Novel Role for Integrin-Linked Kinase in Modulation of Coxsackievirus B3 Replication and Virus-Induced Cardiomyocyte Injury

• Published in: Circulation research Vol. 99; no. 4; pp. 354 - 361
• Main Authors: Esfandiarei, Mitra, Suarez, Agripina, Amaral, Ansel, Si, Xiaoning, Rahmani, Maziar, Dedhar, Shoukat, McManus, Bruce M
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 18-08-2006; Lippincott
• Subjects: Animals; Biological and medical sciences; Cardiology. Vascular system; Cell Line; Coxsackievirus B3; Enterovirus - genetics; Enterovirus - physiology; Enzyme Inhibitors - pharmacology; Fundamental and applied biological sciences. Psychology; Heart; Heart - virology; HeLa Cells; Humans; In Situ Hybridization; Medical sciences; Mice; Muscle Cells - enzymology; Muscle Cells - virology; Myocarditis - virology; Myocarditis. Cardiomyopathies; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; RNA, Viral - genetics; Vertebrates: cardiovascular system; Virus Replication; PKB/Akt; Enzyme; Picornaviridae; Transferases; Cardiovascular disease; Enterovirus; Myocardial disease; Virus; Myocarditis; Vertebrata; Integrin; Mammalia; Kinase; Cell death; Heart disease; Coxsackievirus B3; Replication; Circulatory system; Lesion; CVB3; integrin-linked kinase; viral myocarditis; Heart cell
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.0000237022.72726.01

Viral myocarditis is a major cause of sudden cardiac death in children and young adults. Among viruses, coxsackievirus B3 (CVB3) is the most common agent for myocarditis. Recently, more consideration has been given to the role of signaling pathways in pathogenesis of enteroviral myocarditis, providing new platform for identifying a new potential therapeutic target for this, so far, incurable disease. Previously, we reported on the role of the protein kinase-B/Akt in CVB3 replication and virus-induced cell injury. Here, we report on regulation of virus-induced Akt activation by the integrin-linked kinase in infected mouse cardiomyocytes and HeLa cells. This study also presents the first observation that inhibition of ILK in CVB3-infected cells significantly improves the viability of infected cells, while blocking viral replication and virus release. Complementary experiments using a constitutively active form of Akt1 revealed that the observed protective effect of ILK inhibition is dependent on the associated downregulation of virus-induced Akt activation. To our knowledge, this is the first report of such beneficial effects of ILK inhibition in a viral infection model and conveys new insights in our efforts to characterize a novel therapeutic target for treatment of enteroviral myocarditis.