Early remodeling of repolarizing K + currents in the αMHC 403/+ mouse model of familial hypertrophic cardiomyopathy.

Autor: Hueneke R; Department of Developmental Biology, Washington University Medical School, St. Louis, MO 63110-1093, USA; Department of Anesthesiology, Washington University Medical School, St. Louis, MO 63110-1093, USA., Adenwala A; Department of Developmental Biology, Washington University Medical School, St. Louis, MO 63110-1093, USA., Mellor RL; Department of Developmental Biology, Washington University Medical School, St. Louis, MO 63110-1093, USA; Department of Medicine, Washington University Medical School, St. Louis, MO 63110-1093, USA., Seidman JG; Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA., Seidman CE; Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA., Nerbonne JM; Department of Developmental Biology, Washington University Medical School, St. Louis, MO 63110-1093, USA; Department of Medicine, Washington University Medical School, St. Louis, MO 63110-1093, USA. Electronic address: jnerbonne@wustl.edu.
Jazyk: angličtina
Zdroj: Journal of molecular and cellular cardiology [J Mol Cell Cardiol] 2017 Feb; Vol. 103, pp. 93-101. Date of Electronic Publication: 2017 Jan 13.
DOI: 10.1016/j.yjmcc.2017.01.006
Abstrakt: Familial hypertrophic cardiomyopathy (HCM), linked to mutations in myosin, myosin-binding proteins and other sarcolemmal proteins, is associated with increased risk of life threatening ventricular arrhythmias, and a number of animal models have been developed to facilitate analysis of disease progression and mechanisms. In the experiments here, we use the αMHC 403/+ mouse line in which one αMHC allele harbors a common HCM mutation (in βMHC, Arg403 Gln). Here, we demonstrate marked prolongation of QT intervals in young adult (10-12week) male αMHC 403/+ mice, well in advance of the onset of measurable left ventricular hypertrophy. Electrophysiological recordings from myocytes isolated from the interventricular septum of these animals revealed significantly (P<0.001) lower peak repolarizing voltage-gated K + (Kv) current (I K,peak ) amplitudes, compared with cells isolated from wild type (WT) littermate controls. Analysis of Kv current waveforms revealed that the amplitudes of the inactivating components of the total outward Kv current, I to,f , I to,s and I K,slow , were significantly lower in αMHC 403/+ , compared with WT, septum cells, whereas I ss amplitudes were similar. The amplitudes/densities of I K,peak and I K,slow were also lower in αMHC 403/+ , compared with WT, LV wall and LV apex myocytes, whereas I to,f was attenuated in αMHC 403/+ LV wall, but not LV apex, cells. These regional differences in the remodeling of repolarizing Kv currents in the αMHC 403/+ mice would be expected to increase the dispersion of ventricular repolarization and be proarrhythmic. Quantitative RT-PCR analysis revealed reductions in the expression of transcripts encoding several K + channel subunits in the interventricular septum, LV free wall and LV apex of (10-12week) αMHC 403/+ mice, although this transcriptional remodeling was not correlated with the observed decreases in K + current amplitudes.
(Copyright © 2017 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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