| First Author | Kim KH | Year | 2022 |
| Journal | Am J Physiol Heart Circ Physiol | Volume | 322 |
| Issue | 5 | Pages | H725-H741 |
| PubMed ID | 35245131 | Mgi Jnum | J:322931 |
| Mgi Id | MGI:7257010 | Doi | 10.1152/ajpheart.00572.2021 |
| Citation | Kim KH, et al. (2022) Irx5 and transient outward K(+) currents contribute to transmural contractile heterogeneities in the mouse ventricle. Am J Physiol Heart Circ Physiol |
| abstractText | Previous studies have established that fast transmural gradients of transient outward K(+) current (Ito,f) correlate with regional differences in action potential (AP) profile and excitation-contraction coupling (ECC) with high Ito,f expression in the epimyocardium (EPI) being associated with short APs and low contractility and vice versa. Herein, we investigated the effects of disrupted Ito,f gradient on contractile properties using mouse models of Irx5 knockout (Irx5-KO) for selective Ito,f elevation in the endomyocardium (ENDO) of the left ventricle (LV) and Kcnd2 ablation (KV4.2-KO) for selective Ito,freduction in the EPI. Irx5-KO mice exhibited decreased global LV contractility in association with reductions in cell shortening and Ca(2+) transient amplitudes in isolated ENDO but not EPI cardiomyocytes. Moreover, transcriptional profiling revealed that the primary effect of Irx5 ablation on ECC-related genes was to increase Ito,f gene expression (i.e. Kcnd2 and Kcnip2) in the ENDO, but not the EPI. Indeed, KV4.2-KO mice showed selective increases in cell shortening and Ca(2+) transients in isolated EPI cardiomyocytes, leading to enhanced ventricular contractility and mice lacking both Irx5 and Kcnd2 displayed elevated ventricular contractility comparable to KV4.2-KO mice. Our findings demonstrate that the transmural electromechanical heterogeneities in the healthy ventricles depend on the Irx5-dependent Ito,f gradients. These observations provide a useful framework for assessing the molecular mechanisms underlying the alterations in contractile heterogeneity seen in the diseased heart. |
