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Aspirin Downregulates High Glucose-Induced Matrix Metalloproteinase-2 Expression in Human Aortic Endothelial Cells

Theresa Jacob, PhD, Anil Hingorani, MD, Enrico Ascher, MD, Natalie Marks, MD, Richard Schutzer, MD, Manikyam Mutyala, MD and Alexander Shiferson, MD
Maimononides Medical Center, Brooklyn, NY

Background: Previous work has demonstrated that high levels of glucose cause endothelial cell dysfunction and increase secretion of matrix metalloproteinases (MMPs). Aspirin is known to have salutary effects in vascular disease states, as well as to inhibit MMP secretion in cancer cells. This study investigates whether aspirin alleviates high glucose-induced MMP-2 dysregulation in human vascular endothelial cells.
Methods: Human aortic endothelial cells (HAECs) were grown under physiological glucose (5.5 mM) and hyperglycemic (27.7 mM) conditions, with or without aspirin (5mM) supplementation. MMP-2 activity was evaluated by gel zymography, protein identified by Western analysis, concentration determined by ELISA, and gene expression quantified by real time RT-PCR, in both HAECs and culture supernates. Cell viability and apoptosis in response to aspirin treatment were also quantified.
Results: Under hyperglycemic conditions there was a significant decrease in the number of viable endothelial cells (28.45±4.2%). A significant increase in cells undergoing apoptosis accompanied by a corresponding increase in caspase-3, an apoptosis executioner molecule, was observed (p<0.01). Aspirin treatment limited this inhibitory effect of elevated glucose levels on HAECs. Both high glucose-induced expression and production of MMP-2 were downregulated with aspirin treatment by >40% in cell homogenates (p<0.01).
Conclusions: Hyperglycemia activates HAECs and induces activity and expression of MMP-2. Aspirin inhibits this endothelial cell activity and high glucose-induced MMP-2 dysregulation. The data from this study provide further support for aspirin therapy in vascular disease and its intake may mitigate or delay vascular complications of diabetes.