The effects of sulodexide on both clinical and molecular parameters in patients with mixed arterial and venous ulcers of lower limbs

Abstract

BackgroundMixed venous and arterial ulcers account for approximately 15%–30% of all venous leg ulcerations. Several studies have shown that matrix metalloproteinases (MMPs) and neutrophil gelatinase-associated lipocalin (NGAL) play a central role in the pathophysiology of venous and arterial diseases. Some studies have shown the efficacy of glycosaminoglycans, such as sulodexide (SDX), in treating patients with leg ulcers. The aim of this study was to evaluate clinical effects of SDX and its correlation with MMPs and NGAL expression in patients with mixed arterial and venous leg ulcers.MethodsPatients eligible for this study were of both sexes, older than 20 years, and with a clinical and instrumental diagnosis of mixed ulcer.ResultsFifty-three patients of both sexes were enrolled and divided into two groups by means of randomization tables. Group A (treated group) comprised 18 females and ten males (median age: 68.7 years) treated with standard treatment (compression therapy and surgery) + SDX (600 lipoprotein lipase-releasing units/day intramuscularly) for 15 days followed by SDX 250 lipase-releasing units every 12 hours day orally for 6 months as adjunctive treatment. Group B (control group) comprised 17 females and eight males (median age: 64.2 years) treated with standard treatment only (compression therapy and surgery). The type of surgery was chosen according to anatomical level of vein incompetence: superficial venous open surgery and/or subfascial endoscopic perforating surgery. In all enrolled patients, blood samples were collected in order to evaluate the plasma levels of MMPs and NGAL through enzyme-linked immunosorbent assay. These results were compared to another control group (Group C) of healthy individuals. Moreover, biopsies of ulcers were taken to evaluate the tissue expression of MMPs and NGAL through Western blot analysis. Our results revealed that SDX treatment is able to reduce both plasma levels and tissue expression of MMPs improving the clinical conditions in patients with mixed ulcers.ConclusionInhibition of MMPs could represent a possible therapeutic intervention to limit the progression of leg ulceration. In particular, our findings demonstrate the efficacy of SDX in patients with mixed arterial and venous chronic ulcers of the lower limbs.

Matrix Metalloproteinases as Regulators of Vein Structure and Function: Implications in Chronic Venous Disease

“…Some MMP modulators could enhance MMP activity by preventing MMP degradation. For instance, neutrophil gelatinase-associated lipocalin forms a complex with MMP-9 and thereby protects it from proteolytic degradation and increases its levels (Serra et al, 2014). The list of MMP activators is growing, and whether these activators are increased in VVs needs to be examined.…”

“…Small interfering RNA inhibits the transcriptional product of MMP-2 (Chetty et al, 2006). Glycosaminoglycan sulodexide decreases MMP-9 secretion from white blood cells without MMP prodomain displacement (Mannello et al, 2013), and may specifically inhibit proteases with cysteine residues such as MMP-2 and -9 (Serra et al, 2014). Statins such as atorvastatin inhibit MMP-1, -2, and -9 expression in human retinal pigment epithelial cells (Dorecka et al, 2014) and MMP-1, -2, -3, and -9 secretion from rabbit macrophages and cultured rabbit aortic and human saphenous vein VSMCs (Luan et al, 2003).…”

Hemorrhoids and matrix metalloproteinases: A multicenter study on the predictive role of biomarkers

“…We used the MMP and NGAL kit described previously. [19][20][21] The results were evaluated respect to the control group.…”

“…For Western blot analysis, hemorrhoidal specimens taken at the time of hemorrhoidal operations were lysed in 2 mL of tissue protein extraction reagent as described previously. [19][20][21] Immunoblotting of protein was performed using anti-MMPs and anti-NGAL monoclonal antibodies as described. 19 Antibodies were obtained from (Thermo Scientific, Cambridge, United Kingdom).…”

“…14 Matrix metalloproteinases (MMPs) are enzymes that regulate ECM composition 15 and play a role in several vascular inflammatory conditions that may be related with hemorrhoidal disease. [16][17][18][19][20][21][22][23][24][25][26][27][28][29] Fargo and Latimer documented that the degradation of the ECM with MMP may be involved in the development of hemorrhoidal disease, 30 and we showed that neutrophil gelatinaseassociated lipocalin (NGAL) modulates the activity of MMP-9 in vascular disease. 17 Therefore, to evaluate the role of MMPs and NGAL in the development of hemorrhoidal disease, we evaluated both plasma MMPs and NGAL levels and their tissue expression in patients with different stages of hemorrhoids.…”