Protein Kinase D1 Regulates Cardiac Hypertrophy, Potassium Channel Remodeling, and Arrhythmias in Heart Failure

Abstract

Background Structural and electrophysiological remodeling characterize heart failure (HF) enhancing arrhythmias. PKD1 (protein kinase D1) is upregulated in HF and mediates pathological hypertrophic signaling, but its role in K+ channel remodeling and arrhythmogenesis in HF is unknown. Methods and Results We performed echocardiography, electrophysiology, and expression analysis in wild‐type and PKD1 cardiomyocyte‐specific knockout (cKO) mice following transverse aortic constriction (TAC). PKD1‐cKO mice exhibited significantly less cardiac hypertrophy post‐TAC and were protected from early decline in cardiac contractile function (3 weeks post‐TAC) but not the progression to HF at 7 weeks post‐TAC. Wild‐type mice exhibited ventricular action potential duration prolongation at 8 weeks post‐TAC, which was attenuated in PKD1‐cKO, consistent with larger K+ currents via the transient outward current, sustained current, inward rectifier K+ current, and rapid delayed rectifier K+ current and increased expression of corresponding K+ channels. Conversely, reduction of slowly inactivating K+ current was independent of PKD1 in HF. Acute PKD inhibition slightly increased transient outward current in TAC and sham wild‐type myocytes but did not alter other K+ currents. Sham PKD1‐cKO versus wild‐type also exhibited larger transient outward current and faster early action potential repolarization. Tachypacing‐induced action potential duration alternans in TAC animals was increased and independent of PKD1, but diastolic arrhythmogenic activities were reduced in PKD1‐cKO. Conclusions Our data indicate an important role for PKD1 in the HF‐related hypertrophic response and K+ channel downregulation. Therefore, PKD1 inhibition may represent a therapeutic strategy to reduce hypertrophy and arrhythmias; however, PKD1 inhibition may not prevent disease progression and reduced contractility in HF.

Keywords

• action potential
• cardiac arrhythmia
• heart failure
• hypertrophic signaling
• potassium channels