Differential Effects of Mechanical and Biological Stimuli on Matrix Metalloproteinase Promoter Activation in the Thoracic Aorta

Abstract

Background-The effect of multiple integrated stimuli on vascular wall expression of matrix metalloproteinases (MMPs) remains unknown. Accordingly, this study examined the influence of the vasoactive peptide angiotensin II (Ang II) on wall tension-induced promoter activation of MMP-2, MMP-9, and membrane type-1 MMP (MT1-MMP). Methods and Results-Thoracic aortic rings harvested from transgenic reporter mice containing the MMP-2, MMP-9, or MT1-MMP promoter sequence fused to a reporter gene were subjected to 3 hours of wall tension at 70, 85, or 100 mm Hg, with or without 100 nM Ang II. Total RNA was harvested from the aortic rings, and reporter gene transcripts were quantified by quantitative real-time polymerase chain reaction to measure MMP promoter activity. MT1-MMP promoter activity was increased at both 85 and 100 mm Hg, compared with baseline tension of 70 mm Hg, whereas treatment with Ang II stimulated MT1-MMP promoter activity to the same degree at all tension levels (PϽ0.05). Elevated tension and Ang II displayed a potential synergistic enhancement of MMP-2 promoter activation at 85 and 100 mm Hg, whereas the same stimuli caused a decrease in MMP-9 promoter activity (PϽ0.05) at 100 mm Hg. Conclusions-This study demonstrated that exposure to a relevant biological stimulus (Ang II) in the presence of elevated tension modulated MMP promoter activation. Furthermore, these data suggest that a mechanical-molecular set point exists for the induction of MMP promoter activation and that this set point can be adjusted up or down by a secondary biological stimulus.

Heterogeneity in MT1-MMP activity with ischemia-reperfusion and previous myocardial infarction: relation to regional myocardial function

“…Upregulation of TNF-␣, IL-6, and the endothelin/PKC pathway has been reported after MI (25). In addition, increased mechanical strain can induce MT1-MMP promoter activity (30). Given the heterogeneity of the post-MI myocardium, it is highly likely that mechanical stress/strain patterns are conse- MMP-9 levels were higher in the CIRC region in both MI groups.…”

“…The present study demonstrated elevated MT1-MMP mRNA levels within the MI region, and, therefore, a likely mechanism for the heightened MT1-MMP activity that occurred in the context of a previous MI was due to increased transcription. Bioactive molecules, oxidative stress, and mechanical signals, all which are operative in the post-MI context, are likely contributory factors for inducing MT1-MMP (3,6,29,30). Specifically, MT1-MMP activity/abundance is increased by exposure to TNF-␣, IL-6, and the endothelin/PKC pathway (3,6,29).…”

Matrix metalloproteinases and their inhibitors in pulmonary hypertension

“…The diverse functions of MMPs in vasculature mainly depend on its expression and activity. Under physiological and pathological states, biological, mechanical, haemodynamic or neurohormonal stimuli are described to modulate the vascular cell-specific MMP expression and activity [45].…”

Metalloproteinases in hypertension and cardiac disease: differential expression and mutual regulation

“…Recent work suggests that vascular (aortic) metalloproteinase promoters may be differently responsive to single and collective mechanical (wall tension, up to 100 mmHg) and hormonal (Ang II) stimuli [45]. Increased tension was found to enhance MT1-MMP promoter activity, but further addition of Ang II did not have an additional effect on MT1-MMP promoter activity.…”