In:
PLOS ONE, Public Library of Science (PLoS), Vol. 15, No. 12 ( 2020-12-22), p. e0244096-
Abstract:
Fibrosis is a pathognomonic feature of structural heart disease and counteracted by distinct cardioprotective mechanisms, e.g. activation of the phosphoinositide 3-kinase (PI3K) / AKT pro-survival pathway. The Cullin-RING E3 ubiquitin ligase 7 (CRL7) was identified as negative regulator of PI3K/AKT signalling in skeletal muscle, but its role in the heart remains to be elucidated. Here, we sought to determine whether CRL7 modulates to cardiac fibrosis following pressure overload and dissect its underlying mechanisms. For inactivation of CRL7, the Cullin 7 (Cul7) gene was deleted in cardiac myocytes (CM) by injection of adeno-associated virus subtype 9 (AAV9) vectors encoding codon improved Cre-recombinase (AAV9-CMV-iCre) in Cul7 flox/flox mice. In addition, Myosin Heavy Chain 6 (Myh6; alpha-MHC)-MerCreMer transgenic mice with tamoxifen-induced CM-specific expression of iCre were used as alternate model. After transverse aortic constriction (TAC), causing chronic pressure overload and fibrosis, AAV9-CMV-iCre induced Cul7 -/- mice displayed a ~50% reduction of interstitial cardiac fibrosis when compared to Cul7 +/+ animals (6.7% vs. 3.4%, p 〈 0.01). Similar results were obtained with Cul7 flox/flox Myh6-Mer-Cre-Mer Tg(1/0) mice which displayed a ~30% reduction of cardiac fibrosis after TAC when compared to Cul7 +/+ Myh6-Mer-Cre-Mer Tg(1/0) controls after TAC surgery (12.4% vs. 8.7%, p 〈 0.05). No hemodynamic alterations were observed. AKT Ser473 phosphorylation was increased 3-fold (p 〈 0.01) in Cul7 -/- vs. control mice, together with a ~78% (p 〈 0.001) reduction of TUNEL-positive apoptotic cells three weeks after TAC. In addition, CM-specific expression of a dominant-negative CUL7 1152stop mutant resulted in a 16.3-fold decrease (p 〈 0.001) of in situ end-labelling (ISEL) positive apoptotic cells. Collectively, our data demonstrate that CM-specific ablation of Cul7 restrains myocardial fibrosis and apoptosis upon pressure overload, and introduce CRL7 as a potential target for anti-fibrotic therapeutic strategies of the heart.
Type of Medium:
Online Resource
ISSN:
1932-6203
DOI:
10.1371/journal.pone.0244096
DOI:
10.1371/journal.pone.0244096.g001
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10.1371/journal.pone.0244096.g002
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10.1371/journal.pone.0244096.g003
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10.1371/journal.pone.0244096.g004
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10.1371/journal.pone.0244096.s001
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10.1371/journal.pone.0244096.s002
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10.1371/journal.pone.0244096.s003
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10.1371/journal.pone.0244096.s004
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10.1371/journal.pone.0244096.s005
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10.1371/journal.pone.0244096.s006
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10.1371/journal.pone.0244096.s007
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10.1371/journal.pone.0244096.s008
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10.1371/journal.pone.0244096.s009
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10.1371/journal.pone.0244096.s010
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10.1371/journal.pone.0244096.s011
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10.1371/journal.pone.0244096.s012
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10.1371/journal.pone.0244096.s013
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10.1371/journal.pone.0244096.s014
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10.1371/journal.pone.0244096.s015
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10.1371/journal.pone.0244096.s016
DOI:
10.1371/journal.pone.0244096.r001
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10.1371/journal.pone.0244096.r002
DOI:
10.1371/journal.pone.0244096.r003
DOI:
10.1371/journal.pone.0244096.r004
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2020
detail.hit.zdb_id:
2267670-3
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