Sulodexide Improves Contraction and Decreases Matrix Metalloproteinase-2 and -9 in Veins under Prolonged Stretch

Autor: Raouf A. Khalil, Paolo Mattana, Joseph D. Raffetto, Wentao Yu, Xi Wang, Fiorella Calanni
Rok vydání: 2019
Předmět:
Male
0301 basic medicine
medicine.medical_specialty
Contraction (grammar)
Chronic venous insufficiency
Down-Regulation
Vena Cava
Inferior
In Vitro Techniques
030204 cardiovascular system & hematology
Matrix metalloproteinase
Inferior vena cava
Article
Rats
Sprague-Dawley
Varicose Veins
Glycosaminoglycan
03 medical and health sciences
0302 clinical medicine
Internal medicine
Varicose veins
medicine
Humans
Animals
Vasoconstrictor Agents
Vascular Diseases
Phenylephrine
Glycosaminoglycans
Pharmacology
Chemistry
medicine.disease
Sulodexide
030104 developmental biology
Endocrinology
Matrix Metalloproteinase 9
Venous Insufficiency
medicine.vein
Vasoconstriction
Chronic Disease
Proteolysis
cardiovascular system
Matrix Metalloproteinase 2
medicine.symptom
Cardiology and Cardiovascular Medicine
medicine.drug
Zdroj: J Cardiovasc Pharmacol
ISSN: 0160-2446
DOI: 10.1097/fjc.0000000000000778
Popis: High pressure in the lower-limb veins is often associated with chronic venous insufficiency and varicose veins (VVs), making it important to search for the mechanisms and agents that control venous function. We have shown that protracted increases in venous stretch/wall tension reduce vein contraction and augment matrix metalloproteinase (MMP)-2 and -9. Also, MMP-2 and MMP-9 promote venodilation, a hallmark of VVs. Sulodexide (SDX) is a blend of glycosaminoglycans with efficient profibrinolysis and antithrombosis activities, but its actions on vein function and the mechanisms involved are unclear. We tested the hypothesis that SDX enhances venous contractile response by decreasing MMP expression/activity in veins subjected to protracted stretch. Rat inferior vena cava (IVC) rings were treated with SDX (0.001-1 mg/mL) or vehicle, equilibrated under control 0.5-g resting tension or protracted 2-g stretch for 18 hours, and the contractile response to 96-mM KCl and phenylephrine (Phe) in SDX-treated and nontreated veins was recorded. In IVC rings under control 0.5-g resting tension, SDX caused dose-dependent contraction, 96-mM KCl caused marked contraction (176-mg/mg tissue), and Phe caused dose-dependent contraction with a maximum (56-mg/mg tissue) at 10 M. In IVC subjected to protracted 2-g stretch, 96-mM KCl-induced contraction was reduced to 112 mg/mg and maximal Phe-induced contraction was decreased to 23 mg/mg. In IVC subjected to protracted 2-g stretch plus SDX, 96-mM KCl-induced contraction was restored to 228 mg/mg and maximal Phe-induced contraction was improved to 115 mg/mg. Gelatin zymography and Western blots revealed increases in MMP-2 and MMP-9 levels/gelatinolytic activity in veins subjected to protracted 2-g stretch and reversal to control levels in veins subjected to 2-g stretch plus SDX. Thus, SDX improves vein function and augments the contractile response in veins subjected to protracted stretch. The SDX-induced improvement of contraction and restoration of vein function appear to involve decreases in MMP-2 and MMP-9 and may contribute to the benefits of SDX in chronic venous insufficiency and VVs.
Databáze: OpenAIRE
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