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.

Ion channel trafficking implications in heart failure

“…Hypertrophy is a compensatory response to HF, but sustained cardiac hypertrophy contributes to the development of HF. Remodeling in I Kr and I Ks in HF have also been reported (57)(58)(59). A study conducted in rabbits with atrioventricular block showed a reduction of both I Kr and I Ks , using the patch-clamp technique (60,61).…”

Diabetes and Excess Aldosterone Promote Heart Failure With Preserved Ejection Fraction

“… 35 This was associated with restoration of protein kinase D1 function, 35 which importantly regulates cardiac hypertrophy and progression to heart failure with reduced EF. 36 Aldosterone infusion alone induces mild changes in cardiac function unless accompanied by additional stressors (eg, uninephrectomy+salt water 21 or myocardial infarction). 37 Here we showed that combined db/db +Aldo synergistically induces marked diastolic dysfunction, concentric cardiac hypertrophy, pulmonary congestion, and multiple common comorbidities of HFpEF, including diabetes, obesity, and increased vascular resistance (Figures 1 , 2 , 3 ), more closely recapitulating important aspects of human HFpEF.…”

Effect of deletion of the protein kinase PRKD1 on development of the mouse embryonic heart

“…PRKD is also associated with the phosphorylation of the sarcomeric protein cardiac troponin I (Cuello et al., 2007 ; Haworth et al., 2004 ; Martin‐Garrido et al., 2018 ), indicating that it is a regulator of cardiomyocyte contraction. Further, PRKD1 is known to regulate pathologic cardiac hypertrophy through its action on class II histone deacetylases (HDACs) and signalling via the myocyte enhancer factor‐2 family (MEF2) and TBX5 (Fielitz et al., 2008 ; Ghosh et al., 2009 , 2019 ; Kim et al., 2008 ; Vega et al., 2004 ), and plays a role in the subsequent K + channel remodelling with the potential to cause arrhythmia (Bossuyt et al., 2022 ). It also plays a role in VEGFA‐induced angiogenesis (Di Blasio et al., 2010 ; Wang et al., 2008 ).…”