Abnormal release of Ca2+ from sarcoplasmic reticulum (SR) via the cardiac ryanodine receptor (RyR2) may contribute to contractile dysfunction in heart failure (HF). We previously demonstrated that RyR2 macromol ecular complexes from HF rat were significantly more depleted of FK506 binding protein (FKBP12.6). Here we assess ed expression of key Ca2+ handling proteins and measured SR Ca2+ content in control and HF rat myocytes. Direct measurements of SR Ca2+ content in permeabilized cardiac myocytes demonstrated that SR luminal [Ca2+] is markedly lowered in HF (HF: Δ F / F 0 = 26.4±1.8, n =12; control: Δ F / F 0 = 49.2±2.9, n =10; P <0.01). Furthermore, we demonstrated that the expression of RyR2 associated proteins (including calmodulin, sorcin, calsequestrin, protein phosphatase 1, protein phosphatase 2A), Ca2+ ATPase (SERCA2a), PLB phosphorylation at Ser16 (PLB-S16), PLB phosphorylation at Thr17 (PLB-T17), L-type Ca 2+ channel (Cav1.2) and Na+-Ca 2+ exchanger (NCX) were significantl y reduced in rat HF. Our results suggest that systolic SR reduced Ca2+ release and diastolic SR Ca2+ leak (due to defective protein-protein interaction between RyR2 and its associated proteins) along with reduced SR Ca2+ uptake (due to down-regulation of SERCA2a, PLB-S16 and PLB- T17), abnormal Ca2+ extrusion (due to down-regulation of NCX) and defective Ca2+-induced Ca2+ release (due to down-regulation of Cav1.2) could co ntribute to HF., S.-T. Hu., and Obsahuje bibliografii a bibliografické odkazy
Sophoridine is a type of alkaloid extract derived from the Chinese herb Sophora flavescens Ait (kushen) and possess a variety of pharmacological effects including anti- inflammation, anti - anaphylaxis, anti - cancer, anti - arrhythmic and so on. However, the effect of sophoridine on heart failure has not been known yet. In this study, the effect of sophoridine on heart failure was investigated using Sprague -Dawley (SD) rat model of chronic heart failure. Morphological results showed that in medium and high dose group, myofilaments were arranged orderly and closely, intermyofibrillar ly sis disappeared and mitochondria contained tightly packed cristae compared with heart failure group. We investigated the Ca 2+ induced Ca 2+ transients and assessed the expression of ryanodine receptor (RyR2) and L-type Ca 2+ channel (dihydropyridine receptor, DHPR). We found that the cytosolic Ca 2+ transients were markedly increas ed in amplitude in medium ( ΔF/F 0 =43.33±1.92 ) and high dose groups ( ΔF/F 0 =47.21 ±1.25 ) compared with heart failure group ( ΔF/F 0 =16.7±1.29, P <0.0 1), Moreover, we demonstrated that the expression of cardiac DHPR was significantly increased in medium - and high dose -group compared with heart failure rats. Our results suggest that sophoridine could improve heart failure by ameliorating cardiac Ca 2+ induced Ca 2+ transients, and that thi s amelioration is associated with upregulation of DHPR., S.-T. Hu, Y.-F. Shen, J.-M. Gong, Y.-J. Yang., and Obsahuje bibliografii