Fibulin-1 Is a Marker for Arterial Extracellular Matrix Alterations in Type 2 Diabetes

[摘要] BACKGROUND: Extracellular matrix alterations are important elements in the arterial changes seen in diabetes, being associated with increased vascular stiffness and the development of cardiovascular diseases. However, no biomarkers for diabetes-related arterial changes have been defined.METHODS: Mammary artery specimens from 17 men with type 2 diabetes and 18 nondiabetic individuals were used for microarray expression profiling, quantitative real-time PCR, immunoassay, and immunohistochemical analyses. A derived candidate marker, fibulin-1, which is an elastin-associated matrix molecule, was measured immunochemically in plasma from ( a ) 70 patients scheduled for vascular surgery, ( b ) 305 patients with type 2 diabetes examined with carotid ultrasonography and echocardiography, and ( c ) 308 patients with type 2 diabetes, followed for 15 years.RESULTS: The most upregulated transcript in nonatherosclerotic arterial tissue from patients with type 2 diabetes encoded the extracellular matrix protein, fibulin-1. Higher concentrations of fibulin-1-protein were present in artery extracts from patients with diabetes than extracts from individuals without diabetes, and increased fibulin-1 immunostaining was apparent around the external elastic lamina of diabetic arteries. Patients with diabetes displayed increased plasma concentrations of fibulin-1 ( P = 0.006). Plasma fibulin-1 concentrations correlated with hemoglobin A1c ( P < 0.001), arterial stiffness indices including pulse pressure ( P < 0.001), and carotid compliance ( P = 0.004), as well as plasma N-terminal pro–B-type natriuretic peptide concentrations ( P < 0.001) and were predictive of 15-year mortality ( P = 0.013).CONCLUSIONS: Fibulin-1 accumulates in the arterial wall and in plasma of patients with type 2 diabetes, and appears to be a factor associated with arterial extracellular matrix changes in type 2 diabetes.

[学科分类] 过敏症与临床免疫学