Whole Genome Network Analysis of Ion Channels and Connexins in Myocardial Infarction

It has been well documented that ion channels and intercellular gap junctional proteins participated in the pathophysiological processes of myocardial infarction (MI) which resulted in lethal arrhythmias and sudden cardiac death. miRNA expression is dynamically regulated during MI and altered miRNA expression can induce deregulation of ion channel genes at the post-transcriptional level. We conducted a rationally designed bioinformatics analysis combined with experimental approaches to screen key therapeutic members in the IUPHAR database and Wikipedia, a whole genome protein interaction network was established here and comprehensive topological assessment was applied to confirm the individual network status and to reflect their biological significance. Meanwhile, the number of validated and confidently predicted miRNAs regulating each gene encoding ion channel or gap junction protein was counted. miRNA analysis indicated that connexin 43 was under more intensive miRNA regulation compared with the other ion channel and gap junction proteins. Furthermore, the topological network analysis highlighted the important role of connexin 43 in MI and also identified the important biological roles of TRPV4, SCN5A, CACNA1C and TRPC6. The abnormal expression of TRPC6 was experimentally validated in 1 month MI model of rat, which implied its potential therapeutic target for MI. Our work suggested that network systems approach could gain valuable insight into the pathological mechanism of MI which has not been uncovered by previous experimental studies. Copyright (C) 2011 S. Karger AG, Basel