| First Author | Hueneke R | Year | 2017 |
| Journal | J Mol Cell Cardiol | Volume | 103 |
| Pages | 93-101 | PubMed ID | 28089740 |
| Mgi Jnum | J:253945 | Mgi Id | MGI:6101885 |
| Doi | 10.1016/j.yjmcc.2017.01.006 | Citation | Hueneke R, et al. (2017) Early remodeling of repolarizing K(+) currents in the alphaMHC(403/+) mouse model of familial hypertrophic cardiomyopathy. J Mol Cell Cardiol 103:93-101 |
| abstractText | 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 alphaMHC(403/+) mouse line in which one alphaMHC allele harbors a common HCM mutation (in betaMHC, Arg403 Gln). Here, we demonstrate marked prolongation of QT intervals in young adult (10-12week) male alphaMHC(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 (IK,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, Ito,f, Ito,s and IK,slow, were significantly lower in alphaMHC(403/+), compared with WT, septum cells, whereas Iss amplitudes were similar. The amplitudes/densities of IK,peak and IK,slow were also lower in alphaMHC(403/+), compared with WT, LV wall and LV apex myocytes, whereas Ito,f was attenuated in alphaMHC(403/+) LV wall, but not LV apex, cells. These regional differences in the remodeling of repolarizing Kv currents in the alphaMHC(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) alphaMHC(403/+) mice, although this transcriptional remodeling was not correlated with the observed decreases in K(+) current amplitudes. |
