Obayashi Masakazu, Xiao Bailong, Stuyvers Bruno D, Davidoff Allen W, Mei Jie, Chen S R Wayne, ter Keurs Henk E D J
Department of Medical Bio-regulation, Division of Cardiovascular Medicine, Yamaguchi University School of Medicine, Ube, Yamaguchi, Japan.
Cardiovasc Res. 2006 Jan;69(1):140-51. doi: 10.1016/j.cardiores.2005.07.010. Epub 2005 Aug 22.
The role of phosphorylation of the ryanodine receptor at serine-2808 (RyRS2808) in congestive heart failure (CHF) is controversial, and effects of RyRS2808 phosphorylation on contraction are unclear. It has been reported that diastolic sarcomere length (SL) fluctuations accompany propagating contractile waves due to propagating SR Ca2+ release in trabeculae from rats with CHF. Here, we studied the influence of RyR destabilization by FK506 and isoproterenol on twitch force (Ftw) and SL fluctuations in right ventricular (RV) trabeculae. We measured phosphorylation of RyRS2808 in rats with myocardial infarction (MI) with or without beta-blockade and in rats during isoproterenol stimulation in order to assess the role of RyRS2808 phosphorylation in SL fluctuations in failing hearts.
Five groups of male Lewis Brown-Norway rats were studied 3 months after MI: i) Sham; ii) MI with CHF (cMI); iii) MI without CHF; iv) metoprolol-treated MI, with and without CHF. The root mean square (RMSSL) of SL fluctuations in RV trabeculae was calculated.
RMSSL increased strongly both following a short train of stimuli at 2.5 Hz and following catecholamine activation in trabeculae from MI with CHF, resulting in a decrease in Ftw in proportion to RMSSL. RyRS2808 phosphorylation was increased significantly in the left ventricle (LV; approximately 58%, P<0.05) but not in the RV (n.s.) in MI rats with CHF. FK506 tripled high frequency stimulation-induced RMSSL in nonfailing trabecula but did not further enhance RMSSL in failing trabecula. Isoproterenol increased RMSSL in nonfailing trabeculae only modestly despite a substantial increase in RyRS2808 phosphorylation in the RV (approximately 60%, P<0.05). Isoproterenol induced SL fluctuation without an increase in RV-RyRS2808 phosphorylation in failing trabeculae. Chronic beta-blockade decreased high frequency and catecholamine stimulation-induced RMSSL while RyRS2808 phosphorylation in the RV was indistinguishable from that in cMI.
Acute RyRS2808 phosphorylation by itself does not cause spontaneous contractile waves owing to RyR2 destabilization. Spontaneous contractile waves in CHF are not caused by RyRS2808 phosphorylation alone, suggesting that factors other than RyRS2808 phosphorylation affect RyR function.
兰尼碱受体丝氨酸 - 2808位点（RyRS2808）磷酸化在充血性心力衰竭（CHF）中的作用存在争议，且RyRS2808磷酸化对心肌收缩的影响尚不清楚。据报道，在CHF大鼠的小梁中，由于肌浆网（SR）钙释放的传播，舒张期肌节长度（SL）波动伴随着收缩波的传播。在此，我们研究了FK506和异丙肾上腺素对右心室（RV）小梁抽搐力（Ftw）和SL波动的影响。我们测量了心肌梗死（MI）大鼠在有或无β受体阻滞剂情况下以及异丙肾上腺素刺激期间RyRS2808的磷酸化水平，以评估RyRS2808磷酸化在衰竭心脏SL波动中的作用。
对MI后3个月的五组雄性Lewis Brown - Norway大鼠进行研究：i）假手术组；ii）伴有CHF的MI组（cMI）；iii）无CHF的MI组；iv）美托洛尔治疗的MI组，有或无CHF。计算RV小梁中SL波动的均方根（RMSSL）。
在伴有CHF的MI大鼠的小梁中，无论是在2.5 Hz的短串刺激后还是在儿茶酚胺激活后，RMSSL均显著增加，导致Ftw与RMSSL成比例下降。伴有CHF的MI大鼠左心室（LV）中RyRS2808磷酸化显著增加（约58%，P<0.05），但右心室（RV）中未增加（无统计学差异）。FK506使非衰竭小梁中高频刺激诱导的RMSSL增加两倍，但未进一步增强衰竭小梁中的RMSSL。尽管RV中RyRS2808磷酸化大幅增加（约60%，P<0.05），异丙肾上腺素仅适度增加非衰竭小梁中的RMSSL。在衰竭小梁中，异丙肾上腺素诱导SL波动但未增加RV - RyRS2808磷酸化。慢性β受体阻滞剂降低高频和儿茶酚胺刺激诱导的RMSSL，而RV中RyRS2808磷酸化与cMI组无差异。
急性RyRS2808磷酸化本身不会由于RyR2不稳定而导致自发收缩波。CHF中的自发收缩波并非仅由RyRS2808磷酸化引起，这表明除RyRS2808磷酸化外的其他因素会影响RyR功能。
