Aerobic Exercise Ameliorates Adverse Vascular Remodeling in Diabetes via <scp>PDK1</scp> / <scp>FoxO1</scp> Axis

Diabetic patients often experience poor outcomes due to vascular diseases, yet the current treatments have not been effective. Physical activity is able to improve health conditions in diabetic patients. However, the exact mechanisms are not fully understood. Forkhead Box O1 (FoxO1), a key modulator of cellular metabolism, has been depicted to trigger diabetic vascular remodeling in our previous study. It is reported that improvement of insulin resistance through aerobic exercise is closely linked to the activity of 3-phosphoinositide-dependent kinase 1 (PDK1), which acts as an important upstream component of the FoxO1 signaling pathway. Here, we aimed to explore whether aerobic exercise could ameliorate diabetes-induced vascular remodeling and discuss the role of the PDK1/FoxO1 axis in this process. The type I diabetes mouse models were established by intraperitoneal injection of streptozotocin (STZ) for three months. The structure modeling of the carotid artery was analyzed by immunofluorescence analysis. The expression profiles of PDK1, FoxO1, inflammatory markers (NLRP3, VCAM-1, CCR2, and NF-κB), and contractive/proliferative biomarkers of smooth muscle cells (α-SMA/MMP-2, MMP-9) in both artery tissues and cells were evaluated by immunofluorescence and western blotting analyses. Unpaired t-test and one-way ANOVA were utilized to compare the groups. PDK1 expression in carotid tissues was decreased in diabetic mice after 3 months of STZ induction, whereas the FoxO1 level was upregulated. The diabetic mice exhibited adverse structural changes in the carotid arteries, including thicker walls and a reduced size of the inner cavity. Moreover, these vasculopathies were accompanied by increased levels of inflammatory markers such as NLRP3 and NF-κB. Importantly, these alterations were reversed by 3-month aerobic exercise. Collectively, this study indicates that aerobic exercise plays a protective function in the diseased blood vessels of diabetic mice through activating the PDK1/FoxO1 pathway. Therefore, targeting the PDK1/FoxO1 signaling axis could become a promising option for the treatment of diabetes-associated cardiovascular diseases.