Granzyme B Deficiency Protects against Angiotensin II-Induced Cardiac Fibrosis.
Identifieur interne : 000338 ( Main/Exploration ); précédent : 000337; suivant : 000339Granzyme B Deficiency Protects against Angiotensin II-Induced Cardiac Fibrosis.
Auteurs : Yue Shen [Canada] ; Fang Cheng [Finlande] ; Mehul Sharma [Canada] ; Yulia Merkulova [Canada] ; Sheetal A. Raithatha [Canada] ; Leigh G. Parkinson [Canada] ; Hongyan Zhao [Canada] ; Kathryn Westendorf [Canada] ; Lubos Bohunek [Canada] ; Tatjana Bozin [Canada] ; Ivy Hsu [Canada] ; Lisa S. Ang [Canada] ; Sarah J. Williams [Canada] ; R Chris Bleackley [Canada] ; John E. Eriksson [Finlande] ; Michael A. Seidman [Canada] ; Bruce M. Mcmanus [Canada] ; David J. Granville [Canada]Source :
- The American journal of pathology [ 1525-2191 ] ; 2016.
English descriptors
- KwdEn :
- Adult, Aged, Animals, Disease Models, Animal, Female, Fibrosis (enzymology), Fibrosis (pathology), Fluorescent Antibody Technique, Granzymes (metabolism), Heart Diseases (enzymology), Heart Diseases (pathology), Humans, Immunohistochemistry, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Real-Time Polymerase Chain Reaction, Young Adult.
- MESH :
- chemical , metabolism : Granzymes.
- enzymology : Fibrosis, Heart Diseases.
- pathology : Fibrosis, Heart Diseases.
- Adult, Aged, Animals, Disease Models, Animal, Female, Fluorescent Antibody Technique, Humans, Immunohistochemistry, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Real-Time Polymerase Chain Reaction, Young Adult.
Abstract
Cardiac fibrosis is observed across diverse etiologies of heart failure. Granzyme B (GzmB) is a serine protease involved in cell-mediated cytotoxicity in conjunction with the pore-forming protein, perforin. Recent evidence suggests that GzmB also contributes to matrix remodeling and fibrosis through an extracellular, perforin-independent process. However, the role of GzmB in the onset and progression of cardiac fibrosis remains elusive. The present study investigated the role of GzmB in the pathogenesis of cardiac fibrosis. GzmB was elevated in fibrotic human hearts and in angiotensin II-induced murine cardiac fibrosis. Genetic deficiency of GzmB reduced angiotensin II-induced cardiac hypertrophy and fibrosis, independently of perforin. GzmB deficiency also reduced microhemorrhage, inflammation, and fibroblast accumulation in vivo. In vitro, GzmB cleaved the endothelial junction protein, vascular endothelial (VE)-cadherin, resulting in the disruption of endothelial barrier function. Together, these results suggest a perforin-independent, extracellular role for GzmB in the pathogenesis of cardiac fibrosis.
DOI: 10.1016/j.ajpath.2015.09.010
PubMed: 26610869
Affiliations:
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Ang</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia</wicri:regionArea><wicri:noRegion>British Columbia</wicri:noRegion></affiliation></author><author><name sortKey="Williams, Sarah J" sort="Williams, Sarah J" uniqKey="Williams S" first="Sarah J" last="Williams">Sarah J. Williams</name><affiliation wicri:level="1"><nlm:affiliation>Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia</wicri:regionArea><wicri:noRegion>British Columbia</wicri:noRegion></affiliation></author><author><name sortKey="Bleackley, R Chris" sort="Bleackley, R Chris" uniqKey="Bleackley R" first="R Chris" last="Bleackley">R Chris Bleackley</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Biochemistry, University of Alberta, Edmonton, Alberta</wicri:regionArea><wicri:noRegion>Alberta</wicri:noRegion></affiliation></author><author><name sortKey="Eriksson, John E" sort="Eriksson, John E" uniqKey="Eriksson J" first="John E" last="Eriksson">John E. Eriksson</name><affiliation wicri:level="3"><nlm:affiliation>Department of Biosciences, Turku Centre for Biotechnology, Åbo Akademi University, Turku, Finland.</nlm:affiliation><country xml:lang="fr">Finlande</country><wicri:regionArea>Department of Biosciences, Turku Centre for Biotechnology, Åbo Akademi University, Turku</wicri:regionArea><placeName><settlement type="city">Turku</settlement><region type="région" nuts="2">Finlande occidentale</region></placeName></affiliation></author><author><name sortKey="Seidman, Michael A" sort="Seidman, Michael A" uniqKey="Seidman M" first="Michael A" last="Seidman">Michael A. Seidman</name><affiliation wicri:level="1"><nlm:affiliation>Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, Providence Health Care, Vancouver, British Columbia, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, Providence Health Care, Vancouver, British Columbia</wicri:regionArea><wicri:noRegion>British Columbia</wicri:noRegion></affiliation></author><author><name sortKey="Mcmanus, Bruce M" sort="Mcmanus, Bruce M" uniqKey="Mcmanus B" first="Bruce M" last="Mcmanus">Bruce M. Mcmanus</name><affiliation wicri:level="1"><nlm:affiliation>Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia</wicri:regionArea><wicri:noRegion>British Columbia</wicri:noRegion></affiliation></author><author><name sortKey="Granville, David J" sort="Granville, David J" uniqKey="Granville D" first="David J" last="Granville">David J. Granville</name><affiliation wicri:level="1"><nlm:affiliation>Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada. 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Raithatha</name><affiliation wicri:level="1"><nlm:affiliation>Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia</wicri:regionArea><wicri:noRegion>British Columbia</wicri:noRegion></affiliation></author><author><name sortKey="Parkinson, Leigh G" sort="Parkinson, Leigh G" uniqKey="Parkinson L" first="Leigh G" last="Parkinson">Leigh G. Parkinson</name><affiliation wicri:level="1"><nlm:affiliation>Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia</wicri:regionArea><wicri:noRegion>British Columbia</wicri:noRegion></affiliation></author><author><name sortKey="Zhao, Hongyan" sort="Zhao, Hongyan" uniqKey="Zhao H" first="Hongyan" last="Zhao">Hongyan Zhao</name><affiliation wicri:level="1"><nlm:affiliation>Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia</wicri:regionArea><wicri:noRegion>British Columbia</wicri:noRegion></affiliation></author><author><name sortKey="Westendorf, Kathryn" sort="Westendorf, Kathryn" uniqKey="Westendorf K" first="Kathryn" last="Westendorf">Kathryn Westendorf</name><affiliation wicri:level="1"><nlm:affiliation>Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia</wicri:regionArea><wicri:noRegion>British Columbia</wicri:noRegion></affiliation></author><author><name sortKey="Bohunek, Lubos" sort="Bohunek, Lubos" uniqKey="Bohunek L" first="Lubos" last="Bohunek">Lubos Bohunek</name><affiliation wicri:level="1"><nlm:affiliation>Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia</wicri:regionArea><wicri:noRegion>British Columbia</wicri:noRegion></affiliation></author><author><name sortKey="Bozin, Tatjana" sort="Bozin, Tatjana" uniqKey="Bozin T" first="Tatjana" last="Bozin">Tatjana Bozin</name><affiliation wicri:level="1"><nlm:affiliation>Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia</wicri:regionArea><wicri:noRegion>British Columbia</wicri:noRegion></affiliation></author><author><name sortKey="Hsu, Ivy" sort="Hsu, Ivy" uniqKey="Hsu I" first="Ivy" last="Hsu">Ivy Hsu</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia</wicri:regionArea><wicri:noRegion>British Columbia</wicri:noRegion></affiliation></author><author><name sortKey="Ang, Lisa S" sort="Ang, Lisa S" uniqKey="Ang L" first="Lisa S" last="Ang">Lisa S. Ang</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia</wicri:regionArea><wicri:noRegion>British Columbia</wicri:noRegion></affiliation></author><author><name sortKey="Williams, Sarah J" sort="Williams, Sarah J" uniqKey="Williams S" first="Sarah J" last="Williams">Sarah J. Williams</name><affiliation wicri:level="1"><nlm:affiliation>Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia</wicri:regionArea><wicri:noRegion>British Columbia</wicri:noRegion></affiliation></author><author><name sortKey="Bleackley, R Chris" sort="Bleackley, R Chris" uniqKey="Bleackley R" first="R Chris" last="Bleackley">R Chris Bleackley</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Biochemistry, University of Alberta, Edmonton, Alberta</wicri:regionArea><wicri:noRegion>Alberta</wicri:noRegion></affiliation></author><author><name sortKey="Eriksson, John E" sort="Eriksson, John E" uniqKey="Eriksson J" first="John E" last="Eriksson">John E. Eriksson</name><affiliation wicri:level="3"><nlm:affiliation>Department of Biosciences, Turku Centre for Biotechnology, Åbo Akademi University, Turku, Finland.</nlm:affiliation><country xml:lang="fr">Finlande</country><wicri:regionArea>Department of Biosciences, Turku Centre for Biotechnology, Åbo Akademi University, Turku</wicri:regionArea><placeName><settlement type="city">Turku</settlement><region type="région" nuts="2">Finlande occidentale</region></placeName></affiliation></author><author><name sortKey="Seidman, Michael A" sort="Seidman, Michael A" uniqKey="Seidman M" first="Michael A" last="Seidman">Michael A. Seidman</name><affiliation wicri:level="1"><nlm:affiliation>Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, Providence Health Care, Vancouver, British Columbia, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, Providence Health Care, Vancouver, British Columbia</wicri:regionArea><wicri:noRegion>British Columbia</wicri:noRegion></affiliation></author><author><name sortKey="Mcmanus, Bruce M" sort="Mcmanus, Bruce M" uniqKey="Mcmanus B" first="Bruce M" last="Mcmanus">Bruce M. Mcmanus</name><affiliation wicri:level="1"><nlm:affiliation>Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia</wicri:regionArea><wicri:noRegion>British Columbia</wicri:noRegion></affiliation></author><author><name sortKey="Granville, David J" sort="Granville, David J" uniqKey="Granville D" first="David J" last="Granville">David J. Granville</name><affiliation wicri:level="1"><nlm:affiliation>Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address: david.granville@hli.ubc.ca.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia</wicri:regionArea><wicri:noRegion>British Columbia</wicri:noRegion></affiliation></author></analytic><series><title level="j">The American journal of pathology</title><idno type="eISSN">1525-2191</idno><imprint><date when="2016" type="published">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adult</term><term>Aged</term><term>Animals</term><term>Disease Models, Animal</term><term>Female</term><term>Fibrosis (enzymology)</term><term>Fibrosis (pathology)</term><term>Fluorescent Antibody Technique</term><term>Granzymes (metabolism)</term><term>Heart Diseases (enzymology)</term><term>Heart Diseases (pathology)</term><term>Humans</term><term>Immunohistochemistry</term><term>Male</term><term>Mice</term><term>Mice, Inbred C57BL</term><term>Mice, Knockout</term><term>Middle Aged</term><term>Real-Time Polymerase Chain Reaction</term><term>Young Adult</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Granzymes</term></keywords><keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Fibrosis</term><term>Heart Diseases</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Fibrosis</term><term>Heart Diseases</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Adult</term><term>Aged</term><term>Animals</term><term>Disease Models, Animal</term><term>Female</term><term>Fluorescent Antibody Technique</term><term>Humans</term><term>Immunohistochemistry</term><term>Male</term><term>Mice</term><term>Mice, Inbred C57BL</term><term>Mice, Knockout</term><term>Middle Aged</term><term>Real-Time Polymerase Chain Reaction</term><term>Young Adult</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Cardiac fibrosis is observed across diverse etiologies of heart failure. Granzyme B (GzmB) is a serine protease involved in cell-mediated cytotoxicity in conjunction with the pore-forming protein, perforin. Recent evidence suggests that GzmB also contributes to matrix remodeling and fibrosis through an extracellular, perforin-independent process. However, the role of GzmB in the onset and progression of cardiac fibrosis remains elusive. The present study investigated the role of GzmB in the pathogenesis of cardiac fibrosis. GzmB was elevated in fibrotic human hearts and in angiotensin II-induced murine cardiac fibrosis. Genetic deficiency of GzmB reduced angiotensin II-induced cardiac hypertrophy and fibrosis, independently of perforin. GzmB deficiency also reduced microhemorrhage, inflammation, and fibroblast accumulation in vivo. In vitro, GzmB cleaved the endothelial junction protein, vascular endothelial (VE)-cadherin, resulting in the disruption of endothelial barrier function. Together, these results suggest a perforin-independent, extracellular role for GzmB in the pathogenesis of cardiac fibrosis.</div></front></TEI><affiliations><list><country><li>Canada</li><li>Finlande</li></country><region><li>Finlande occidentale</li></region><settlement><li>Turku</li></settlement></list><tree><country name="Canada"><noRegion><name sortKey="Shen, Yue" sort="Shen, Yue" uniqKey="Shen Y" first="Yue" last="Shen">Yue Shen</name></noRegion><name sortKey="Ang, Lisa S" sort="Ang, Lisa S" uniqKey="Ang L" first="Lisa S" last="Ang">Lisa S. Ang</name><name sortKey="Bleackley, R Chris" sort="Bleackley, R Chris" uniqKey="Bleackley R" first="R Chris" last="Bleackley">R Chris Bleackley</name><name sortKey="Bohunek, Lubos" sort="Bohunek, Lubos" uniqKey="Bohunek L" first="Lubos" last="Bohunek">Lubos Bohunek</name><name sortKey="Bozin, Tatjana" sort="Bozin, Tatjana" uniqKey="Bozin T" first="Tatjana" last="Bozin">Tatjana Bozin</name><name sortKey="Granville, David J" sort="Granville, David J" uniqKey="Granville D" first="David J" last="Granville">David J. Granville</name><name sortKey="Hsu, Ivy" sort="Hsu, Ivy" uniqKey="Hsu I" first="Ivy" last="Hsu">Ivy Hsu</name><name sortKey="Mcmanus, Bruce M" sort="Mcmanus, Bruce M" uniqKey="Mcmanus B" first="Bruce M" last="Mcmanus">Bruce M. Mcmanus</name><name sortKey="Merkulova, Yulia" sort="Merkulova, Yulia" uniqKey="Merkulova Y" first="Yulia" last="Merkulova">Yulia Merkulova</name><name sortKey="Parkinson, Leigh G" sort="Parkinson, Leigh G" uniqKey="Parkinson L" first="Leigh G" last="Parkinson">Leigh G. Parkinson</name><name sortKey="Raithatha, Sheetal A" sort="Raithatha, Sheetal A" uniqKey="Raithatha S" first="Sheetal A" last="Raithatha">Sheetal A. Raithatha</name><name sortKey="Seidman, Michael A" sort="Seidman, Michael A" uniqKey="Seidman M" first="Michael A" last="Seidman">Michael A. Seidman</name><name sortKey="Sharma, Mehul" sort="Sharma, Mehul" uniqKey="Sharma M" first="Mehul" last="Sharma">Mehul Sharma</name><name sortKey="Westendorf, Kathryn" sort="Westendorf, Kathryn" uniqKey="Westendorf K" first="Kathryn" last="Westendorf">Kathryn Westendorf</name><name sortKey="Williams, Sarah J" sort="Williams, Sarah J" uniqKey="Williams S" first="Sarah J" last="Williams">Sarah J. Williams</name><name sortKey="Zhao, Hongyan" sort="Zhao, Hongyan" uniqKey="Zhao H" first="Hongyan" last="Zhao">Hongyan Zhao</name></country><country name="Finlande"><region name="Finlande occidentale"><name sortKey="Cheng, Fang" sort="Cheng, Fang" uniqKey="Cheng F" first="Fang" last="Cheng">Fang Cheng</name></region><name sortKey="Eriksson, John E" sort="Eriksson, John E" uniqKey="Eriksson J" first="John E" last="Eriksson">John E. Eriksson</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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