Defective proteolytic systems in Mybpc3-targeted mice with cardiac hypertrophy.
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Defective proteolytic systems in Mybpc3-targeted mice with cardiac hypertrophy. / Schlossarek, Saskia; Englmann, Daniel R; Sultan, Karim R; Sauer, Markus; Eschenhagen, Thomas; Carrier, Lucie.
in: BASIC RES CARDIOL, Jahrgang 107, Nr. 1, 1, 2012, S. 235.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Defective proteolytic systems in Mybpc3-targeted mice with cardiac hypertrophy.
AU - Schlossarek, Saskia
AU - Englmann, Daniel R
AU - Sultan, Karim R
AU - Sauer, Markus
AU - Eschenhagen, Thomas
AU - Carrier, Lucie
PY - 2012
Y1 - 2012
N2 - Several lines of evidence suggest that alterations of the ubiquitin-proteasome system (UPS) and autophagy-lysosome pathway (ALP) may be involved in cardiac diseases. Little is known, however, in hypertrophic cardiomyopathy (HCM). This study studied these pathways in two mouse models of HCM that mainly differ by the presence or absence of truncated mutant proteins. Analyses were performed in homozygous Mybpc3-targeted knock-in (KI) mice, carrying a HCM mutation and exhibiting low levels of mutant cardiac myosin-binding protein C (cMyBP-C), and in Mybpc3-targeted knock-out (KO) mice expressing no cMyBP-C, thus serving as a model of pure cMyBP-C insufficiency. In the early postnatal development of cardiac hypertrophy, both models showed higher levels of ubiquitinated proteins and greater proteasomal activities. To specifically monitor the degradation capacity of the UPS with age, mice were crossed with transgenic mice that overexpress Ub(G76V)-GFP. Ub(G76V)-GFP protein levels were fourfold higher in 1-year-old KI, but not KO mice, suggesting a specific UPS impairment in mice expressing truncated cMyBP-C. Whereas protein levels of key ALP markers were higher, suggesting ALP activation in both mutant mice, their mRNA levels did not differ between the groups, underlying rather defective ALP-mediated degradation. Analysis of key proteins regulated in heart failure did not reveal specific alterations in KI and KO mice. Our data suggest (1) UPS activation in early postnatal development of cardiac hypertrophy, (2) specific UPS impairment in old KI mice carrying a HCM mutation, and (3) defective ALP as a common mechanism in genetically engineered mice with cardiac hypertrophy.
AB - Several lines of evidence suggest that alterations of the ubiquitin-proteasome system (UPS) and autophagy-lysosome pathway (ALP) may be involved in cardiac diseases. Little is known, however, in hypertrophic cardiomyopathy (HCM). This study studied these pathways in two mouse models of HCM that mainly differ by the presence or absence of truncated mutant proteins. Analyses were performed in homozygous Mybpc3-targeted knock-in (KI) mice, carrying a HCM mutation and exhibiting low levels of mutant cardiac myosin-binding protein C (cMyBP-C), and in Mybpc3-targeted knock-out (KO) mice expressing no cMyBP-C, thus serving as a model of pure cMyBP-C insufficiency. In the early postnatal development of cardiac hypertrophy, both models showed higher levels of ubiquitinated proteins and greater proteasomal activities. To specifically monitor the degradation capacity of the UPS with age, mice were crossed with transgenic mice that overexpress Ub(G76V)-GFP. Ub(G76V)-GFP protein levels were fourfold higher in 1-year-old KI, but not KO mice, suggesting a specific UPS impairment in mice expressing truncated cMyBP-C. Whereas protein levels of key ALP markers were higher, suggesting ALP activation in both mutant mice, their mRNA levels did not differ between the groups, underlying rather defective ALP-mediated degradation. Analysis of key proteins regulated in heart failure did not reveal specific alterations in KI and KO mice. Our data suggest (1) UPS activation in early postnatal development of cardiac hypertrophy, (2) specific UPS impairment in old KI mice carrying a HCM mutation, and (3) defective ALP as a common mechanism in genetically engineered mice with cardiac hypertrophy.
KW - Animals
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - Gene Knock-In Techniques
KW - Proteasome Endopeptidase Complex/metabolism
KW - Lysosomes/metabolism
KW - Aging/metabolism
KW - Autophagy
KW - Cardiomegaly/genetics
KW - Cardiomyopathy, Hypertrophic/etiology/metabolism
KW - Carrier Proteins/genetics
KW - Heart Failure/metabolism
KW - Ubiquitin/metabolism
KW - Animals
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - Gene Knock-In Techniques
KW - Proteasome Endopeptidase Complex/metabolism
KW - Lysosomes/metabolism
KW - Aging/metabolism
KW - Autophagy
KW - Cardiomegaly/genetics
KW - Cardiomyopathy, Hypertrophic/etiology/metabolism
KW - Carrier Proteins/genetics
KW - Heart Failure/metabolism
KW - Ubiquitin/metabolism
U2 - 10.1007/s00395-011-0235-3
DO - 10.1007/s00395-011-0235-3
M3 - SCORING: Journal article
C2 - 22189562
VL - 107
SP - 235
JO - BASIC RES CARDIOL
JF - BASIC RES CARDIOL
SN - 0300-8428
IS - 1
M1 - 1
ER -
