BAG3 promotes proliferation and migration of arterial smooth muscle cells by regulating STAT3 phosphorylation in diabetic vascular remodeling

Abstract

Abstract Diabetic vascular remodeling is the most important pathological basis of diabetic cardiovascular complications. The accumulation of advanced glycation end products (AGEs) caused by elevated blood glucose promotes the proliferation and migration of vascular smooth muscle cells (VSMCs), leading to arterial wall thickening and ultimately vascular remodeling. Therefore, the excessive proliferation and migration of VSMCs is considered as an important therapeutic target for vascular remodeling in diabetes mellitus. However, due to the lack of breakthrough in experiments, there is currently no effective treatment for the excessive proliferation and migration of VSMCs in diabetic patients. Bcl-2-associated athanogene 3 (BAG3) protein is a multifunctional protein highly expressed in skeletal muscle and myocardium. Previous research has confirmed that BAG3 can not only regulate cell survival and apoptosis, but also affect cell proliferation and migration. Since the excessive proliferation and migration of VSMCs is an important pathogenesis of vascular remodeling in diabetes, the role of BAG3 in the excessive proliferation and migration of VSMCs and its molecular mechanism deserve further investigation. In this study, BAG3 gene was manipulated in smooth muscle to acquire SM22αCre；BAG3FL/FL mice. Using SM22αCre；BAG3FL/FL mice and human aorta smooth muscle cell line (HASMC), we demonstrated that elevated blood sugar or AGEs could both promote the interaction between BAG3 and STAT3, while BAG3 simultaneously enhanced the interaction between STAT3 and JAK2 and reduced the interaction between STAT3 and ERK1/2, leading to accumulated p-STAT3(705) and decreased p-STAT3(727). Subsequently, the expression of MMP2 is upregulated, thus promoting the migration of VSMCs. In conclusion, our study provides a new orientation for the prevention and treatment of diabetic vascular remodeling.