Abstract 3741.5 Genomic Characteristics Of Kcnh2, Kcnq1 And Kcne1 Genes for Transcriptional Regulation by Adrenergic, Angiotensin Ii and Insulin Pathways
Several long QT syndrome (LQTS) genes have been isolated, which when genetically defected (loss-of-function mutations) can lead to different forms of LQTS. Among these LQTS genes, KCNQ1 and KCNH2 (encoding KvLQT1 and HERG K+ channel α-pore-forming subunits, respectively) are responsible for a majority (~85–90%) of cases of inherited LQTS. Moreover, KCNE1 encodes a β-subunit (minK) that can co-assemble with HERG or KvLQT1 to form rapid and slow delayed rectifier K+ currents IKr and IKs, respectively, which play critical roles in determining cardiac repolarization thereby the likelihood of LQTS. To test our hypothesis that excessive expression downregulation of these genes could lead to LQTS, we have characterized the genomic structures of these genes to identify the regulatory elements determining their transcriptional activities. We found that the promoter activity of KCNH2 was significantly diminished by β-adrenergic stimulation induced by isoproterenol, but enhanced by angiotensin II, insulin and PKB, as revealed by luciferase reporter assays. The promoter activities of KCNQ1 and KCNE1 were also depressed by isoproterenol, but were unaffected by angiotensin II, insulin and PKB. The effects of isoproterenol were abolished by β-blocker propranolol and mimicked by a cAMP analog. The results were verified in native ventricular tissues of rabbits using quantitative real-time RT-PCR for the mRNA levels of the genes. Also striking is that angiotensin II magnified the interventricular gradients of KCNH2 expression. Our findings suggest that
the well-recognized sympathetic promotion of LQTS is partially ascribed to transcriptional downregulation of KCNH2, KCNQ1 and KCNE1 by β-stimulation,
upregulation of KCNH2 transcription by the insulin pathway explains for the previously observed rescuing of depressed IKr in diabetic hearts, and
the augmentation of regional heterogeneity of KCNH2 expression caused by angiotensin II may underlie its well-known ability to promote arrhythmias.