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Cyclin-dependent kinase 2 signaling regulates myocardial ischemia/reperfusion injury

Liem, David A. ; Zhao, Peng ; Angelis, Ekaterini ; Chan, Shing S. ; Zhang, Jun ; Wang, Guangwu ; Berthet, Cyril ; Kaldis, Philipp LU ; Ping, Peipei and MacLellan, W. Robb (2008) In Journal of Molecular and Cellular Cardiology 45(5). p.610-616
Abstract

Ischemia/reperfusion (I/R) injury to the heart is accompanied by the upregulation and posttranslational modification of a number of proteins normally involved in regulating cell cycle progression. Two such proteins, cyclin-dependent kinase-2 (Cdk2) and its downstream target, the retinoblastoma gene product (Rb), also play a critical role in the control of apoptosis. Myocardial ischemia activates Cdk2, resulting in the phosphorylation and inactivation of Rb. Blocking Cdk2 activity reduces apoptosis in cultured cardiac myocytes. Genetic or pharmacological inhibition of Cdk2 activity in vivo during I/R injury led to a 36% reduction in infarct size (IFS), when compared to control mice, associated with a reduction in apoptotic myocytes. To... (More)

Ischemia/reperfusion (I/R) injury to the heart is accompanied by the upregulation and posttranslational modification of a number of proteins normally involved in regulating cell cycle progression. Two such proteins, cyclin-dependent kinase-2 (Cdk2) and its downstream target, the retinoblastoma gene product (Rb), also play a critical role in the control of apoptosis. Myocardial ischemia activates Cdk2, resulting in the phosphorylation and inactivation of Rb. Blocking Cdk2 activity reduces apoptosis in cultured cardiac myocytes. Genetic or pharmacological inhibition of Cdk2 activity in vivo during I/R injury led to a 36% reduction in infarct size (IFS), when compared to control mice, associated with a reduction in apoptotic myocytes. To confirm that Rb was the critical target in Cdk2-mediated I/R injury, we determined the consequences of I/R injury in cardiac-specific Rb-deficient mice (CRbL/L). IFS was increased 140% in CRbL/L mice compared to CRb+/+ controls. TUNEL positive nuclei and caspase-3 activity were augmented by 92% and 36%, respectively, following injury in the CRbL/L mice demonstrating that loss of Rb in the heart significantly exacerbates I/R injury. These data suggest that Cdk2 signaling pathways are critical regulators of cardiac I/R injury in vivo and support a cardioprotective role for Rb.

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author
; ; ; ; ; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
keywords
Apoptosis, Cardioprotection, Cyclin-dependent kinase 2, Myocardial ischemia, Retinoblastoma gene
in
Journal of Molecular and Cellular Cardiology
volume
45
issue
5
pages
610 - 616
publisher
Elsevier
external identifiers
  • scopus:55649119998
  • pmid:18692063
ISSN
0022-2828
DOI
10.1016/j.yjmcc.2008.07.003
language
English
LU publication?
no
id
9a5799a8-4103-45f8-8531-62569554d6d9
date added to LUP
2019-09-18 14:12:52
date last changed
2020-04-07 05:37:04
@article{9a5799a8-4103-45f8-8531-62569554d6d9,
  abstract     = {<p>Ischemia/reperfusion (I/R) injury to the heart is accompanied by the upregulation and posttranslational modification of a number of proteins normally involved in regulating cell cycle progression. Two such proteins, cyclin-dependent kinase-2 (Cdk2) and its downstream target, the retinoblastoma gene product (Rb), also play a critical role in the control of apoptosis. Myocardial ischemia activates Cdk2, resulting in the phosphorylation and inactivation of Rb. Blocking Cdk2 activity reduces apoptosis in cultured cardiac myocytes. Genetic or pharmacological inhibition of Cdk2 activity in vivo during I/R injury led to a 36% reduction in infarct size (IFS), when compared to control mice, associated with a reduction in apoptotic myocytes. To confirm that Rb was the critical target in Cdk2-mediated I/R injury, we determined the consequences of I/R injury in cardiac-specific Rb-deficient mice (CRb<sup>L/L</sup>). IFS was increased 140% in CRb<sup>L/L</sup> mice compared to CRb<sup>+/+</sup> controls. TUNEL positive nuclei and caspase-3 activity were augmented by 92% and 36%, respectively, following injury in the CRb<sup>L/L</sup> mice demonstrating that loss of Rb in the heart significantly exacerbates I/R injury. These data suggest that Cdk2 signaling pathways are critical regulators of cardiac I/R injury in vivo and support a cardioprotective role for Rb.</p>},
  author       = {Liem, David A. and Zhao, Peng and Angelis, Ekaterini and Chan, Shing S. and Zhang, Jun and Wang, Guangwu and Berthet, Cyril and Kaldis, Philipp and Ping, Peipei and MacLellan, W. Robb},
  issn         = {0022-2828},
  language     = {eng},
  month        = {11},
  number       = {5},
  pages        = {610--616},
  publisher    = {Elsevier},
  series       = {Journal of Molecular and Cellular Cardiology},
  title        = {Cyclin-dependent kinase 2 signaling regulates myocardial ischemia/reperfusion injury},
  url          = {http://dx.doi.org/10.1016/j.yjmcc.2008.07.003},
  doi          = {10.1016/j.yjmcc.2008.07.003},
  volume       = {45},
  year         = {2008},
}