Matrix Metalloproteinases and Tissue Remodeling in Health and Disease: Cardiovascular Remodeling

306 Pages·2017·6.745 MB· 320 \306

by  Raouf A. Khalil (Eds.)

AcademicPressisanimprintofElsevier
50HampshireStreet,5thFloor,Cambridge,MA02139,UnitedStates
525BStreet,Suite1800,SanDiego,CA92101-4495,UnitedStates
TheBoulevard,LangfordLane,Kidlington,OxfordOX51GB,UnitedKingdom
125LondonWall,LondonEC2Y5AS,UnitedKingdom
Firstedition2017
Copyright©2017ElsevierInc.Allrightsreserved.
Nopartofthispublicationmaybereproducedortransmittedinanyformorbyanymeans,
electronicormechanical,includingphotocopying,recording,oranyinformationstorageand
retrievalsystem,withoutpermissioninwritingfromthepublisher.Detailsonhowtoseek
permission,furtherinformationaboutthePublisher’spermissionspoliciesandour
arrangementswithorganizationssuchastheCopyrightClearanceCenterandtheCopyright
LicensingAgency,canbefoundatourwebsite:www.elsevier.com/permissions.
Thisbookandtheindividualcontributionscontainedinitareprotectedundercopyrightby
thePublisher(otherthanasmaybenotedherein).
Notices
Knowledgeandbestpracticeinthisfieldareconstantlychanging.Asnewresearchand
experiencebroadenourunderstanding,changesinresearchmethods,professionalpractices,
ormedicaltreatmentmaybecomenecessary.
Practitionersandresearchersmustalwaysrelyontheirownexperienceandknowledgein
evaluatingandusinganyinformation,methods,compounds,orexperimentsdescribed
herein.Inusingsuchinformationormethodstheyshouldbemindfuloftheirownsafetyand
thesafetyofothers,includingpartiesforwhomtheyhaveaprofessionalresponsibility.
Tothefullestextentofthelaw,neitherthePublishernortheauthors,contributors,oreditors,
assumeanyliabilityforanyinjuryand/ordamagetopersonsorpropertyasamatterof
productsliability,negligenceorotherwise,orfromanyuseoroperationofanymethods,
products,instructions,orideascontainedinthematerialherein.
ISBN:978-0-12-811637-1
ISSN:1877-1173
ForinformationonallAcademicPresspublications
visitourwebsiteathttps://www.elsevier.com/books-and-journals
Publisher:ZoeKruze
AcquisitionEditor:AlexWhite
EditorialProjectManager:HeleneKabes
ProductionProjectManager:JamesSelvam
CoverDesigner:VictoriaPearson
TypesetbySPiGlobal,India
CONTRIBUTORS
ValerieArpino
CentreforCriticalIllnessResearch,LawsonHealthResearchInstitute;SchulichSchoolof
MedicineandDentistry,WesternUniversity,London,ON,Canada
BethanA.Brown
SchoolofClinicalSciences,UniversityofBristol,Bristol,UnitedKingdom
YunfeiChen
VascularSurgeryResearchLaboratories,BrighamandWomen’sHospital,HarvardMedical
School,Boston,MA,UnitedStates
NingCui
VascularSurgeryResearchLaboratories,BrighamandWomen’sHospital,HarvardMedical
School,Boston,MA,UnitedStates
KristineY.DeLeon-Pennell
MississippiCenterforHeartResearch,UMMC;ResearchService,G.V.(Sonny)
MontgomeryVeteransAffairsMedicalCenter,Jackson,MS,UnitedStates
EmanuelaFalcinelli
SectionofInternalandCardiovascularMedicine,UniversityofPerugia,Perugia,Italy
SarahJ.George
SchoolofClinicalSciences,UniversityofBristol,Bristol,UnitedKingdom
SeanE.Gill
CentreforCriticalIllnessResearch,LawsonHealthResearchInstitute;SchulichSchoolof
MedicineandDentistry,WesternUniversity,London,ON,Canada
PaoloGresele
SectionofInternalandCardiovascularMedicine,UniversityofPerugia,Perugia,Italy
MinHu
VascularSurgeryResearchLaboratories,BrighamandWomen’sHospital,HarvardMedical
School,Boston,MA,UnitedStates
MiraJung
MississippiCenterforHeartResearch,UMMC,Jackson,MS,UnitedStates
RaoufA.Khalil
VascularSurgeryResearchLaboratories,BrighamandWomen’sHospital,HarvardMedical
School,Boston,MA,UnitedStates
ChristopherK.S.Lee
CentreforCriticalIllnessResearch,LawsonHealthResearchInstitute;SchulichSchoolof
MedicineandDentistry,WesternUniversity,London,ON,Canada
MerryL.Lindsey
MississippiCenterforHeartResearch,UMMC;ResearchService,G.V.(Sonny)
MontgomeryVeteransAffairsMedicalCenter,Jackson,MS,UnitedStates
ix
x Contributors
MarcelloG.Masciantonio
CentreforCriticalIllnessResearch,LawsonHealthResearchInstitute;SchulichSchoolof
MedicineandDentistry,WesternUniversity,London,ON,Canada
SanjayMehta
CentreforCriticalIllnessResearch,LawsonHealthResearchInstitute,London,ON,
Canada
CesarA.Meschiari
MississippiCenterforHeartResearch,UMMC,Jackson,MS,UnitedStates
StefaniaMomi
SectionofInternalandCardiovascularMedicine,UniversityofPerugia,Perugia,Italy
WilliamC.Parks
Women’sGuildLungInstitute,Cedars-SinaiMedicalCenter,LosAngeles,CA,United
States
WeiPeng
VascularSurgeryResearchLaboratories,BrighamandWomen’sHospital,HarvardMedical
School,Boston,MA,UnitedStates
SimonW.Rabkin
UniversityofBritishColumbia,Vancouver,BC,Canada
JosephD.Raffetto
VascularSurgeryResearchLaboratories,BrighamandWomen’sHospital,HarvardMedical
School,Boston,MA,UnitedStates
ManuelaSebastiano
SectionofInternalandCardiovascularMedicine,UniversityofPerugia,Perugia,Italy
KateS.Smigiel
Women’sGuildLungInstitute,Cedars-SinaiMedicalCenter,LosAngeles,CA,United
States
HelenWilliams
SchoolofClinicalSciences,UniversityofBristol,Bristol,UnitedKingdom
PREFACE
Matrix metalloproteinases (MMPs) are a family of structurally related zinc-
containing proteolytic enzymes that degrade various components of the
extracellular matrix and connective tissue proteins. The MMP family
includes collagenases, gelatinases, stromelysins, matrilysins and membrane-
type MMPs, and other MMPs. MMPs are important regulators of tissue
remodeling, cell migration, and adhesion molecules. In addition to their
proteolytic effects on the extracellular matrix, recent studies suggest novel
effectsofMMPsontransmembraneandintracellularsignalinginmanycell
types including the vascular endothelium and smooth muscle. MMPs are
tightly regulated at the transcription level and can be activated by other
MMPsorproteasesintotheirproteolyticactiveformsthatinteractwithvar-
ious substrates and signaling pathways. MMP activity is also regulated by
endogenoustissueinhibitorsofmetalloproteinases(TIMPs),whichprovide
abalancingmechanismtopreventexcessivedegradationoftheextracellular
matrix. MMP/TIMP imbalance could lead to pathological conditions and
major cardiovascular, metabolic, and musculoskeletal disorders as well as
cancer.ModulationofMMPactivityusinggeneticmanipulationsofendog-
enous TIMPs or synthetic pharmacological inhibitors could control MMP
activity and may provide new approaches in the management of MMP-
related diseases.
ThisvolumeofProgressinMolecularBiologyandTranslationalSciencepro-
vides insights into MMPs and Tissue Remodeling in Health and Disease.
Because MMPs play a role in a large number of biological processes and
could be involved in numerous pathological conditions, we divided this
volume into two parts. Part I focuses on Cardiovascular Remodeling, and
Part II covers the role of MMPs in other target tissues and diseases and
thepotentialbenefitsofMMPinhibitors.Renownscientistsandresearchers
haveagreedtosharetheirexpertiseandadvancedknowledgeonMMPs.In
Part I on the role of MMPs on Cardiovascular Remodeling we will cover
several important topics regarding the basic biochemical and biological
properties of MMPs; the role of MMPs in myocardial infarction and heart
failure; the MMP/TIMP balance and microvascular endothelial function
anddysfunction;MMPsinbloodplateletsandleukocyteactivation;therole
of MMPs in atherosclerosis, aneurysm, and hepatic ischemia/reperfusion
injury; and the role of MMPs in remodeling of lower extremity veins and
xi
xii Preface
chronic venous disease. These important reviews were written by research
investigators and clinician–scientists from different parts of the world, thus
promotingdifferentviewpointsinthepathogenesisofcardiovasculardisease
andhighlightingdifferentapproachesinthediagnosisandmanagementofcar-
diovasculardisorders.Thankstothegoodworkofthecontributingauthors,
andthecarefulreviewofourdedicatedReviewersandEditors,wewereable
toputtogethertheseimportanttopics,andpresentthemtoourreadersina
clear, concise, and informative fashion. I encourage every researcher, clini-
cian, medical, graduate, and undergraduate student with aspiration to work
inthecardiovascularfieldtoreadthisstate-of-the-artsynopsisonMMPs.
I would like to dedicate this volume to the late Dr. P. Michael Conn,
thepastSeriesEditorofProgressinMolecularBiologyandTranslationalScience.
Dr.ConngavemethegreatopportunitytobetheEditorofthisspecialand
timelyvolume,andforthisIwillalwaysbeverygrateful.Ialsowouldliketo
thankouroutstandingSeniorEditorialProjectManagerMrs.HeleneKabes
and our hardworking Editorial Staff who spared no effort to ensure the
highestqualityofthearticles.Ialsowouldliketoacknowledgeourcontrib-
uting authors not only for their excellent articles but also for sharing some
of the reviewers’ duties, and for being very generous with their time and
effort in providing other authors with helpful comments and constructive
criticism.IparticularlywishtothankourreadersfortheirinterestinMMPs
and cardiovascular remodeling. I encourage all of you to provide feedback
and contact me directly if you have any questions, comments, suggestions,
criticism, or ideas that could further enhance our knowledge and help us
achieve our goals and meet the highest expectations of our readers.
RAOUF A. KHALIL
Harvard Medical School, Brigham and Women’s Hospital,
Boston, MA, United States
CHAPTER ONE
Biochemical and Biological
Attributes of Matrix
Metalloproteinases
Ning Cui, Min Hu, Raouf A. Khalil1
VascularSurgeryResearchLaboratories,BrighamandWomen’sHospital,HarvardMedicalSchool,Boston,
MA,UnitedStates
1Correspondingauthor:e-mailaddress:[email protected]
Contents
1. Introduction 3
2. MMPStructure 4
3. SourcesandTissueDistributionofMMPs 5
4. MMPActivation 11
5. MMPSubstrates 13
6. MMPs,ECMDegradation,andTissueRemodeling 16
7. MMPsandCellSignaling 18
7.1 MMPsandVSMFunction 18
7.2 MMPsandEndothelialCellFunction 20
8. SpecialAttributesofSpecificMMPs 20
8.1 Collagenases 20
8.2 Gelatinases 26
8.3 Stromelysins 29
8.4 Matrilysins 35
8.5 Membrane-TypeMMPs 38
8.6 OtherMMPs 48
9. MMP/TIMPRatio 60
10. ConcludingRemarks 60
Acknowledgments 61
References 61
Abstract
Matrixmetalloproteinases(MMPs)areafamilyofzinc-dependentendopeptidasesthat
areinvolvedinthedegradationofvariousproteinsintheextracellularmatrix(ECM).Typ-
ically, MMPshaveapropeptide sequence, acatalytic metalloproteinase domainwith
catalytic zinc, a hinge region or linker peptide, and a hemopexin domain. MMPs are
commonlyclassifiedonthebasisoftheirsubstratesandtheorganizationoftheirstruc-
turaldomainsintocollagenases,gelatinases,stromelysins,matrilysins,membrane-type
(MT)-MMPs, andotherMMPs.MMPsaresecretedbymanycellsincludingfibroblasts,
ProgressinMolecularBiologyandTranslationalScience,Volume147 #2017ElsevierInc. 1
ISSN1877-1173 Allrightsreserved.
http://dx.doi.org/10.1016/bs.pmbts.2017.02.005
2 NingCuietal.
vascularsmoothmuscle(VSM),andleukocytes.MMPsareregulatedatthelevelofmRNA
expressionandbyactivationoftheirlatentzymogenform.MMPsareoftensecretedas
inactive pro-MMP form which is cleaved to the active form by various proteinases
including other MMPs. MMPs cause degradation of ECM proteins such as collagen
andelastin,butcouldinfluenceendothelialcellfunctionaswellasVSMcellmigration,
proliferation,Ca2+signaling,andcontraction.MMPsplayaroleintissueremodelingdur-
ingvariousphysiologicalprocessessuchasangiogenesis,embryogenesis,morphogen-
esis, and wound repair, as well as in pathological conditions such as myocardial
infarction,fibroticdisorders,osteoarthritis,andcancer.IncreasesinspecificMMPscould
play a role in arterial remodeling, aneurysm formation, venous dilation, and lower
extremity venousdisorders.MMPs alsoplayamajor role inleukocyte infiltration and
tissue inflammation. MMPs have been detected in cancer, and elevated MMP levels
havebeenassociatedwithtumorprogressionandinvasiveness.MMPscanberegulated
byendogenoustissueinhibitorsofmetalloproteinases(TIMPs),andtheMMP/TIMPratio
oftendeterminestheextentofECMproteindegradationandtissueremodeling.MMPs
havebeenproposedasbiomarkersfornumerouspathologicalconditionsandarebeing
examinedaspotentialtherapeutictargetsinvariouscardiovascularandmusculoskeletal
disordersaswellascancer.
ABBREVIATIONS
BKCa largeconductanceCa2+-activatedK+channel
CXCR C-X-Cchemokinereceptor
ECM extracellularmatrix
EDHF endothelium-derivedhyperpolarizingfactor
EMMPRIN extracellularmatrixmetalloproteinaseinducer
ERK extracellularsignal-regulatedkinase
GM-CSF granulocyte-macrophagecolony-stimulatingfactor
GPI glycosylphosphatidylinositol
HIF hypoxia-induciblefactor
IFN interferon
IL interleukin
IVC inferiorvenacava
MAPK mitogen-activatedproteinkinase
MI myocardialinfarction
miR microRNA
MMP matrixmetalloproteinase
MT-MMP membrane-typeMMP
NF-κB nuclearfactor-kappa-light-chain-enhancerofactivatedBcells
PAR protease-activatedreceptor
PDGF platelet-derivedgrowthfactor
PI3K phosphoinositide3-kinase
PMNs polymorphonuclearleukocytes
RGD Arg-Gly-Asp
siRNA small-interferingRNA
BiochemistryandBiologyofMMPs 3
SNP single-nucleotidepolymorphism
TGF-β transforminggrowthfactor-β
TIMP tissueinhibitorsofmetalloproteinases
TNF-α tumornecrosisfactor-α
VEGF vascularendothelialgrowthfactor
VSM vascularsmoothmuscle
VSMC vascularsmoothmusclecell
Zn2+ zinc
1. INTRODUCTION
Matrix metalloproteinases (MMPs) are a family of zinc-dependent
endoproteases with multiple roles in tissue remodeling and degradation of
variousproteinsintheextracellularmatrix(ECM).MMPspromotecellpro-
liferation, migration, and differentiation, and could play a role in cell apo-
ptosis, angiogenesis, tissue repair, and immune response. MMPs may also
affect bioactive molecules on the cell surface and modulate various cellular
andsignalingpathways.AlterationsinMMPexpressionandactivityoccurin
normalbiologicalprocesses,e.g.,duringpregnancyandwoundhealing,but
have also been observed in cardiovascular diseases such as atherosclerosis,
aneurysms,andvaricoseveins,musculoskeletaldisorderssuchasosteoarthri-
tisandboneresorption,andinvariouscancers.MMPshavealsobeenimpli-
cated in tumor progression and invasiveness.
In this chapter, we will use data reported in PubMed and other scien-
tificdatabasesaswellasdatafromourlaboratorytoprovideageneralover-
viewofthebiochemicalandbiologicalpropertiesofMMPswithemphasis
onMMPstructure,tissuedistribution,andproteinsubstrates.Wewillthen
describe special properties of specific classes of MMPs and provide some
examples of their role in cardiovascular diseases, inflammatory, and mus-
culoskeletal disorders, as well as cancer. We will then briefly discuss the
regulation of MMP activity by endogenous tissue inhibitors of
metalloproteinases(TIMPs).Wewillconcludethechapterbyhighlighting
the potential benefits of MMPs as biomarkers and therapeutic targets in
cardiovascular conditions, musculoskeletal disorders, and cancer. Addi-
tionalinformationregardingspecificMMPfunctionscanbefoundinother
reports1–4 and are elegantly reviewed in detail in the other chapters of
this book.
4 NingCuietal.
2. MMP STRUCTURE
Intheearly1960s,MMPswerefirstidentifiedasacollagenproteolytic
activity that causes ECMprotein degradation during resorption of thetad-
poletail.5MMPsarenowgrowntoafamilyofendopeptidasesormatrixins
that belong to the metzincins superfamily of proteases. MMPs are highly
homologous,multidomain, zinc(Zn2+)-containing metalloproteinasesthat
degrade various protein components of ECM. The MMP family shares a
common core structure. Typically MMPs consist of a propeptide of about
80 amino acids, a catalytic metalloproteinase domain of about 170 amino
acids, a linker peptide (hinge region) of variable length, and a hemopexin
domain of about 200 amino acids (Fig. 1).6–9
Most MMPs also share three important characteristics. First, MMPs
show homology to collagenase-1 (MMP-1). MMP-7, -23, and -26 are
exceptions as they lack the linker peptide and the hemopexin domain.
MMP-23 has a unique C-terminal cysteine-rich domain and an
immunoglobulin-likedomainimmediatelyaftertheC-terminusofthecat-
alyticdomain.Second,MMPscontainacysteine-switchmotifPRCGXPD
in which the cysteine sulfhydryl group chelates the active site Zn2+ thus
keepingMMPsin theirinactivepro-MMPzymogenform.Third,thecat-
alytic domain of MMPs harbors a Zn2+-binding motif to which the Zn2+
ion is bound by three histidines from the conserved sequence
HEXXHXXGXXH, with the assistance of a conserved glutamate, and a
conserved methionine sequence XBMX (Met-turn) located 8-residues
downfromtheZn2+-bindingmotifthatsupportsthestructuresurrounding
the catalytic Zn2+ (Fig. 1).10–12
In vertebrates, the MMP family comprises 28 members, at least 23 are
expressedinhumantissues,and14ofthoseMMPsareexpressedinthevas-
culature (Table 1).10 MMPs are commonly classified on the basis of their
substratesandtheorganizationoftheirstructuraldomainsintocollagenases,
gelatinases, stromelysins, matrilysins, membrane-type (MT)-MMPs, and
otherMMPs.Additionally,differentclassesofMMPshavespecificstructural
features that distinguish them from the prototypical MMP structure
(Fig.1).2,13,14ThetopologyofMMPsiswellconserved,andamajordiffer-
0
ence between MMPs lies in the S1 subsite, a well-defined hydrophobic
pocket of variable depth that is critical for specific MMP–substrate
interaction.15
BiochemistryandBiologyofMMPs 5
Cysteine- Catalytic domain
(cid:129)(cid:129) CStoMrlolMamgPee-lny1sa, is8ne,s s13, 18 seSqiugennacle sPwRitCchG XmPoDt-ifSHCa2+1Z7n02 a+a Ca2+ rHeignigoen Hedmomopaeinxin Tail
MMP-3, 10 N Propeptide Sn, S2, S1 S1(cid:2), S2(cid:2), Sn(cid:2) C
(cid:129) Other MMPs 80 aa HEXXHXXGXXH 15–65 aa 200 aa
MMP-12, 19, 20, 22, 27
Zn2+-binding sequence
(cid:129) Gelatinases Zn2+
MMP-2, 9
3 Type II fibronectin repeats
(cid:129) Matrilysins Zn2+
MMP-7, 26
Furin-like
(cid:129) Furin-containing MMPs motif
-Secreted Zn2+
MMP-11, 21, 28
Cytoplasmic
tail
-Type I MT-MMPs Zn2+
(MT-1, 2, 3, 5-MMP)
(MMP-14, 15, 16, 24) Transmembrane
domain
-GPI-anchored MT-MMPs Zn2+
(MT-4, 6-MMP)
(MMP-17, 25)
GPI
Type II signal Cysteine-rich anchor
-Type II MT-MMPs anchor Zn2+ region Proline-rich
(MMP-23) region
Fig.1 MajorMMPssubtypesandtheirstructure.AtypicalMMPconsistsofapropeptide,
acatalyticmetalloproteinasedomain,alinkerpeptide(hingeregion),andahemopexin
domain. The propeptide has a cysteine-switch PRCGXPD whose cysteine sulfhydryl
(–SH) group chelates the active site Zn2+, keeping the MMP in the latent pro-MMP
zymogenform.ThecatalyticdomaincontainstheZn2+bindingmotifHEXXHXXGXXH,
twoZn2+ions(onecatalyticandonestructural),specificS1,S2,…,SnandS10,S20,…,Sn0
pockets, which confer specificity, and two or three Ca2+ ions for stabilization. Some
MMPs show exceptions in their structures. Gelatinases have three type II fibronectin
repeats in the catalytic domain. Matrilysins have neither a hinge region nor a
hemopexin domain. Furin-containing MMPs such as MMP-11, -21, and -28 have a
furin-likepro-protein convertase recognitionsequenceinthepropeptideC-terminus.
MMP-28hasaslightlydifferentcysteine-switchmotifPRCGVTD.Membrane-typeMMPs
(MT-MMPs)typicallyhaveatransmembranedomainandacytosolicdomain.MMP-17
and-25haveaglycosylphosphatidylinositol(GPI)anchor.MMP-23lackstheconsensus
PRCGXPDmotif,hasacysteineresiduelocatedinadifferentsequenceALCLLPA,may
remain in the latent inactive proform through its type II signal anchor, and has a
cysteine-richregionandanimmunoglobulin-likeproline-richregion.
3. SOURCES AND TISSUE DISTRIBUTION OF MMPs
MMPsareproducedbymultipletissuesandcells(Table1).MMPsare
secreted by connective tissue, proinflammatory, and uteroplacental cells