Abstract 18: The Role of Matrix Metalloproteinase 12 in Vascular Stiffness, Inflammation and Hypertension
Vascular wall remodeling and inflammation contribute to hypertension. These processes decrease arterial elasticity due to a loss of elastin and deposition of collagen. Metalloproteinase-12 (MMP12) is an elastase produced by macrophages and vascular cells. Cleavage of elastin by MMP12 could increase vascular stiffness and lead to release of pro-inflammatory elastin fragments. We sought to determine if MMP12 contributes to hypertension and vascular stiffness in response to angiotensin II and to understand mechanisms responsible for its expression. To determine if mechanical stretch activates MMP12 we subjected cultured murine endothelial cells to 0%, 5% (normotensive) or 10% (hypertensive) uniaxial stretch for 48 hours. Real-time RT-PCR showed that 10% stretch increases MMP12 mRNA by 4 fold compared to 0% or 5% stretch. Western blots and casein zymography indicated that 10% stretch significantly increases MMP12 protein expression and activity, respectively. Western blots also revealed an increase in elastin fragments in the media of cells exposed to 10% stretch compared to those exposed to 5% stretch. To understand the role of MMP12 in hypertension, we infused angiotensin II in wild-type and MMP12-/- mice. In keeping with the studies of cultured endothelial cells, angiotensin II markedly increased vascular MMP12 mRNA (10-fold) and protein levels. The hypertension caused by angiotensin II was markedly blunted in MMP12-/- mice (122 ± 3 vs. 173 ± 5, p < 0.0001). Immunohistochemistry with a CD68 specific antibody indicated a significant decrease in macrophages accumulation in the perivascular tissues of MMP12-/- compared to WT mice. We also examined distensibility of aortic segments in vitro, and quantified this as the percent change in diameter over a pressure change from 75 to 125 mmHg. Angiotensin II markedly decreased this distensibility index from 24 ± 3 to 9 ± 2%, but only to 16 ± 3% in MMP12-/- mice (p < 0.05). In conclusion, these studies show that mechanical stretch in vitro and hypertension in vivo cause a striking increase in endothelial cell and vascular MMP12 expression and activity. MMP12 activation promotes aortic stiffening and ultimately hypertension. Thus, modulation of MMP12 might be a therapeutic target in hypertension.
- © 2012 by American Heart Association, Inc.