Underlying mechanisms of cardiovascular outcomes in Diabetes: the role of glycated collagen

• Grant number: 22/05750-7
• Support Opportunities: Generation Project Research Grant
• Start date: June 01, 2023
• End date: May 31, 2028
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Renato Simões Gaspar
• Grantee: Renato Simões Gaspar
• Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated scholarship(s): 24/07470-7 - Investigation of the biophysical and signalling aspects of platelets exposed to glycated collagen, BP.DR; 24/02620-0 - Glycated collagen as an underlying mechanism for endothelial dysfunction in Diabetes, BP.DD; 23/07341-0 - Underlying mechanisms of cardiovascular outcome in Diabetes: the role of glycated collagen, BP.GR

Abstract

Type 2 Diabetes Mellitus (T2DM) is a chronic and epidemic disease with high socio-economical cost worldwide, leading to an increased risk of cardiovascular disease (CVD) and thromboembolic events. These processes are largely mediated by platelet activation and endothelial dysfunction. Current anti-diabetic therapies provide limited cardiovascular protection, suggesting that diabetic patients incur in a permanent and/or structural modification that is not targeted by current treatments. In this regard, chronic hyperglycaemia leads to the formation of advanced glycation endproducts (AGEs) through a non-enzymatic addition of glucose molecules to proteins - a reaction termed glycation. Although most proteins have a short (days to weeks) half-life, fibrillar type I collagen, which is found in the subendothelium of arteries, has a half-life of over 10 years. Indeed, non-glycated collagen I has been extensively studied with regards to its ability to stimulate platelets and induce thrombosis. Thus, it is reasonable to speculate that the vasculature of diabetic patients accumulates glycated collagen in a process that is not targeted by current anti-diabetic drugs. This could potentially explain why diabetic patients are at a high risk of developing CVD in spite of a strict glycaemic control, i.e. because the damage is already established by chronic hyperglycaemia that occurs before diagnosis. Nevertheless, it is as of yet unclear if or how glycated collagen stimulates thrombus formation and endothelial dysfunction. It is possible that molecular changes in glycated collagen (e.g. crosslinking) concur on altered physical properties of the collagen mesh that affect the way cardiovascular cells sense these fibres. Therefore, this proposal aims to investigate if glycated collagen leads to an aberrant activation of platelets and endothelial dysfunction thus contributing to the increased cardiovascular risk of diabetic individuals. Specifically, we will assess 1) molecular and physical properties of glycated collagen and its interaction with the receptor for AGE (RAGE), 2) how platelets and endothelial cells mechanosense and signal in response to glycated collagen, 3) whether the physical properties of the extracellular matrix contribute to how cells sense glycated collagen and 4) if glycated collagen found in arteries of T2DM individuals affects thrombus formation and vascular function. Data derived from this proposal may identify a novel strategy to treat CVD and thromboembolic events in T2DM individuals and characterize a novel underlying mechanism to explain such increased CVD risk in these patients. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

GASPAR, RENATO S.; FRANCA, ALEFE ROGER SILVA; OLIVEIRA, PERCILLIA VICTORIA SANTOS; DINIZ-FILHO, JOEL FELIX SILVA; TEIXEIRA, LIVIA; VALADAO, IURI CORDEIRO; DEBBAS, VICTOR; SANTOS, CLENILTON COSTA DOS; MASSAFERA, MARIANA PEREIRA; BUSTOS, SILVINA ODETE; et al. Endothelial protein disulfide isomerase A1 enhances membrane stiffness and platelet-endothelium interaction in hyperglycemia via SLC3A2 and LAMC1. Journal of Thrombosis and Haemostasis, v. 22, n. 11, p. 17-pg., 2024-10-24. (20/15944-8, 13/07937-8, 22/05750-7, 23/00995-4, 20/03838-9, 16/00696-3)