Deletion of Kvβ1.1 subunit leads to electrical and haemodynamic changes causing cardiac hypertrophy in female murine hearts

Abstract

Cardiovascular disease is the leading cause of death and debility in women in the USA, and cardiac arrhythmias are a major concern. Voltage-gated potassium (Kv) channels along with the binding partners; Kvβ subunits are major regulators of the action potential (AP) shape and duration (APD). The regulation of Kv channels by the Kvβ1 subunit is unknown in female hearts. In the present study, we hypothesized that the Kvβ1 subunit is an important regulator of female cardiac physiology. To test this hypothesis, we ablated (knocked out; KO) the KCNAB1 isoform 1 (Kvβ1.1) subunit in mice and evaluated cardiac function and electrical activity by using ECG, monophasic action potential recordings and echocardiography. Our results showed that the female Kvβ1.1 KO mice developed cardiac hypertrophy, and the hearts were structurally different, with enlargement and increased area. The electrical derangements caused by Kvβ1.1 KO in female mice included long QTc and QRS intervals along with increased APD (APD20–90% repolarization). The male Kvβ1.1 KO mice did not develop cardiac hypertrophy, but they showed long QTc and prolonged APD. Molecular analysis showed that several genes that support cardiac hypertrophy were significantly altered in Kvβ1.1 KO female hearts. In particular, myosin heavy chain αexpression was significantly elevated in Kvβ1.1 KO mouse heart. Using a small interfering RNA strategy, we identified that knockdown of Kvβ1 increases myosin heavy chain αexpression in H9C2 cells. Collectively, changes in molecular and cell signalling pathways clearly point towards a distinct electrical and structural remodelling consistent with cardiac hypertrophy in the Kvβ1.1 KO female mice.

Emerging potential benefits of modulating NAD+metabolism in cardiovascular disease

“…K v ␤1.1 knockout (K v ␤1.1 Ϫ/Ϫ ) mice have electrophysiological changes at baseline, including prolongation of the QTc and reduction in P wave duration and PR interval compared with wild-type mice. Unlike wild-type mice, K v ␤1.1 Ϫ/Ϫ mice do not appear to experience further QTc prolongation after isoproterenol-mediated hypertrophy, a model known to decrease the NAD ϩ -to-NADH ratio (96,97). This further suggests that K v ␤1.1 senses metabolic changes and modulates K v 4.2.…”

Emerging roles for multifunctional ion channel auxiliary subunits in cancer

“…K v β 1 and K v β 2 are both expressed in developing rat heart and skeletal muscle and during induced myogenesis of L6E9 cells [ 140 ]. Furthermore, deletion of K v β 1 results in aberrant cardiac electrical activity and cardiac hypertrophy in female mice [ 141 ]. K v β 2 deletion leads to reduced K v 1.5 surface expression in coronary arterial myocytes and a reduction in total skeletal muscle volume, potentially mediated through downregulation of Pax7 and upregulation of NEDD4 [ 133 , 142 ].…”

Genetic Polymorphisms and Ischemic Heart Disease

“…The single-nucleotide polymorphism c.501G>C determines a single amino acid change (K>N at codon 167) reduces ox-LDL binding and uptake. Ox-LDL activated extracellular signal-regulated kinases 1 and 2 (ERK 1/2) is inhibited [54][55][56].…”