Modulation of plasma matrix metalloproteinase 9 and its inhibitors by vitamin D.

Abstract

Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are upregulated in a variety of diseases. Hypothesis: As TIMP-1 levels are elevated in liver fibrosis, might a similar process occur in essential hypertension driven left ventricular hypertrophy and furthermore may TIMP-1 be a marker of vascular disease? If TIMP-1 levels are a potential marker of cardiovascular disease could their levels be modulated by vitamin D? Methods: Plasma TIMP-1 levels and aldosterone were measured a) in patients with essential hypertension who had never been on treatment or had been off treatment for 1 month and b) healthy controls. All participants underwent echocardiography. To assess whether TIMP-1 was a marker of vascular disease insulin, sCRP, fibrinogen, homocysteine, PAI-1 were measured in Bangladeshis pre supplementation with vitamin D. TIMP-1, MMP2, 9 and 25 hydroxyvitamin D 25(OH)vitD were also measured pre and post supplementation. Subsequent studies included measurements of MMP2, 9 and TIMP-1and 4 in submariners pre and post patrol and MMP9 and 25(OH)vitD in patients who re-stenosed post angioplasty. TIMP-4 was validated using a radioimmunoassay, 25(OH)vitD measured using a triple quad MS and other assays using ELISAs. Results: Plasma TIMP-1 was higher in hypertensive patients than in the controls (p<0.0001) and was correlated with left ventricular hypertrophy and with aldosterone. In the Bangladeshi study,. TIMP-1 was not correlated with other markers of vascular disease. TIMP-1 was correlated with systolic blood pressure (p<0.007) There was an inverse correlation of 25(OH)vitD with MMP9 (P<0.001) and TIMP-1 (p<0.05) and sCRP (p<0.05). The inverse relationship between MMP9 and 25(OH)vitD was also repeated in the submariner and restenosis studies. Conclusions: Plasma TIMP-1 may be an important determinant in essential hypertension and 25(OH)vit D may have a positive effect in reducing the inflammatory response as measured by MMP9. The increased 25(OH)vitD may also act by reducing aldosterone levels and thus suppressing TIMP-1 levels