β-Adrenergic Receptor Blockers Restore Cardiac Calcium Release Channel (Ryanodine Receptor) Structure and Function in Heart Failure

Abstract

Background-␤-Adrenergic receptor blockade is one of the most effective treatments for heart failure, a leading cause of mortality worldwide. The use of ␤-adrenergic receptor blockers in patients with heart failure is counterintuitive, however, because they are known to decrease contractility in normal hearts. The ryanodine receptor (RyR2) on cardiac sarcoplasmic reticulum is the key calcium release channel required for excitation-contraction coupling. In failing hearts, the stoichiometry and function of the RyR2 macromolecular complex is altered. Decreased levels of phosphatases (PP1 and PP2A) and hyperphosphorylation by protein kinase A result in dissociation of the regulatory protein FKBP12.6 and channels with increased open probability. Methods and Results-Here, we show that systemic oral administration of a ␤-adrenergic receptor blocker reverses protein kinase A hyperphosphorylation of RyR2, restores the stoichiometry of the RyR2 macromolecular complex, and normalizes single-channel function in a canine model of heart failure. Conclusions-These results may, in part, explain the improved cardiac function observed in heart failure patients treated with ␤-adrenergic receptor blockers. Key Words: heart failure Ⅲ calcium Ⅲ sarcoplasmic reticulum Ⅲ ion channels Ⅲ receptors, adrenergic, beta C linical trials have shown that ␤-adrenergic receptor blocker therapy results in a 20% to 66% reduction in mortality at 12 months in patients with heart failure (HF). [1][2][3] It is not intuitively obvious, however, how ␤-adrenergic receptor blockers can improve cardiac function in failing hearts, because they are known to decrease contractility in normal hearts. 4 -6 HF is a complex disease 7 that is characterized by a hyperadrenergic state. 8 However, ␤ 1 -adrenergic receptors are downregulated and uncoupled from G proteins in failing hearts. 9,10 Nevertheless, we recently showed that ryanodine receptor (RyR2) is protein kinase A (PKA)-hyperphosphorylated in HF, 11 indicating that the net effect of ␤-adrenergic signaling is upregulated in HF with respect to RyR2 as a substrate for PKA phosphorylation. It is likely that the PKA hyperphosphorylation of RyR2 is a maladaptive response, 12 because it results in the depletion of the regulatory subunit FKBP12.6, 11,13 yielding channels that are pathologically sensitive to Ca 2ϩ -induced Ca 2ϩ release from the sarcoplasmic reticulum (SR). 11 RyR2 is a macromolecular complex that includes FKBP12.6 as well as PKA and 2 phosphatases (PP1 and PP2A) that are bound to the cytoplasmic domain of the channel via targeting proteins. 11,14 In failing hearts, the RyR2 macromolecular complex undergoes remodeling characterized by a reduction in the amounts of PP1, PP2A, and FKBP12.6 that are bound to the cytoplasmic domain of the channel. 11 In the present study, we used a well-characterized canine model of pacing-induced HF to show that ␤-adrenergic receptor blockade both restores the normal stoichiometry of the RyR2 macromolecular complex and normalizes the function of the channel. Methods H...

Sudden Death in Familial Polymorphic Ventricular Tachycardia Associated With Calcium Release Channel (Ryanodine Receptor) Leak

“…Thus, the present studies not only provide a basis for treating exercise-induced cardiac arrhythmias that cause SCD but also indicate that JTV519 could be beneficial in the treatment of heart failure, which is associated with aberrant SR Ca 2ϩ leak via calstabin2-depleted RyR2 channels. 9,33 Furthermore, these studies confirm results with a high-affinity calstabin2-D37S mutant that normalized the channel function of constitutively PKA-phosphorylated RyR2 channels. 12 In summary, genotype-phenotype studies in RyR2 mutation carriers showed high mortality rates and a reproducible threshold heart rate above which ventricular arrhythmias occur.…”

“…31,32 Treatment with ␤-adrenergic receptor blockers reverses PKA hyperphosphorylation and calstabin2 depletion in heart failure, and the beneficial effects of ␤-blocker treatment in patients with exercise-induced arrhythmias may be related to prevention of RyR2-mediated SR Ca 2ϩ leak. 33 Recently it was reported that the 1,4-benzothiazepine derivative JTV519 inhibits FK506-induced intracellular Ca 2ϩ leak in the heart and may normalize leaky RyR2 in failing hearts. 13,15 Treatment of phosphorylated RyR2-P2328S channels with 1.0 mol/L JTV519 completely normalized the gain-of-function defect, and the significant leftward shift of Ca 2ϩ sensitivity was rescued ( Figure 5).…”

Valsartan Restores Sarcoplasmic Reticulum Function With No Appreciable Effect on Resting Cardiac Function in Pacing-Induced Heart Failure

“…2 We previously reported that in a dog model of pacinginduced heart failure, a prominent abnormal Ca 2ϩ leak occurs through the RyR owing to a partial loss of RyR-bound FKBP12.6. 3 ␤-Adrenergic receptor blockade has been shown to correct the defective interaction of FKBP12.6 with RyR 4,5 that is triggered by the protein kinase A (PKA)-mediated hyperphosphorylation of RyR. 6 Indeed, this correction leads to a restoration of the stoichiometry of the RyR2 macromolecular complex, 4 a normalization of the single-channel function of RyR, 4 and a prevention of the Ca 2ϩ leak from RyR.…”

“…3 ␤-Adrenergic receptor blockade has been shown to correct the defective interaction of FKBP12.6 with RyR 4,5 that is triggered by the protein kinase A (PKA)-mediated hyperphosphorylation of RyR. 6 Indeed, this correction leads to a restoration of the stoichiometry of the RyR2 macromolecular complex, 4 a normalization of the single-channel function of RyR, 4 and a prevention of the Ca 2ϩ leak from RyR. 5 Recently, we found that a new cardioprotective agent, JTV519, corrects the defective FKBP12.6-mediated stabilization of RyR, leading to an improvement in cardiac function during the development of heart failure.…”

Targeting Altered Calcium Physiology in the Heart: Translational Approaches to Excitation, Contraction, and Transcription

“…It remains to be seen to what extend the beneficial aspects of JTV519 and future derivatives rely on the direct actions of FKBP rebinding to RyR and thus a novel mechanism. In addition, it is not known whether bringing back FKBP could really add benefit on-top of existing pharmacological interventions: Marks' group has shown that ␤-adrenergic blockade, a clinically well proven strategy to treat heart failure and arrhythmia, could already completely normalize the stochiometry of the RyR multi-protein complex with respect to the five proteins mentioned above and reverted the increased open probability of isolated channels (40). Likewise, low-dose propranolol treatment completely prevented SR Ca leak in a dog model of heart failure and conformational changes in RyR as well as RyR-FKBP12.6 stochiometry (9), questioning potential on-top benefits of strategies to restore FKBP12.6-RyR binding.…”