Enhancing calstabin binding to ryanodine receptors improves cardiac and skeletal muscle function in heart failure

Wehrens, Xander H.T.; Lehnart, Stephan E.; Reiken, Steven; Nagel, Roel van der; Morales, Raymond; Sun, Jie; Cheng, Zhenzhuang; Deng, Shi-Xiang; Windt, León J. De; Landry, Donald W.; Marks, Andrew R.

doi:10.1073/pnas.0500353102

Cited by 158 publications

(160 citation statements)

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“…23). Moreover, during exercise followed by catecholamine injection, RyR2 is PKA phosphorylated at serine 2808 as we have previously reported, and mice harboring RyR2 that cannot be PKA phosphorylated (Ryr2-S2808A mice) are protected against stress-induced RyR2 leak (57). A recent article by Valdivia and colleagues has challenged the role of PKA phosphorylation of Ryr2-S2808 (58); however, as we have previously noted, their study examined a mouse model of cardiac hypertrophy that is not characterized by leaky RyR2 (59).…”

Section: Figurementioning

confidence: 81%

Leaky Ca2+ release channel/ryanodine receptor 2 causes seizures and sudden cardiac death in mice

Lehnart

Mongillo²,

Bellinger³

et al. 2008

J. Clin. Invest.

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262

365

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The Ca 2+ release channel ryanodine receptor 2 (RyR2) is required for excitation-contraction coupling in the heart and is also present in the brain. Mutations in RyR2 have been linked to exercise-induced sudden cardiac death (catecholaminergic polymorphic ventricular tachycardia [CPVT]). CPVT-associated RyR2 mutations result in "leaky" RyR2 channels due to the decreased binding of the calstabin2 (FKBP12.6) subunit, which stabilizes the closed state of the channel. We found that mice heterozygous for the R2474S mutation in Ryr2 (Ryr2-R2474S mice) exhibited spontaneous generalized tonic-clonic seizures (which occurred in the absence of cardiac arrhythmias), exercise-induced ventricular arrhythmias, and sudden cardiac death. Treatment with a novel RyR2-specific compound (S107) that enhances the binding of calstabin2 to the mutant Ryr2-R2474S channel inhibited the channel leak and prevented cardiac arrhythmias and raised the seizure threshold. Thus, CPVT-associated mutant leaky Ryr2-R2474S channels in the brain can cause seizures in mice, independent of cardiac arrhythmias. Based on these data, we propose that CPVT is a combined neurocardiac disorder in which leaky RyR2 channels in the brain cause epilepsy, and the same leaky channels in the heart cause exerciseinduced sudden cardiac death. IntroductionPharmacological seizure models have implicated abnormalities in intracellular Ca 2+ cycling of inhibitory interneurons and/or astrocytes as a mechanism of seizure generation (1, 2), and the inositol 1,4,5-trisphosphate receptor (IP3R), an intracellular calcium release channel on the ER, has been associated with seizures in mice (3). However, a causal relationship between defective intracellular calcium release channels and seizures has not been reported. Calcium stored within the ER contributes to neuronal signaling and is controlled by intracellular Ca 2+ release channels, in particular ryanodine receptors (RyRs) (4-6) and IP3Rs (7,8). To explore the underlying mechanism for seizures in CPVT we generated mice that harbor a missense mutation (RyR2-R2474S) that has been linked to exercise-induced cardiac arrhythmias in humans (9-12).More than 50 distinct RYR2 mutations have been linked to catecholaminergic polymorphic ventricular tachycardia (CPVT), an arrhythmogenic cardiomyopathy (13-15). CPVT patients experience syncope and sudden cardiac death (SCD) from the toddler to adult ages, and by 35 years age the mortality is up to 50% (13,16,17).

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Section: Figurementioning

confidence: 81%

Leaky Ca2+ release channel/ryanodine receptor 2 causes seizures and sudden cardiac death in mice

Lehnart

Mongillo²,

Bellinger³

et al. 2008

J. Clin. Invest.

Self Cite

262

365

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“…We have previously shown that JTV-519, a 1,4-benzothiazepine, inhibits depletion of calstabin2 from PKA-hyperphosphorylated RyR2 channels and reduces HF progression and ventricular arrhythmias by inhibiting diastolic SR Ca 2+ leak via RyR2 (16,39,40). Moreover, these effects of JTV-519 (K201) were not observed in casltabin2-deficient mice, demonstrating the importance of calstabin2 in the mechanism of action of this class of drugs (39).…”

Section: Figurementioning

confidence: 98%

“…Mice were randomized to undergo either MI or a sham procedure. Ligation of the left anterior descending artery was performed as previous described (39). At different time points after MI, mice were anesthetized with 1.0%-1.5% isoflurane in O2, placed on a heating pad (37°C), and cardiac function was assessed by echocardiography, using a Visualsonic Vevo 770 ultrasound equipped with a 30-MHz transducer applied to the chest wall.…”

Section: Methodsmentioning

confidence: 99%

“…Cardiac ventricular dimensions and EF were assessed in the 2D mode. Cardiac catheterization was used to assess contractility using a 1.4F high-fidelity micromanometer catheter (Millar Instruments) advanced via the right carotid artery into the LV (39). The IOX data acquisition system was used to analyze pressure-volume relationships (Emka Technologies).…”

Section: Methodsmentioning

confidence: 99%

“…Moreover, these effects of JTV-519 (K201) were not observed in casltabin2-deficient mice, demonstrating the importance of calstabin2 in the mechanism of action of this class of drugs (39). In addition to acting on the RyR2 channel to prevent depletion of calstabin2, JTV-519 is also a multichannel blocker (41).…”

Section: Figurementioning

confidence: 99%

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Role of chronic ryanodine receptor phosphorylation in heart failure and β-adrenergic receptor blockade in mice

Shan¹,

Betzenhauser²,

Kushnir³

et al. 2010

J. Clin. Invest.

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211

253

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Increased sarcoplasmic reticulum (SR) Ca 2+ leak via the cardiac ryanodine receptor/calcium release channel (RyR2) is thought to play a role in heart failure (HF) progression. Inhibition of this leak is an emerging therapeutic strategy. To explore the role of chronic PKA phosphorylation of RyR2 in HF pathogenesis and treatment, we generated a knockin mouse with aspartic acid replacing serine 2808 (mice are referred to herein as RyR2-S2808D +/+ mice). This mutation mimics constitutive PKA hyperphosphorylation of RyR2, which causes depletion of the stabilizing subunit FKBP12.6 (also known as calstabin2), resulting in leaky RyR2. RyR2-S2808D +/+ mice developed age-dependent cardiomyopathy, elevated RyR2 oxidation and nitrosylation, reduced SR Ca 2+ store content, and increased diastolic SR Ca 2+ leak. After myocardial infarction, RyR2-S2808D +/+ mice exhibited increased mortality compared with WT littermates. Treatment with S107, a 1,4-benzothiazepine derivative that stabilizes RyR2-calstabin2 interactions, inhibited the RyR2-mediated diastolic SR Ca 2+ leak and reduced HF progression in WT and RyR2-S2808D +/+ mice. In contrast, β-adrenergic receptor blockers improved cardiac function in WT but not in RyR2-S2808D +/+ mice.Thus, chronic PKA hyperphosphorylation of RyR2 results in a diastolic leak that causes cardiac dysfunction. Reversing PKA hyperphosphorylation of RyR2 is an important mechanism underlying the therapeutic action of β-blocker therapy in HF.

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The Role of Translational Medicine and Predictive Biomarkers in the Development of Novel, Innovative Treatments for the Management of Chronic Heart Failure:APharmaceutical Industry Perspective

Douglas¹,

Feuerstein²

2010

Burger's Medicinal Chemistry and Drug Discovery

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Chronic heart failure (CHF) represents one of the few cardiovascular diseases with an incidence that continues to rise. While the socio‐economic burden associated with this malignant disease remains high, recent attempts to develop novel, differentiated therapies for the management of CHF (ET‐1, TNFα, dual ACE/NEP inhibitors) have met with failure due to lack of differentiated efficacy and/or safety concerns. Such disappointments have drawn attention to the difficulties faced today in (a) the selection of the most appropriate, innovative targets for the management of this disease; (b) the development of predictive biomarkers that validate the target, define compound pharmacodynamic/‐kinetic (safety/efficacy) relationships, catalog disease modification, and/or assist in patient selection/stratification; and (c) optimal CHF clinical trial design. The present commentary discusses the role of Translational Medicine in the preclinical and clinical CHF Drug Discovery process and details how this emerging scientific discipline can be best used to minimize investment risk/cost.

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Enhancing calstabin binding to ryanodine receptors improves cardiac and skeletal muscle function in heart failure

Cited by 158 publications

References 40 publications

Leaky Ca2+ release channel/ryanodine receptor 2 causes seizures and sudden cardiac death in mice

Leaky Ca2+ release channel/ryanodine receptor 2 causes seizures and sudden cardiac death in mice

Role of chronic ryanodine receptor phosphorylation in heart failure and β-adrenergic receptor blockade in mice

The Role of Translational Medicine and Predictive Biomarkers in the Development of Novel, Innovative Treatments for the Management of Chronic Heart Failure:APharmaceutical Industry Perspective

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