Serum Iron and Matrix Metalloproteinase-9 Variations in Limbs Affected by Chronic Venous Disease and Venous Leg Ulcers

Abstract

BACKGROUND. Severe chronic venous disease (CVD) is characterized by both dermal hemosiderin accumulation and matrix metalloproteinase (MMP) hyperactivation. The iron-driven pathway is one of the recognized mechanisms of MMP hyperactivation. OBJECTIVE. To investigate the potential consequences of leg hemosiderin deposits on both iron metabolism and activation of MMPs.METHODS. We contemporaneously assessed the following in the serum of the arm and ankle veins of 30 patients (C4-6) with CVD and 14 normal subjects: ferritin, transferrin, iron, percentage of transferrin iron binding capacity (%TIBC), and MMP-9. Optical microscopy examinations with Perls' staining of chronic wounds were also performed. RESULTS. Histology consistently revealed iron deposits. Serum ferritin, iron, and %TIBC were significantly increased in the legs affected by severe CVD compared with the arm of the same subjects or the controls. In addition, iron and %TIBC were significantly elevated in the legs of ulcer patients. The rate of activation of MMP-9 was significantly elevated in CVD.CONCLUSIONS. The increased iron deposition in legs affected by CVD seems to be more instable in ulcer patients, leading to iron release in the serum of the affected leg. Our data suggest the iron-driven pathway as a further mechanism for MMP hyperexpression leading to tissue lesion.

The Causal Effects of Blood Iron and Copper on Lipid Metabolism Diseases: Evidence from Phenome-Wide Mendelian Randomization Study

“…Iron overload and its causal HFE genetic variations have been associated with the development of varicose veins [58]. Mechanistically, iron overload induces oxidative stress and the hyperactivation of matrix-degrading enzymes [59]. Other significant mineral-outcome relationships are also worth mentioning.…”

An overview of the relationship between anaemia, iron, and venous leg ulcers

“…When stratified for CEAP classification, those with stage 5–6 disease had significantly higher iron levels in the leg than those with CEAP 4 (86 vs 65 mg/100 mL; P < .0004). Other iron parameters were also significantly higher in the legs than in the arms of affected patients, %total iron binding capacity (TIBC) (24 vs 22%; P = .002), and ferritin (125 mg/100 mg vs 119 mg/100 mL; P = .0001); however, TIBC and transferrin did not show any significant difference …”

Acute venous occlusion enhances matrix metalloprotease activity: Implications on endothelial dysfunction

“…MMP-1, -2, -3, -9 and -12 activity has been detected in chronic human models of venous hypertension (Buján J et al, 2000; Sansilvestri-Morel P et al, 2007; Sansilvestri-Morel P et al, 2005; Pascarella L et al, 2005; Woodside KJ et al, 2003; Zamboni P et al, 2005). In the current model there is insufficient time for de-novo synthesis of new MMPs, and likely both MMP-8 and MMP-1/-9 are already constitutively expressed.…”

“…MMPs are also involved in the regulation of apoptosis (Egeblad, M et al, 2002). A number of studies have suggested that MMPs, especially MMP-1, -2, -3, -9 and -12 and their endogenous inhibitors (TIMPs), may play a role in the pathogenesis of venous hypertension and structuring of the venous wall (Buján J et al, 2000; Sansilvestri-Morel P et al, 2007; Sansilvestri-Morel P et al, 2005; Pascarella L et al, 2005; Woodside KJ et al, 2003; Zamboni P et al, 2005) (Herouy Y et al, 1998; Tarlton JF et al, 1999). Yet, there are no studies that have examined MMP activity over different time periods of venous pressure elevation to identify early versus later stage MMP expression patterns.…”