Atrial fibrillation increases atrial-cardiomyocyte nucleoplasmic Ca2+ via IP3R1 upregulation involving miR-26a, leading to enhanced IP3R1-CaMKII-HDAC4 signaling.
AF upregulates IP3R1 via miR-26a downregulation, increasing nuclear calcium and altering CaMKII-HDAC4 signaling, which may contribute to AF pathophysiology.
Rationale: The mechanisms underlying atrial fibrillation (AF), the most common clinical arrhythmia, are poorly understood. Nucleoplasmic Ca 2+ regulates gene expression, but the nature and significance of nuclear Ca 2+ -changes in AF are largely unknown. Objective: To elucidate mechanisms by which AF alters atrial-cardiomyocyte nuclear Ca 2+ (Ca 2+ Nuc ) and CaMKII (Ca 2+ /calmodulin-dependent protein kinase-II)-related signaling. Methods and Results: Atrial cardiomyocytes were isolated from control and AF dogs (kept in AF by atrial tachypacing 600 bpm × 1 week). Ca 2+ Nuc and cytosolic Ca 2+ (Ca 2+ Cyto ) were recorded via confocal microscopy. Diastolic Ca 2+ Nuc was greater than Ca 2+ Cyto under control conditions, while resting Ca 2+ Nuc was similar to Ca 2+ Cyto ; both diastolic and resting Ca 2+ Nuc increased with AF. IP 3 R (Inositol-trisphosphate receptor) stimulation produced larger Ca 2+ Nuc increases in AF versus control cardiomyocytes, and IP 3 R-blockade suppressed the AF-related Ca 2+ Nuc differences. AF upregulated nuclear protein expression of IP 3 R1 (IP 3 R-type 1) and of phosphorylated CaMKII (immunohistochemistry and immunoblot) while decreasing the nuclear/cytosolic expression ratio for HDAC4 (histone deacetylase type-4). Isolated atrial cardiomyocytes tachypaced at 3 Hz for 24 hours mimicked AF-type Ca 2+ Nuc changes and L-type calcium current decreases versus 1-Hz-paced cardiomyocytes; these changes were prevented by IP 3 R knockdown with short-interfering RNA directed against IP 3 R1. Nuclear/cytosolic HDAC4 expression ratio was decreased by 3-Hz pacing, while nuclear CaMKII phosphorylation was increased. Either CaMKII-inhibition (by autocamtide-2-related peptide) or IP 3 R-knockdown prevented the CaMKII-hyperphosphorylation and nuclear-to-cytosolic HDAC4 shift caused by 3-Hz pacing. In human atrial cardiomyocytes from AF patients, nuclear IP 3 R1-expression was significantly increased, with decreased nuclear/nonnuclear HDAC4 ratio. MicroRNA-26a was predicted to target ITPR1 (confirmed by luciferase assay) and was downregulated in AF atrial cardiomyocytes; microRNA-26a silencing reproduced AF-induced IP 3 R1 upregulation and nuclear diastolic Ca 2+ -loading. Conclusions: AF increases atrial-cardiomyocyte nucleoplasmic Ca 2+ by IP 3 R1-upregulation involving miR-26a, leading to enhanced IP 3 R1-CaMKII-HDAC4 signaling and L-type calcium current downregulation. Graphic Abstract: A graphic abstract is available for this article.
Qi et al. (Wed,) conducted a other in Atrial fibrillation. Atrial fibrillation / tachypacing vs. Control / 1-Hz pacing was evaluated on Nucleoplasmic Ca2+ and CaMKII-related signaling changes. Atrial fibrillation increases atrial-cardiomyocyte nucleoplasmic Ca2+ via IP3R1 upregulation involving miR-26a, leading to enhanced IP3R1-CaMKII-HDAC4 signaling.