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Integrin‐Linked Kinase (ILK) Modulates Coxsackievirus B3‐Induced Myocardial Injury via Protein Kinase B/Akt Activation: A Potential Therapeutic Approach for Entorviral Myocarditis
Author(s) -
Esfandiarei Mitra,
Dedhar Shoukat,
McManus Bruce M.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1123-b
Subject(s) - integrin linked kinase , protein kinase b , myocarditis , kinase , viral replication , small interfering rna , pi3k/akt/mtor pathway , gsk 3 , chemistry , microbiology and biotechnology , cancer research , virus , signal transduction , protein kinase a , biology , virology , medicine , rna , biochemistry , cyclin dependent kinase 2 , gene
Coxsackievirus B3 (CVB3), a single stranded RNA enterovirus, is the most common infective agent causing myocarditis in children and young adults. Previously, we reported that inhibition of integrin‐linked kinase (ILK) could significantly decrease CVB3 replication. In the present study, using ILK kinase‐inactive mutants and RNA inhibition (siRNA), we demonstrate for the first time that ILK regulates CVB3 replication and virus‐induced cardiomyocyte injury through an Akt‐dependent pathway in mouse cardiomyocytes. Over‐expression of a constitutively active form of Akt1 reverses the protective effect of ILK inhibition, leading to a major increase in virus‐induced cardiomyocyte cell death and virus replication and release, as measured by fluorescent microscopy, Western blot, and plaque assay, respectively. These findings indicate a causal relationship between the loss of ILK activation, the resulting Akt inhibition, and subsequent restriction of cytopathic effects, signifying that the beneficial effects of ILK suppression in infected cardiomyocytes is highly dependent on associated Akt inhibition. To our knowledge, this is the first report of such protective role for ILK inhibition in viral myocarditis; and conveys new insights in our efforts to establish a novel therapeutic target for treatment of this, so far, incurable entity. This work was supported by the Canadian Institutes of Health Research (CIHR) and the Heart & Stroke Foundation of BC & Yukon.