The extracellular matrix degradation of arteries by matrix metalloproteinases (MMPs) may contribute to an altered collagen-elastin ratio associated with stiffer arteries. MMPs may also provide a new therapeutic target. In a previous communication (McNulty et al., 2003) we have shown increased concentrations of active MMPs in the aorta in comparison with the internal mammary artery in patients undergoing coronary artery bypass graft. Serological collagen derived peptides have been used as markers of fibrillar collagen turnover in myocardial fibrosis (Querejeta et al., 2000). We now explore the relationship between interstitial collagenase (MMP-1), tissue inhibitor of metalloproteinase (TIMP-1) and markers of collagen synthesis and degradation respectively, carboxy-terminal propeptide of collagen-type 1 (PICP) and carboxy-terminal telopeptide of collagen-type 1 (CITP) and arterial stiffness, particularly in the aorta.

Twenty-nine untreated hypertensive patients (17 male, 12 female aged 47±2, mean ±SEM) had samples drawn following an overnight fast and plasma was collected and stored at -80ºC until use. Patients with diabetes were excluded and there were 6 smokers. Plasma MMP-1, TIMP-1, PICP and ICTP levels were determined by enzyme immunoassay (Amersham Biosciences, Chemicon International, Takara Bio and Orion Diagnostica respectively). Aortic stiffness was measured from the carotid femoral pulse wave velocity (PWV) with the Complior using the foot-to-foot method. In addition, aortic pulse pressures and the augmentation pressure and index (height of the late systolic peak divided over pulse pressure) was computed from the aortic pressure waveform (Sphygmocor). Blood pressure was measured by a semi-automated oscillometric device (Omron 705 CM). Statistical analysis was performed using JMP (SAS Version 8.1).

There was a significant positive correlation (r=0.49, p<0.01) between MMP-1 and PWV. The PIP-ICTP ratio, a measure of collagen turnover was negatively related to PWV (r= -0.38, p<0.05) suggesting either higher synthesis or reduced degradation may be related to arterial compliance. There was no such relationship with TIMP-1.

This data suggests that increased extracellular degradation of collagen as measured by MMP-1 is associated with evidence of increased arterial stiffness and higher central pressures in hypertension. The negative correlation with the PIP-ICTP ratio favours enhanced breakdown rather than reduced synthesis as a possible mechanism. Studies with other MMPs, particularly MMP-2 and MMP-9 are required to further elucidate the role of the extracellular matrix in the pathogenesis of arterial stiffness. Drug therapy to reduce arterial stiffness in hypertension may need to target specific MMPs.

McNulty, M, et al. (2003). Br J Clin Pharmacol. 55:435-436.
Querejeta, R, et al. (2000). Circulation. 101:1729-1735.