expression was increased in the carotid artery after 8-week diabetes, with adverse vascular remodeling which shows increased carotid wall thickness, medial carotid cross-sectional area, and carotid lumen ratio, accompanied by decreased carotid lumen area. Pharmacological inhibition of FoxO1 with 50mg/kg AS1842856 (AS) reversed the above changes induced by high glucose levels in diabetic rats. Besides, these vascular remodeling in type 1 diabetes mellitus (T1DM) was indicated to be accompanied with several upregulated pro-inflammatory factors, adhesion factors, cell apoptosis, nod-like receptor family protein-3(NLRP3) inflammasome activation, and arterial smooth muscle cell phenotypic switching, all of which were ameliorated by AS treatment. Moreover, FoxO1 inhibition offsets the downregulation of pyruvate dehydrogenase kinase 1(PDK1), the activation of which in turn reduced the nuclear translocation of FoxO1, resulting in subsequent transcriptional regulation in hyperglycemia. To sum up, this study illustrate that FoxO1 is a key regulator for the progression of vascular remodeling in rats caused by type 1 diabetes via its initiation of NLRP3 inflammasome-dependent inflammation, and the interaction between PDK1/FoxO1/NLRP3 inflammasome may provide a potential choice of therapy for diabetes-related cardiovascular disease.