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The coexistence of depression and diabetes is a serious challenge in cardiovascular disease. However, extracellular matrix (ECM) under stress model associated or not with diabetes remains unknown. This study aims to investigate the involvement of diabetes and unpredictable chronic mild stress (UCMS) on ECM remodelling. Rats were exposed to UCMS, diabetes or combined treatment. mRNA expression of matrix metalloproteinases (MMP-2 and MMP-9), plasminogen activator (t-PA) and inhibitor (PAI-1) was examined by Q-RT-PCR. ECM was determined by ELISA. MMP-2 and MMP-9 mRNA was lower in diabetes (P <0.05). UCMS increased MMP-2 and MMP-9 compared to control and diabetic group. Compared to the control and diabetes groups, MMP-2 and MMP-9 mRNA was significantly increased in the combined treatment group. UCMS increased MMP-2 expression in the diabetic group (P <0.01). Compared to control, gelatinase activity was higher in diabetes and UCMS (P <0.05). Combined diabetes and UCMS significantly increased gelatinase activity compared to T2D and UCMS groups. Collagen, hydroxyproline and fibronectin content were significantly increased in diabetes and combined groups. UCMS combined with diabetes exacerbated diabetes-induced MMPs and fibronectin deposition. In conclusion, comorbidity between diabetes and UCMS may exacerbate ECM remodelling. These findings will be useful in understanding diabetes-induced cardiovascular disease. [ABSTRACT FROM AUTHOR]