-
Journal of Cardiovascular Translational... Apr 2024The effect of Ryanodine receptor2 (RyR2) and its stabilizer on cardiac hypertrophy is not well known. C57/BL6 mice underwent transverse aortic contraction (TAC) or sham...
The effect of Ryanodine receptor2 (RyR2) and its stabilizer on cardiac hypertrophy is not well known. C57/BL6 mice underwent transverse aortic contraction (TAC) or sham surgery were administered dantrolene, the RyR2 stabilizer, or control drug. Dantrolene significantly alleviated TAC-induced cardiac hypertrophy in mice, and RNA sequencing was performed implying calcineurin/NFAT3 and TNF-α/NF-κB/NLRP3 as critical signaling pathways. Further expression analysis and Western blot with heart tissue as well as neonatal rat cardiomyocyte (NRCM) model confirmed dantrolene decreases the activation of calcineurin/NFAT3 signaling pathway and TNF-α/NF-κB/NLRP3 signaling pathway, which was similar to FK506 and might be attenuated by calcineurin overexpression. The present study shows for the first time that RyR2 stabilizer dantrolene attenuates cardiac hypertrophy by inhibiting the calcineurin, therefore downregulating the TNF-α/NF-κB/NLRP3 pathway.
PubMed: 38652413
DOI: 10.1007/s12265-023-10376-8 -
BMC Pulmonary Medicine Apr 2024Patients with congenital myopathies may experience respiratory involvement, resulting in restrictive ventilatory dysfunction and respiratory failure. Pulmonary...
BACKGROUND
Patients with congenital myopathies may experience respiratory involvement, resulting in restrictive ventilatory dysfunction and respiratory failure. Pulmonary hypertension (PH) associated with this condition has never been reported in congenital ryanodine receptor type 1(RYR1)-related myopathy.
CASE PRESENTATION
A 47-year-old woman was admitted with progressively exacerbated chest tightness and difficulty in neck flexion. She was born prematurely at week 28. Her bilateral lower extremities were edematous and muscle strength was grade IV. Arterial blood gas analysis revealed hypoventilation syndrome and type II respiratory failure, while lung function test showed restrictive ventilation dysfunction, which were both worse in the supine position. PH was confirmed by right heart catheterization (RHC), without evidence of left heart disease, congenital heart disease, or pulmonary artery obstruction. Polysomnography indicated nocturnal hypoventilation. The ultrasound revealed reduced mobility of bilateral diaphragm. The level of creatine kinase was mildly elevated. Magnetic resonance imaging showed myositis of bilateral thigh muscle. Muscle biopsy of the left biceps brachii suggested muscle malnutrition and congenital muscle disease. Gene testing revealed a missense mutation in the RYR1 gene (exon33 c.C4816T). Finally, she was diagnosed with RYR1-related myopathy and received long-term non-invasive ventilation (NIV) treatment. Her symptoms and cardiopulmonary function have been greatly improved after 10 months.
CONCLUSIONS
We report a case of RYR1-related myopathy exhibiting hypoventilation syndrome, type II respiratory failure and PH associated with restrictive ventilator dysfunction. Pulmonologists should keep congenital myopathies in mind in the differential diagnosis of type II respiratory failure, especially in patients with short stature and muscle weakness.
Topics: Humans; Female; Ryanodine Receptor Calcium Release Channel; Middle Aged; Muscle Weakness; Hypertension, Pulmonary; Respiratory Insufficiency; Mutation, Missense; Magnetic Resonance Imaging; Muscular Diseases
PubMed: 38649898
DOI: 10.1186/s12890-024-03016-7 -
JA Clinical Reports Apr 2024Malignant hyperthermia (MH) is a rare, life-threatening disorder of calcium homeostasis in skeletal muscle cells that is triggered by volatile anesthetics and...
BACKGROUND
Malignant hyperthermia (MH) is a rare, life-threatening disorder of calcium homeostasis in skeletal muscle cells that is triggered by volatile anesthetics and succinylcholine, leading to a hypermetabolic reaction. The pathogenic ryanodine receptor 1 (RYR1) gene variant is critical. Patients susceptible to MH should avoid triggering agents, and total intravenous anesthesia (TIVA) is preferred. Remimazolam is safe in patients with suspected MH.
CASE PRESENTATION
We present the first case of remimazolam treatment in a genetically confirmed patient with MH without MH development. A 72-year-old man with a family history of MH underwent remimazolam-based TIVA. After informed consent was obtained, a muscle biopsy and genetic testing were performed. Intraoperatively and postoperatively, the patient exhibited no signs of MH. An enhanced function of the RYR1 channel into releasing calcium was indicated, and the genetic testing revealed a pathogenic variant of RYR1.
CONCLUSIONS
Remimazolam-based TIVA is safe in patients confirming the diagnosis of MH.
PubMed: 38647904
DOI: 10.1186/s40981-024-00710-7 -
IScience May 2024Glucagon is secreted by pancreatic α-cells to counteract hypoglycaemia. How glucose regulates glucagon secretion remains unclear. Here, using mouse islets, we studied...
Glucagon is secreted by pancreatic α-cells to counteract hypoglycaemia. How glucose regulates glucagon secretion remains unclear. Here, using mouse islets, we studied the role of transmembrane and endoplasmic reticulum (ER) Ca on intrinsic α-cell glucagon secretion. Blocking isradipine-sensitive L-type voltage-gated Ca (Ca) channels abolished α-cell electrical activity but had little impact on its cytosolic Ca oscillations or low-glucose-stimulated glucagon secretion. In contrast, depleting ER Ca with cyclopiazonic acid or blocking ER Ca-releasing ryanodine receptors abolished α-cell glucose sensitivity and low-glucose-stimulated glucagon secretion. ER Ca mobilization in α-cells is regulated by intracellular ATP and likely to be coupled to Ca influx through P/Q-type Ca channels. ω-Agatoxin IVA blocked α-cell ER Ca release and cell exocytosis, but had no additive effect on glucagon secretion when combined with ryanodine. We conclude that glucose regulates glucagon secretion through the control of ER Ca mobilization, a mechanism that can be independent of α-cell electrical activity.
PubMed: 38646167
DOI: 10.1016/j.isci.2024.109665 -
Chemical & Pharmaceutical Bulletin 2024Ryanodine receptor 2 (RyR2) is a large Ca-release channel in the sarcoplasmic reticulum (SR) of cardiac muscle cells. It serves to release Ca from the SR into the...
Ryanodine receptor 2 (RyR2) is a large Ca-release channel in the sarcoplasmic reticulum (SR) of cardiac muscle cells. It serves to release Ca from the SR into the cytosol to initiate muscle contraction. RyR2 overactivation is associated with arrhythmogenic cardiac disease, but few specific inhibitors have been reported so far. Here, we identified an RyR2-selective inhibitor 1 from the chemical compound library and synthesized it from glycolic acid. Synthesis of various derivatives to investigate the structure-activity relationship of each substructure afforded another two RyR2-selective inhibitors 6 and 7, among which 6 was the most potent. Notably, compound 6 also inhibited Ca release in cells expressing the RyR2 mutants R2474S, R4497C and K4750Q, which are associated with cardiac arrhythmias such as catecholaminergic polymorphic ventricular tachycardia (CPVT). This inhibitor is expected to be a useful tool for research on the structure and dynamics of RyR2, as well as a lead compound for the development of drug candidates to treat RyR2-related cardiac disease.
Topics: Humans; Calcium; Dose-Response Relationship, Drug; Drug Discovery; HEK293 Cells; Molecular Structure; Ryanodine Receptor Calcium Release Channel; Structure-Activity Relationship; Calcium Channel Blockers; Anti-Arrhythmia Agents; Tachycardia, Ventricular
PubMed: 38644198
DOI: 10.1248/cpb.c24-00114 -
Life Sciences Jun 2024Calcium ion (Ca) dysregulation is one of the main causes of neuronal cell death and brain damage after cerebral ischemia. During ischemic stroke, the ability of neurons... (Review)
Review
Calcium ion (Ca) dysregulation is one of the main causes of neuronal cell death and brain damage after cerebral ischemia. During ischemic stroke, the ability of neurons to maintain Ca homeostasis is compromised. Ca regulates various functions of the nervous system, including neuronal activity and adenosine triphosphate (ATP) production. Disruptions in Ca homeostasis can trigger a cascade of events, including activation of the unfolded protein response (UPR) pathway, which is associated with endoplasmic reticulum (ER) stress and mitochondrial dysfunction. This response occurs when the cell is unable to manage protein folding within the ER due to various stressors, such as a high influx of Ca. Consequently, the UPR is initiated to restore ER function and alleviate stress, but prolonged activation can lead to mitochondrial dysfunction and, ultimately, cell death. Hence, precise regulation of Ca within the cell is mandatory. The ER and mitochondria are two such organelles that maintain intracellular Ca homeostasis through various calcium-operating channels, including ryanodine receptors (RyRs), inositol trisphosphate receptors (IP3Rs), sarco/endoplasmic reticulum calcium ATPases (SERCAs), the mitochondrial Na/Ca exchanger (NCLX), the mitochondrial calcium uniporter (MCU) and voltage-dependent anion channels (VDACs). These channels utilize Ca sequestering and release mechanisms to maintain intracellular Ca homeostasis and ensure proper cellular function and survival. The present review critically evaluates the significance of Ca and its physiological role in cerebral ischemia. We have compiled recent findings on calcium's role and emerging treatment strategies, particularly targeting mitochondria and the endoplasmic reticulum, to address Ca overload in cerebral ischemia.
Topics: Humans; Ischemic Stroke; Animals; Calcium; Neurons; Cell Death; Mitochondria; Endoplasmic Reticulum Stress; Endoplasmic Reticulum; Brain Ischemia; Unfolded Protein Response; Calcium Signaling; Homeostasis
PubMed: 38642844
DOI: 10.1016/j.lfs.2024.122651 -
Proceedings of the National Academy of... Apr 2024Inherited arrhythmia syndromes (IASs) can cause life-threatening arrhythmias and are responsible for a significant proportion of sudden cardiac deaths (SCDs). Despite...
Inherited arrhythmia syndromes (IASs) can cause life-threatening arrhythmias and are responsible for a significant proportion of sudden cardiac deaths (SCDs). Despite progress in the development of devices to prevent SCDs, the precise molecular mechanisms that induce detrimental arrhythmias remain to be fully investigated, and more effective therapies are desirable. In the present study, we screened a large-scale randomly mutagenized mouse library by electrocardiography to establish a disease model of IASs and consequently found one pedigree that exhibited spontaneous ventricular arrhythmias (VAs) followed by SCD within 1 y after birth. Genetic analysis successfully revealed a missense mutation (p.I4093V) of the ryanodine receptor 2 gene to be a cause of the arrhythmia. We found an age-related increase in arrhythmia frequency accompanied by cardiomegaly and decreased ventricular contractility in the mice. Ca signaling analysis and a ryanodine binding assay indicated that the mutant ryanodine receptor 2 had a gain-of-function phenotype and enhanced Ca sensitivity. Using this model, we detected the significant suppression of VA following flecainide or dantrolene treatment. Collectively, we established an inherited life-threatening arrhythmia mouse model from an electrocardiogram-based screen of randomly mutagenized mice. The present IAS model may prove feasible for use in investigating the mechanisms of SCD and assessing therapies.
Topics: Mice; Animals; Tachycardia, Ventricular; Ryanodine Receptor Calcium Release Channel; Arrhythmias, Cardiac; Flecainide; Mutation, Missense; Death, Sudden, Cardiac; Mutation
PubMed: 38621141
DOI: 10.1073/pnas.2218204121 -
ESC Heart Failure Apr 2024Hyperactivity of Ca/calmodulin-dependent protein kinase II (CaMKII) has emerged as a central cause of pathologic remodelling in heart failure. It has been suggested that...
AIMS
Hyperactivity of Ca/calmodulin-dependent protein kinase II (CaMKII) has emerged as a central cause of pathologic remodelling in heart failure. It has been suggested that CaMKII-induced hyperphosphorylation of the ryanodine receptor 2 (RyR2) and consequently increased diastolic Ca leak from the sarcoplasmic reticulum (SR) is a crucial mechanism by which increased CaMKII activity leads to contractile dysfunction. We aim to evaluate the relevance of CaMKII-dependent RyR2 phosphorylation for CaMKII-induced heart failure development in vivo.
METHODS AND RESULTS
We crossbred CaMKIIδC overexpressing [transgenic (TG)] mice with RyR2-S2814A knock-in mice that are resistant to CaMKII-dependent RyR2 phosphorylation. Ca-spark measurements on isolated ventricular myocytes confirmed the severe diastolic SR Ca leak previously reported in CaMKIIδC TG [4.65 ± 0.73 mF/F vs. 1.88 ± 0.30 mF/F in wild type (WT)]. Crossing in the S2814A mutation completely prevented SR Ca-leak induction in the CaMKIIδC TG, both regarding Ca-spark size and frequency, demonstrating that the CaMKIIδC-induced SR Ca leak entirely depends on the CaMKII-specific RyR2-S2814 phosphorylation. Yet, the RyR2-S2814A mutation did not affect the massive contractile dysfunction (ejection fraction = 12.17 ± 2.05% vs. 45.15 ± 3.46% in WT), cardiac hypertrophy (heart weight/tibia length = 24.84 ± 3.00 vs. 9.81 ± 0.50 mg/mm in WT), or severe premature mortality (median survival of 12 weeks) associated with cardiac CaMKIIδC overexpression. In the face of a prevented SR Ca leak, the phosphorylation status of other critical CaMKII downstream targets that can drive heart failure, including transcriptional regulator histone deacetylase 4, as well as markers of pathological gene expression including Xirp2, Il6, and Col1a1, was equally increased in hearts from CaMKIIδC TG on a RyR WT and S2814A background.
CONCLUSIONS
S2814 phosphoresistance of RyR2 prevents the CaMKII-dependent SR Ca leak induction but does not prevent the cardiomyopathic phenotype caused by enhanced CaMKIIδC activity. Our data indicate that additional mechanisms-independent of SR Ca leak-are critical for the maladaptive effects of chronically increased CaMKIIδC activity with respect to heart failure.
PubMed: 38616546
DOI: 10.1002/ehf2.14772 -
Cells Apr 2024During pregnancy, uterine vasculature undergoes significant circumferential growth to increase uterine blood flow, vital for the growing feto-placental unit. However,...
During pregnancy, uterine vasculature undergoes significant circumferential growth to increase uterine blood flow, vital for the growing feto-placental unit. However, this process is often compromised in conditions like maternal high blood pressure, particularly in preeclampsia (PE), leading to fetal growth impairment. Currently, there is no cure for PE, partly due to the adverse effects of anti-hypertensive drugs on maternal and fetal health. This study aimed to investigate the vasodilator effect of extra virgin olive oil (EVOO) phenols on the reproductive vasculature, potentially benefiting both mother and fetus. Isolated uterine arteries (UAs) from pregnant rats were tested with EVOO phenols in a pressurized myograph. To elucidate the underlying mechanisms, additional experiments were conducted with specific inhibitors: L-NAME/L-NNA (10 M) for nitric oxide synthases, ODQ (10 M) for guanylate cyclase, Verapamil (10 M) for the L-type calcium channel, Ryanodine (10 M) + 2-APB (3 × 10 M) for ryanodine and the inositol triphosphate receptors, respectively, and Paxilline (10 M) for the large-conductance calcium-activated potassium channel. The results indicated that EVOO-phenols activate Ca signaling pathways, generating nitric oxide, inducing vasodilation via cGMP and BKCa signals in smooth muscle cells. This study suggests the potential use of EVOO phenols to prevent utero-placental blood flow restriction, offering a promising avenue for managing PE.
Topics: Rats; Pregnancy; Female; Animals; Uterine Artery; Calcium; Olive Oil; Nitric Oxide; Placenta; Ryanodine; Phenols; Dilatation; Large-Conductance Calcium-Activated Potassium Channels; Endothelium
PubMed: 38607058
DOI: 10.3390/cells13070619 -
Heart Rhythm Apr 2024Catecholaminergic polymorphic ventricular tachycardia (CPVT) may cause sudden cardiac death (SCD) despite medical therapy. Therefore, implantable...
An international multicenter cohort study on implantable cardioverter-defibrillators for the treatment of symptomatic children with catecholaminergic polymorphic ventricular tachycardia.
BACKGROUND
Catecholaminergic polymorphic ventricular tachycardia (CPVT) may cause sudden cardiac death (SCD) despite medical therapy. Therefore, implantable cardioverter-defibrillators (ICDs) are commonly advised. However, there is limited data on the outcomes of ICD use in children.
OBJECTIVE
The purpose of this study was to compare the risk of arrhythmic events in pediatric patients with CPVT with and without an ICD.
METHODS
We compared the risk of SCD in patients with RYR2 (ryanodine receptor 2) variants and phenotype-positive symptomatic CPVT patients with and without an ICD who were younger than 19 years and had no history of sudden cardiac arrest at phenotype diagnosis. The primary outcome was SCD; secondary outcomes were composite end points of SCD, sudden cardiac arrest, or appropriate ICD shocks with or without arrhythmic syncope.
RESULTS
The study included 235 patients, 73 with an ICD (31.1%) and 162 without an ICD (68.9%). Over a median follow-up of 8.0 years (interquartile range 4.3-13.4 years), SCD occurred in 7 patients (3.0%), of whom 4 (57.1%) were noncompliant with medications and none had an ICD. Patients with ICD had a higher risk of both secondary composite outcomes (without syncope: hazard ratio 5.85; 95% confidence interval 3.40-10.09; P < .0001; with syncope: hazard ratio 2.55; 95% confidence interval 1.50-4.34; P = .0005). Thirty-one patients with ICD (42.5%) experienced appropriate shocks, 18 (24.7%) inappropriate shocks, and 21 (28.8%) device-related complications.
CONCLUSION
SCD events occurred only in patients without an ICD and mostly in those not on optimal medical therapy. Patients with an ICD had a high risk of appropriate and inappropriate shocks, which may be reduced with appropriate device programming. Severe ICD complications were common, and risks vs benefits of ICDs need to be considered.
PubMed: 38588993
DOI: 10.1016/j.hrthm.2024.04.006