Matrix Metalloproteinases and Diabetic Vascular Complications

Abstract

Diabetes mellitus (DM) is associated with an increased incidence of cardiovascular events and microvascular complications. These complications contribute to the morbidity and mortality associated with DM. There is increasing evidence supporting a role for matrix metalloproteinases (MMPs) and their inhibitors (tissue inhibitors of matrix metalloproteinases - TIMPs) in the atherosclerotic process. However, the relationship between MMPs/TIMPs and diabetic angiopathy is less well defined. Hyperglycemia directly or indirectly (eg, via oxidative stress or advanced glycation products) increases MMP expression and activity. These changes are associated with histologic alterations in large vessels. On the other hand, low proteolytic activity of MMPs contributes to diabetic nephropathy. Within atherosclerotic plaques an imbalance between MMPs and TIMPs may induce matrix degradation, resulting in an increased risk of plaque rupture. Furthermore, because MMPs enhance blood coagulability, MMPs and TIMPs may play a role in acute thrombotic occlusion of vessels and consequent cardiovascular events. Some drugs can inhibit MMP activity. However, the precise mechanisms involved are still not defined. Further research is required to demonstrate the causative relationship between MMPs/TIMPs and diabetic atherosclerosis. It also remains to be established if the long-term administration of MMP inhibitors can prevent acute cardiovascular events.

Peroxisome Proliferator-Activated Receptor-γ Activation With Angiotensin II Type 1 Receptor Blockade Is Pivotal for the Prevention of Blood-Brain Barrier Impairment and Cognitive Decline in Type 2 Diabetic Mice

“…28 Expression and activity of the gelatinases MMP-2 and MMP-9 were enhanced by hyperglycemia in vitro 29 and elevated in patients with type 1 and type 2 diabetes mellitus. 30,31 Moreover, recent data suggested roles of MMPs in regulating TJ proteins.…”

Immunolocalization of advanced glycation end products in human diabetic eyes: an immunohistochemical study

“…Occlusion of the central retinal artery/vein is a known ocular complication of diabetes [20]. Hyperglycemia leads to matrix metalloproteinase expression via AGE formation, which subsequently contributes to histological alterations and accelerated plaque formation in large vessels [19,21]. These findings suggest that AGE plays a potential role in the pathogenesis, not only of microangiopathy, but of retinal vessel occlusion in diabetes.…”

Matrix Metalloproteinase-9 and Augmentation Index are Reduced with an 8-Week Green-Exercise Walking Programme

“…Given the extracellular site of action MMP-9 [35], ELISA measurements determining levels of secreted MMP-9 within the plasma were also carried out; no significant difference between the baseline-to-8-week changes for the adherent group and the non-adherent group were observed, although there appeared to be a greater reduction in MMP-9 levels in the adherent group (Ad: -28.4 ± 21.1ng/mL v. Non-Ad: -20.5 ± 6.0 ng/mL, P = NS) and when change in plasma MMP-9 levels was correlated against change in MMP-9 mRNA expression, a significant and positive relationship between the two was observed (r = 0.64, P = 0.002; See Figure, Supplemental Digital Content 1, which demonstrates the significant and positive relationship between the change in plasma MMP-9 levels and the change in MMP-9 mRNA expression) [35].…”