Abstract
Aims/HypothesisDiabetes with hypertension rapidly accelerates vascular disease, but the underlying mechanism remains unclear. We evaluated the hypothesis that the receptor of advanced glycation end products (RAGE) might mediate combined signals initiated by diabetes-related AGEs and hypertension-induced mechanical stress as a common molecular sensor.Methods In vivo surgical vein grafts created by grafting vena cava segments from C57BL/6J mice into the common carotid arteries of streptozotocin (STZ)-treated and untreated isogenic mice for 4 and 8 weeks were analyzed using morphometric and immunohistochemical techniques. In vitro quiescent mouse vascular smooth muscle cells (VSMCs) with either knockdown or overexpression of RAGE were subjected to cyclic stretching with or without AGEs. Extracellular signal-regulated kinase (ERK) phosphorylation and Ki-67 expression were investigated.ResultsSignificant increases in neointimal formation, AGE deposition, Ki-67 expression, and RAGE were observed in the vein grafts of STZ-induced diabetic mice. The highest levels of ERK phosphorylation and Ki-67 expression in VSMCs were induced by simultaneous stretch stress and AGE exposure. The synergistic activation of ERKs and Ki-67 in VSMCs was significantly inhibited by siRNA-RAGE treatment and enhanced by over-expression of RAGE.ConclusionRAGE may mediate synergistically increased ERK activation and VSMC proliferation induced by mechanical stretching with and without AGEs. It may serve as a common molecular bridge between the two, accelerating vascular remodeling. This study provides potential drug targets and novel therapeutic strategies for the treatment of vascular diseases resulting from diabetes with hypertension.
Highlights
Diabetes and hypertension are independent risk factors of atherosclerosis
Assuming that receptor of advanced glycation end products (RAGE) is one kind of transmembrane receptor present in vascular smooth muscle cells (VSMCs), we proposed that RAGE would be a common sensor, capable of simultaneously mediating signals induced by mechanical stretching and advanced glycation end products (AGEs), contributing to vascular remodeling in patients with diabetes and hypertension
Because VSMC proliferation plays a key role in neointimal formation in vein grafts, we investigated the molecular mechanism underlying the role of AGE/RAGE in VSMC proliferation
Summary
Diabetes and hypertension are independent risk factors of atherosclerosis. up to 70% of patients with type 2 and up to 40% of patients with type 1 diabetes have arterial hypertension [1,2]. Diabetes-related vascular injury is closely associated with the deposition of advanced glycation end products (AGEs) as a result of prolonged hyperglycemia through non-enzymatic reactions between glucose and long-lived proteins (e.g. vessel wall collagen), lipids, and nucleic acids in plasma and tissues [6,7,8]. These modified proteins interact with AGE receptor (RAGE) to initiate intracellular signaling, e.g. extracellular signal-regulated kinase (ERK) activation [9]. This triggers altered vascular structure and function, which accelerates the progression of atherosclerosis and hypertension in diabetic patients or animals [10,11,12,13, 14,15,16]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
