In Vivo Cardiac Gene Transfer of Kv4.3 Abrogates the Hypertrophic Response in Rats After Aortic Stenosis

Abstract

Background-Prolongation of the action potential duration (APD) and decreased transient outward K ϩ current (I to ) have been consistently observed in cardiac hypertrophy. The relation between electrical remodeling and cardiac hypertrophy in vivo is unknown. Methods and Results-We studied rat hearts subjected to pressure overload by surgical ascending aortic stenosis (AS) and simultaneously infected these hearts with an adenovirus carrying either the Kv4.

Calcineurin Increases Cardiac Transient Outward K+ Currents via Transcriptional Up-regulation of Kv4.2 Channel Subunits

“…Specifically, as already mentioned, many hypertrophic stimuli, including ␣ 1 AR stimulation and heart disease, reduce I to,f as well as Kv4.2, Kv4.3, and KChIP2 expression (8,45,46). These conditions have also been linked to Cn activation (8,45,47), which is expected from our results to limit the extent of I to,f down-regulation. Preventing excessive I to,f reductions may be of critical importance because changes in I to,f can lead to altered electrical and contractile properties of the myocardium, which may contribute to impaired pump function and arrhythmias (6, 48 -51).…”

“…Thus, Cn activation not only induces hypertrophy, but also modulates the extent of the electrical and contractile changes induced as a result of I to,f reduction caused by hypertrophic stimuli. In addition, a recent study found that increased I to,f by adenoviral overexpression of Kv4.3 can prevent hypertrophy (45), whereas increased I to,f in NRVMs treated with PE prevents both myocyte hypertrophy and Cn activation (8), suggesting that, at least in these models, increased I to,f by Cn could limit the degree of hypertrophy.…”

Basal and IGF-I-dependent regulation of potassium channels by MAP kinases and PI3-kinase during eccentric cardiac hypertrophy

“…However, their effects on the regulation of the electrical activity of the heart are not yet well studied, specifically in terms of the role of potassium channels (namely, I K and I K1 ) during eccentric cardiac hypertrophy. Its importance stems from the fact that cardiac hypertrophy is characterized by a prolongation of the action potential duration, an almost universal finding in ventricular cells exposed to chronic workload leading to cardiac hypertrophy (33,34,36,60). Alterations in the activity of the potassium channels have direct effects on the action potential duration and configuration, which are important determinants of myocardial contraction (33,34).…”

SERCA 2a Gene Therapy, Game-Changer for Heart Failure

“…SERCA2a gene therapy has been tested in a wide variety of preclinical models, including acute ischaemia/reperfusion, chronic pressure overload and chronic myocardial infarction, has resulted in a reduction in ventricular arrhythmias experimental studies have demonstrated that gene therapy could be an effective option to treat the failing myocardium [18][19][20][21][22].…”

“…These studies led to the development of in vivo gene transfer using catheter-based techniques to introduce SERCA2a into the myocardium [18][19][20][21][22][23]. Adenoviral mediated SERCA2a gene transfer in a rat model of pressure-overload hypertrophy (in which SERCA2a levels were decreased and severe contractile dysfunction was evident) restored both systolic and diastolic dysfunction to normal levels.…”