In vivo cardiac gene transfer of Kv4.3 abrogates the hypertrophic response in rats after aortic stenosis

Area of Science:

• Cardiology
• Molecular Biology
• Electrophysiology

Background:

• Cardiac hypertrophy is associated with prolonged action potential duration (APD) and reduced transient outward potassium current (I(to)).
• The relationship between electrical remodeling and cardiac hypertrophy in vivo remains unclear.

Purpose of the Study:

• To investigate the link between electrical remodeling and cardiac hypertrophy in a rat model of pressure overload.
• To evaluate the therapeutic potential of in vivo Kv4.3 gene transfer in reversing these changes.

Main Methods:

• Rats underwent surgical ascending aortic stenosis (AS) to induce pressure overload.
• Adenovirus-mediated gene transfer was used to deliver either Kv4.3 or beta-galactosidase genes.
• Cardiac function, gene expression (Kv4.2, Kv4.3, calcineurin, NFATc1), and electrophysiological parameters (I(to) density, APD50) were assessed.

Main Results:

• AS rats exhibited reduced I(to) density, prolonged APD50, and decreased Kv4.2/Kv4.3 expression.
• Cardiac hypertrophy was confirmed in AS rats, with increased calcineurin and NFATc1 expression.
• In vivo Kv4.3 gene transfer normalized I(to) density, shortened APD50, and significantly reduced calcineurin and NFAT expression.

Conclusions:

• Downregulation of I(to) and APD prolongation are early events in AS-induced cardiac hypertrophy.
• In vivo Kv4.3 gene transfer effectively restores electrical parameters and mitigates cardiac hypertrophy.
• The calcineurin signaling pathway is implicated in mediating the hypertrophic response to AS.