C-Cbl inhibition improves cardiac function and survival in response to myocardial ischemia

Khadija Rafiq, Mikhail A. Kolpakov, Rachid Seqqat, Jianfen Guo, Xinji Guo, Zhao Qi, Daohai Yu, Bhopal Mohapatra, Neha Zutshi, Wei An, Hamid Band, Archana Sanjay, Steven R. Houser, Abdelkarim Sabri

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

BACKGROUND - : The proto-oncogene Casitas b-lineage lymphoma (c-Cbl) is an adaptor protein with an intrinsic E3 ubiquitin ligase activity that targets receptor and nonreceptor tyrosine kinases, resulting in their ubiquitination and downregulation. However, the function of c-Cbl in the control of cardiac function is currently unknown. In this study, we examined the role of c-Cbl in myocyte death and cardiac function after myocardial ischemia. METHODS AND RESULTS - : We show increased c-Cbl expression in human ischemic and dilated cardiomyopathy hearts and in response to pathological stress stimuli in mice. c-Cbl-deficient mice demonstrated a more robust functional recovery after myocardial ischemia/reperfusion injury and significantly reduced myocyte apoptosis and improved cardiac function. Ubiquitination and downregulation of key survival c-Cbl targets, epidermal growth factor receptors and focal adhesion kinase, were significantly reduced in c-Cbl knockout mice. Inhibition of c-Cbl expression or its ubiquitin ligase activity in cardiac myocytes offered protection against H2O2 stress. Interestingly, c-Cbl deletion reduced the risk of death and increased cardiac functional recovery after chronic myocardial ischemia. This beneficial effect of c-Cbl deletion was associated with enhanced neoangiogenesis and increased expression of vascular endothelial growth factor-a and vascular endothelial growth factor receptor type 2 in the infarcted region. CONCLUSIONS - : c-Cbl activation promotes myocyte apoptosis, inhibits angiogenesis, and causes adverse cardiac remodeling after myocardial infarction. These findings point to c-Cbl as a potential therapeutic target for the maintenance of cardiac function and remodeling after myocardial ischemia.

Original languageEnglish (US)
Pages (from-to)2031-2043
Number of pages13
JournalCirculation
Volume129
Issue number20
DOIs
StatePublished - May 20 2014

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Myocardial Ischemia
Survival
Ubiquitination
Cardiac Myocytes
Muscle Cells
Down-Regulation
Apoptosis
Myocardial Reperfusion Injury
Vascular Endothelial Growth Factor Receptor-2
Focal Adhesion Protein-Tyrosine Kinases
Ubiquitin-Protein Ligases
Proto-Oncogenes
Dilated Cardiomyopathy
Receptor Protein-Tyrosine Kinases
Ligases
Ubiquitin
Reperfusion Injury
Knockout Mice
Vascular Endothelial Growth Factor A
Lymphoma

Keywords

  • angiogenesis
  • apoptosis
  • myocardial ischemia
  • ubiquitin

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Rafiq, K., Kolpakov, M. A., Seqqat, R., Guo, J., Guo, X., Qi, Z., ... Sabri, A. (2014). C-Cbl inhibition improves cardiac function and survival in response to myocardial ischemia. Circulation, 129(20), 2031-2043. https://doi.org/10.1161/CIRCULATIONAHA.113.007004

C-Cbl inhibition improves cardiac function and survival in response to myocardial ischemia. / Rafiq, Khadija; Kolpakov, Mikhail A.; Seqqat, Rachid; Guo, Jianfen; Guo, Xinji; Qi, Zhao; Yu, Daohai; Mohapatra, Bhopal; Zutshi, Neha; An, Wei; Band, Hamid; Sanjay, Archana; Houser, Steven R.; Sabri, Abdelkarim.

In: Circulation, Vol. 129, No. 20, 20.05.2014, p. 2031-2043.

Research output: Contribution to journalArticle

Rafiq, K, Kolpakov, MA, Seqqat, R, Guo, J, Guo, X, Qi, Z, Yu, D, Mohapatra, B, Zutshi, N, An, W, Band, H, Sanjay, A, Houser, SR & Sabri, A 2014, 'C-Cbl inhibition improves cardiac function and survival in response to myocardial ischemia', Circulation, vol. 129, no. 20, pp. 2031-2043. https://doi.org/10.1161/CIRCULATIONAHA.113.007004
Rafiq, Khadija ; Kolpakov, Mikhail A. ; Seqqat, Rachid ; Guo, Jianfen ; Guo, Xinji ; Qi, Zhao ; Yu, Daohai ; Mohapatra, Bhopal ; Zutshi, Neha ; An, Wei ; Band, Hamid ; Sanjay, Archana ; Houser, Steven R. ; Sabri, Abdelkarim. / C-Cbl inhibition improves cardiac function and survival in response to myocardial ischemia. In: Circulation. 2014 ; Vol. 129, No. 20. pp. 2031-2043.
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AU - Kolpakov, Mikhail A.

AU - Seqqat, Rachid

AU - Guo, Jianfen

AU - Guo, Xinji

AU - Qi, Zhao

AU - Yu, Daohai

AU - Mohapatra, Bhopal

AU - Zutshi, Neha

AU - An, Wei

AU - Band, Hamid

AU - Sanjay, Archana

AU - Houser, Steven R.

AU - Sabri, Abdelkarim

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N2 - BACKGROUND - : The proto-oncogene Casitas b-lineage lymphoma (c-Cbl) is an adaptor protein with an intrinsic E3 ubiquitin ligase activity that targets receptor and nonreceptor tyrosine kinases, resulting in their ubiquitination and downregulation. However, the function of c-Cbl in the control of cardiac function is currently unknown. In this study, we examined the role of c-Cbl in myocyte death and cardiac function after myocardial ischemia. METHODS AND RESULTS - : We show increased c-Cbl expression in human ischemic and dilated cardiomyopathy hearts and in response to pathological stress stimuli in mice. c-Cbl-deficient mice demonstrated a more robust functional recovery after myocardial ischemia/reperfusion injury and significantly reduced myocyte apoptosis and improved cardiac function. Ubiquitination and downregulation of key survival c-Cbl targets, epidermal growth factor receptors and focal adhesion kinase, were significantly reduced in c-Cbl knockout mice. Inhibition of c-Cbl expression or its ubiquitin ligase activity in cardiac myocytes offered protection against H2O2 stress. Interestingly, c-Cbl deletion reduced the risk of death and increased cardiac functional recovery after chronic myocardial ischemia. This beneficial effect of c-Cbl deletion was associated with enhanced neoangiogenesis and increased expression of vascular endothelial growth factor-a and vascular endothelial growth factor receptor type 2 in the infarcted region. CONCLUSIONS - : c-Cbl activation promotes myocyte apoptosis, inhibits angiogenesis, and causes adverse cardiac remodeling after myocardial infarction. These findings point to c-Cbl as a potential therapeutic target for the maintenance of cardiac function and remodeling after myocardial ischemia.

AB - BACKGROUND - : The proto-oncogene Casitas b-lineage lymphoma (c-Cbl) is an adaptor protein with an intrinsic E3 ubiquitin ligase activity that targets receptor and nonreceptor tyrosine kinases, resulting in their ubiquitination and downregulation. However, the function of c-Cbl in the control of cardiac function is currently unknown. In this study, we examined the role of c-Cbl in myocyte death and cardiac function after myocardial ischemia. METHODS AND RESULTS - : We show increased c-Cbl expression in human ischemic and dilated cardiomyopathy hearts and in response to pathological stress stimuli in mice. c-Cbl-deficient mice demonstrated a more robust functional recovery after myocardial ischemia/reperfusion injury and significantly reduced myocyte apoptosis and improved cardiac function. Ubiquitination and downregulation of key survival c-Cbl targets, epidermal growth factor receptors and focal adhesion kinase, were significantly reduced in c-Cbl knockout mice. Inhibition of c-Cbl expression or its ubiquitin ligase activity in cardiac myocytes offered protection against H2O2 stress. Interestingly, c-Cbl deletion reduced the risk of death and increased cardiac functional recovery after chronic myocardial ischemia. This beneficial effect of c-Cbl deletion was associated with enhanced neoangiogenesis and increased expression of vascular endothelial growth factor-a and vascular endothelial growth factor receptor type 2 in the infarcted region. CONCLUSIONS - : c-Cbl activation promotes myocyte apoptosis, inhibits angiogenesis, and causes adverse cardiac remodeling after myocardial infarction. These findings point to c-Cbl as a potential therapeutic target for the maintenance of cardiac function and remodeling after myocardial ischemia.

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