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Page 20 of 30 Raffetto et al. Vessel Plus 2021;5:36 https://dx.doi.org/10.20517/2574-1209.2021.16

2+
2+
2+
2+
2+
Divalent ions such as Cu , Mg , and Mn inhibit MMPs by interfering with Zn at the Zn binding site in
2+
[206]
the MMP catalytic domain . The MMP Zn binding property has been utilized to develop several MMP
2+
inhibitors [4,207] . Inhibitors of MMPs usually have a Zn binding side-chain such as carboxylic acid,
2+
[208]
hydroxamic acid, or a sulfhydryl group . Zn binding globulins (ZBGs) inhibit MMPs by displacing the
Zn -bound water molecule in the MMP catalytic domain. ZBG also functions as anchors to keep the MMP
2+
[209]
inhibitor attached to the MMP active site and allow it to diffuse inside the substrate-binding pocket .
Hydroxamic acid-based MMP inhibitors include phosphinamide, succinyl, and sulfonamide
hydroxamates [208,210,211] . Succinyl hydroxamates such as batimastat (BB-94), marimastat (BB-2516), and
ilomastat (GM6001) have a structure similar to collagen, and function as broad spectrum MMP inhibitors
through bidentate chelation of Zn 2+[208,212] . Other ZBGs such as aminomethyl benzimidazole-containing
ZBGs, nitrogen- and phosphorous-based ZBGs, carboxylic acids, sulfonylhydrazides, thiols, and
heterocyclic bidentate chelators have also been developed [209,213,214] . Mechanism-based MMP inhibitors and
tetracyclines also inhibit MMPs by chelation of Zn from the MMP active site . An example of
2+
[208]
mechanism-based MMP inhibitors is SB-3CT or compound-40 which coordinates with the MMP Zn and
2+
allows the conserved Glu202 in the MMP molecule to initiate a nucleophilic attack and form a covalent
bond with the MMP inhibitor . The mechanism-based MMP inhibitors have an advantage over other Zn
2+
[209]
chelating MMP inhibitors, as the strong covalent bond between SB-3CT and the MMP molecule prevents
dissociation of the MMP inhibitor, and thereby reduces the concentration of MMP inhibitor required to
saturate the MMP active site .
[215]
Other MMP inhibitors including compound-37 do not have ZBGs, and do not bind to the highly-conserved
Zn binding site, but rather interact non-covalently with the S1’, S2’, S3’, and S4’ pockets in the MMP
2+
[216]
molecule in a manner similar to that of the substrate P1’, P2’, P3’, and P4’ substituents . The efficacy and
specificity of these MMP inhibitors depend on which of the pockets it blocks in the MMP molecule .
[208]
MMP-specific siRNA inhibits the transcription of specific MMPs . Also, some compounds could have
[217]
pleiotropic properties including inhibition of MMPs. For instance, statins such as atorvastatin decrease
MMP-1, -2, and -9 expression in human retinal pigment epithelial cells , and inhibit MMP-1, -2, -3, and
[218]
[219]
-9 release from human saphenous vein SMCs, rabbit macrophages and rabbit aortic SMCs . Also,
treatment of rat models of heart failure with pravastatin suppresses the increases in activity of MMP-2 and
[220]
-9 . Although the design and development of MMP inhibitors has shown great advances, doxycycline
remains the only MMP inhibitor approved by the FDA . Patients with VLU who received basic
[221]
compression therapy with or without VVs surgery in addition to oral doxycycline 20 mg b.i.d. for 3 months
showed a higher rate of healed VLU than patients receiving basic therapy alone. Of note, the lower VLU
healing rate in patients who received basic therapy alone was also associated with increased MMP-9, NGAL
and VEGF levels in the plasma, wound fluid and tissue biopsies. Doxycycline therapy through its anti-
inflammatory actions and MMP inhibition could also improve ECM function and facilitate VLU
healing . MMP inhibitors have major limitations as they cause several musculoskeletal side-effects
[222]
including joint pain, stiffness, inflammation, and tendonitis . Improved selectivity of MMP inhibitors and
[223]
their directed targeting locally to the dilated venous segments could enhance their therapeutic potential and
minimize their systemic side-effects in the management of CVD.

CONCLUSION AND PERSPECTIVE
CVD is a challenging venous disorder in terms of understanding its underlying mechanisms and providing
effective management. Demographic, genetic and environmental factors have been suggested as
predisposing risk factors for CVD. Changes in MMPs could also promote venous dilation. Changes in
venous shear stress and endothelial glycocalyx lead to leukocyte and adhesion molecule activation.