Heart failure in mice induces a dysfunction of the sinus node associated with reduced CaMKII signaling

Abstract

Dysfunction of the sinoatrial node (SAN), the natural heart pacemaker, is common in heart failure (HF) patients. SAN spontaneous activity relies on various ion currents in the plasma membrane (voltage clock), but intracellular Ca2+ ([Ca2+]i) release via ryanodine receptor 2 (RYR2; Ca2+ clock) plays an important synergetic role. Whereas remodeling of voltage-clock components has been revealed in HF, less is known about possible alterations to the Ca2+ clock. Here, we analyzed [Ca2+]i handling in SAN from a mouse HF model after transverse aortic constriction (TAC) and compared it with sham-operated animals. ECG data from awake animals showed slower heart rate in HF mice upon autonomic nervous system blockade, indicating intrinsic sinus node dysfunction. Confocal microscopy analyses of SAN cells within whole tissue showed slower and less frequent [Ca2+]i transients in HF. This correlated with fewer and smaller spontaneous Ca2+ sparks in HF SAN cells, which associated with lower RYR2 protein expression level and reduced phosphorylation at the CaMKII site. Moreover, PLB phosphorylation at the CaMKII site was also decreased in HF, which could lead to reduced sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) function and lower sarcoplasmic reticulum Ca2+ content, further depressing the Ca2+ clock. The inhibition of CaMKII with KN93 slowed [Ca2+]i transient rate in both groups, but this effect was smaller in HF SAN, consistent with less CaMKII activation. In conclusion, our data uncover that the mechanism of intrinsic pacemaker dysfunction in HF involves reduced CaMKII activation.

Dual effect of cardiac FKBP12.6 overexpression on excitation-contraction coupling and the incidence of ventricular arrhythmia depending on its expression level

“…One possibility of incomplete protection is that, in this CPVT model, FKBP12.6 overexpression unmasked bradycardia, a feature that we found previously in this CPVT model ex-vivo [ 39 ] and in TG2 mice. Thus, both borderline effects can be cumulative and unmask bradycardia in DT mice, which may predispose them to ventricular arrhythmias [ 52 ]. Another reason for the incomplete protection might be that the RyR2 R420Q cardiomyocytes show ultrastructural alterations associated with lower junctophilin binding [ 40 ], a pathophysiological trait that could not be overcome by the effects of FKBP12.6 overexpression.…”

“…The SR Ca 2+ load was estimated after rapid caffeine (10 mM) application recorded at 2.5 ms/line following steady-state pacing. The time constant of the [Ca 2+ ] i transient decay was obtained by fitting the descending portion of the fluorescence trace to a single exponential function, as previously described [ 12 , 52 ]. After 1 min without electrical stimulation, spontaneous Ca 2+ releases (Ca 2+ sparks and Ca 2+ waves) were recorded at a speed of 1.43 ms/line in quiescent cells.…”

Synergy between Membrane Currents Prevents Severe Bradycardia in Mouse Sinoatrial Node Tissue

“…To investigate the internal dynamics of SAN cells treated with different blockers, we used our previously published computational model of the mouse SAN cell [ 13 ], which itself based on previous publications [ 5 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 ]. The model contains 43 state variables and differential equations describing the dynamics of cell membrane potential, ion currents, Ca 2+ cycling, and post-translational modifications during an AP ( Figure 1 D).…”

“…Here, we focus on I pacemaker (“funny”) current (I f ), which is one of the elements that contribute to the generation of spontaneous diastolic depolarization and an important stabilizer of heart rhythm [ 5 ]. Reduction in I f was previously shown in heart failure conditions [ 6 , 7 ], aging [ 8 ], pulmonary hypertension [ 9 ], diabetes [ 10 ], and atrial fibrillation [ 11 ].…”

Calcium/Calmodulin-Stimulated Protein Kinase II (CaMKII): Different Functional Outcomes from Activation, Depending on the Cellular Microenvironment

“…CaMKII also plays important roles in several neuronal pathologies, including impaired learning, transient focal or global ischaemia, excitotoxic neuronal cell death, Alzheimer's disease, epileptogenesis, tissue-injury evoked persistent pain, and Parkinson's disease [9][10][11][12][13][14][15][16][17][18][19][20]. Further, non-neuronal CaMKII has been implicated in regulating a variety of other cellular processes, including the cell cycle, fertilisation, cancer cell proliferation and metastasis, contractioninduced glucose uptake in skeletal muscle, insulin secretion, CD8 T cell function, intestinal motility, differentiation, cardiac function, and vascular tone [21][22][23][24][25][26][27][28][29][30][31][32].…”