Abstract-Abnormal release of Ca from sarcoplasmic reticulum (SR) via the cardiac ryanodine receptor (RyR2) may contribute to contractile dysfunction and arrhythmogenesis in heart failure (HF). We previously demonstrated decreased Ca transient amplitude and SR Ca load associated with increased Na/Ca exchanger expression and enhanced diastolic SR Ca leak in an arrhythmogenic rabbit model of nonischemic HF. Here we assessed expression and phosphorylation status of key Ca handling proteins and measured SR Ca leak in control and HF rabbit myocytes. With HF, expression of RyR2 and FK-506 binding protein 12.6 (FKBP12.6) were reduced, whereas inositol trisphosphate receptor (type 2) and Ca/calmodulin-dependent protein kinase II (CaMKII) expression were increased 50% to 100%. The RyR2 complex included more CaMKII (which was more activated) but less calmodulin, FKBP12.6, and phosphatases 1 and 2A. The RyR2 was more highly phosphorylated by both protein kinase A (PKA) and CaMKII. Total phospholamban phosphorylation was unaltered, although it was reduced at the PKA site and increased at the CaMKII site. SR Ca leak in intact HF myocytes (which is higher than in control) was reduced by inhibition of CaMKII but was unaltered by PKA inhibition. CaMKII inhibition also increased SR Ca content in HF myocytes. Our results suggest that CaMKIIdependent phosphorylation of RyR2 is involved in enhanced SR diastolic Ca leak and reduced SR Ca load in HF, and may thus contribute to arrhythmias and contractile dysfunction in HF. Key Words: ryanodine receptor Ⅲ CaMKII Ⅲ phosphorylation Ⅲ heart failure Ⅲ arrhythmia C ontractile dysfunction in HF is caused by diminished sarcoplasmic reticulum (SR) Ca load that could arise from enhanced activity of Na/Ca exchange (NCX), reduced SR Ca ATPase (SERCA) function, and increased diastolic SR Ca leak via ryanodine receptors (RyR), 1-5 all of which we have demonstrated to occur in our arrhythmogenic rabbit model of nonischemic HF. [1][2][3] HF is also associated with a nearly 50% incidence of sudden cardiac death from ventricular tachycardia (VT) that degenerates to ventricular fibrillation (VF). 6 In 3D cardiac mapping studies in our HF rabbit model, we showed that spontaneously occurring VT initiates by nonreentrant mechanisms 7 associated with delayed afterdepolarizations. 2 These arise from spontaneous SR Ca release that activates a transient inward current (I ti ) carried primarily by NCX. 2 Thus abnormal SR Ca release via RyR may contribute to both contractile dysfunction and arrhythmogenesis.The cardiac RyR (RyR2) is the center of a large macromolecular protein complex that directly or indirectly interacts with RyR2 and modulates its function. The complex includes FK506 binding protein 12.6 (FKBP12.6), calmodulin (CaM), protein kinase A (PKA), Ca/CaM-dependent protein kinase (CaMKII), protein phosphatases PP1 and PP2A, mAKAP, and other associated proteins such as spinophilin, calsequestrin, and sorcin. 8 It was shown 9 in HF that PKA mediates RyR2 hyperphosphorylation at the RyR2-Ser2809 site (th...

No abstract

Anti-synthetase syndrome is an autoimmune condition, characterized by antibodies directed against an aminoacycl transfer RNA synthetase along with clinical features that can include interstitial lung disease, myositis, Raynaud’s phenomenon, and arthritis. There is a higher prevalence and increased severity of interstitial lung disease in patients with anti-synthetase syndrome, as compared to dermatomyositis and polymyositis, inflammatory myopathies with which it may overlap phenotypically. Diagnosis is made by a multidisciplinary approach, synthesizing rheumatology and pulmonary evaluations, along with serologic, radiographic, and occasionally muscle and/or lung biopsy results. Patients with anti-synthetase syndrome often require multi-modality immunosuppressive therapy in order to control the muscle and/or pulmonary manifestations of their disease. The long-term care of these patients mandates careful attention to the adverse effects and complications of chronic immunosuppressive therapy, as well as disease-related sequelae that can include progressive interstitial lung disease necessitating lung transplantation, pulmonary hypertension, malignancy and decreased survival. It is hoped that greater awareness of the clinical features of this syndrome will allow for earlier diagnosis and appropriate treatment to improve outcomes in patients with anti-synthetase syndrome.