Article ; Online: Protein Kinase D1 Regulates Cardiac Hypertrophy, Potassium Channel Remodeling, and Arrhythmias in Heart Failure.
Journal of the American Heart Association
2022 Volume 11, Issue 19, Page(s) e027573
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 ... ...
| 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. |
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| MeSH term(s) | Animals ; Mice ; Action Potentials/physiology ; Arrhythmias, Cardiac/genetics ; Arrhythmias, Cardiac/metabolism ; Cardiomegaly/metabolism ; Heart Failure/genetics ; Heart Failure/metabolism ; Myocytes, Cardiac/metabolism ; Potassium/metabolism ; Potassium Channels/metabolism ; Protein Kinase C/genetics ; Protein Kinase C/metabolism |
| Chemical Substances | Potassium (RWP5GA015D) ; Potassium Channels ; Protein Kinase C (EC 2.7.11.13) ; protein kinase D (EC 2.7.10.-) |
| Language | English |
| Publishing date | 2022-09-29 |
| Publishing country | England |
| Document type | Journal Article ; Research Support, N.I.H., Extramural |
| ZDB-ID | 2653953-6 |
| ISSN | 2047-9980 ; 2047-9980 |
| ISSN (online) | 2047-9980 |
| ISSN | 2047-9980 |
| DOI | 10.1161/JAHA.122.027573 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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