AN ANTISENSE OLIGONUCLEOTIDE DERIVATIVE TO THE MRNA OF THE NAV1.5 SODIUM CHANNEL GENE (SCN5A) DECREASES THE HEART RATE
S.I. Oshevskii1, Yu.I. Ragino2, E.V. Kashtanova2, Yu.V. Polonskaya2, E.M. Stakhneva2, V.P. Nikolin1, N.A. Popova1,3, N.A. Kolchanov1, M.I. Voevoda1,2,3
1The Federal Research Center Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences, 630090, Novosibirsk, Academician Lavrent’ev av., 10
2Institute of Internal and Preventive Medicine, 630089, Novosibirsk, Boris Bogatkov str., 175/1
3National Reseach Novosibirsk State University, 630090, Novosibirsk, Pirogov str., 2
Keywords: antisense oligonucleotide derivative, SCN5A gene, C57BL/6J mice, heart rate
Abstract
Objective: To assess the potential of a new approach to altering the heart rate by expression inhibition of the SCN5A gene, encoding a classical sodium channel, Nav1.5, with an antisense oligonucleotide derivative in the case study of the mouse. Material and methods: C57BL/6J male mice; oligonucleotide derivative with a length of 15 nucleotides protected from nucleases by the presence of internucleotide phosphorothioate bonds and LNA (locked nucleic acids) blocks at the 5ʹ and 3ʹ ends (ASO); standard injection of ASO in physiological saline solution into the mouse caudal vein; standard technique for determination of the heart rate and blood pressure in mice with a CODA Surgical Monitor (Kent Scientific, United States); and standard quantification of apoB apolipoprotein and lipoproteins HDL-C, LDL-C, total cholesterol, TG, and ALT in the blood serum. Results: ASO decreases the heart rate in mice by 12 % over 10 days and further uniformly accelerates the heart rate to almost initial level by day 16 as well as gently decreases the mean values of systolic and diastolic pressures with their subsequent increase and gradual redistribution of “excess” pressure in the control and experimental animal groups. The level of lipid metabolism in experimental animals is decreased. Conclusions: The new approach to alter the heart rate by inhibition of the SCN5A gene expression with an antisense oligonucleotide derivative is shown to be feasible. The impact is accompanied by minor changes in the systolic and diastolic pressures and a decrease in the level of lipid metabolism. The preparation is promising in terms of the influence on the heart rate taking into account the further insight into its effect at different concentrations and possible insignificant side effects.
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