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

• Published in: Cardiovascular diabetology 2024-04, Vol.23 (1), p.140-140, Article 140
• Main Authors: Huang, Xinyue, Guo, Jiayan, Ning, Anqi, Zhang, Naijin, Sun, Yingxian
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Advanced glycosylation end products; Animals; Antibodies; Aorta; Apoptosis; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Autophagy; BAG3; Bcl-2 protein; Cell culture; Cell migration; Cell Movement; Cell Proliferation; Cell survival; Cell viability; Cells, Cultured; Cholecystokinin; Coronary vessels; Diabetes; Diabetes mellitus; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - pathology; Diabetic Angiopathies - etiology; Diabetic Angiopathies - genetics; Diabetic Angiopathies - metabolism; Diabetic Angiopathies - pathology; Diabetic Angiopathies - physiopathology; Diabetic vascular remodeling; Ethanol; Experiments; Extracellular signal-regulated kinase; Gelatinase A; Genetic engineering; Glucose; Glycation End Products, Advanced - metabolism; Humans; Immunoassay; Immunofluorescence; Immunoprecipitation; Janus kinase; Janus kinase 2; Laboratory animals; Male; Medical research; Metalloproteinase; Mice, Inbred C57BL; Mice, Knockout; Molecular modelling; Muscle, Smooth, Vascular - metabolism; Muscle, Smooth, Vascular - pathology; Myocardium; Myocytes, Smooth Muscle - metabolism; Myocytes, Smooth Muscle - pathology; Peptidase; Phalloidin; Phosphorylation; Precipitation; Proteins; Signal Transduction; Skeletal muscle; Smooth muscle; STAT3; Stat3 protein; STAT3 Transcription Factor - metabolism; Streptozocin; Transcription factors; Transgenic animals; Ultrasonic imaging; Vascular Remodeling; VSMCs
• ISSN: 1475-2840; 1475-2840
• DOI: 10.1186/s12933-024-02216-z

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; BAG3 mice and streptozotocin (STZ) was used to simulate diabetes. Expression of proteins and aortic thickness of mice were detected by immunofluorescence, ultrasound and hematoxylin-eosin (HE) staining. Using human aorta smooth muscle cell line (HASMC), cell viability was measured by CCK-8 and proliferation was measured by colony formation experiment. Migration was detected by transwell, scratch experiments and Phalloidin staining. Western Blot was used to detect protein expression and Co-Immunoprecipitation (Co-IP) was used to detect protein interaction. In diabetic vascular remodeling, AGEs could promote the interaction between BAG3 and signal transducer and activator of transcription 3 (STAT3), leading to the enhanced interaction between STAT3 and Janus kinase 2 (JAK2) and reduced interaction between STAT3 and extracellular signal-regulated kinase 1/2 (ERK1/2), resulting in accumulated p-STAT3(705) and reduced p-STAT3(727). Subsequently, the expression of matrix metallopeptidase 2 (MMP2) is upregulated, thus promoting the migration of VSMCs. BAG3 upregulates the expression of MMP2 by increasing p-STAT3(705) and decreasing p-STAT3(727) levels, thereby promoting vascular remodeling in diab