CaMKIIδC Drives Early Adaptive Ca(2+) Change and Late Eccentric Cardiac Hypertrophy.
CaMKIIδC Drives Early Adaptive Ca(2+) Change and Late Eccentric Cardiac Hypertrophy.
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DOI：
10.1161/circresaha.120.316947
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发表时间：
2020-10-09
影响因子：
20.1
通讯作者：
Bers DM
中科院分区：
文献类型：
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作者：
Ljubojevic-Holzer S;Herren AW;Djalinac N;Voglhuber J;Morotti S;Holzer M;Wood BM;Abdellatif M;Matzer I;Sacherer M;Radulovic S;Wallner M;Ivanov M;Wagner S;Sossalla S;von Lewinski D;Pieske B;Brown JH;Sedej S;Bossuyt J;Bers DM
补充数字内容可在正文中找到。CaMKII(钙-钙调蛋白依赖蛋白激酶)δC的激活与心力衰竭(HF)的病理进展有关，CaMKIIδC转基因小鼠迅速发展为心力衰竭和心律失常。然而，肥厚和心力衰竭早期的时空钙处理和CaMKII激活机制知之甚少。目的：研究CaMKIIδC信号在成年心肌细胞、经主动脉缩窄(TAC)和CaMKIIδC转基因小鼠中的时间和位置依赖性激活。我们使用了来自正常心脏和心力衰竭心脏的人组织，4个小鼠系：野生型，KO(CaMKIIδ基因敲除)，CaMKIIδC转基因在野生型(TG)或KO背景下，以及暴露于TAC的野生型小鼠。共聚焦成像和生物化学显示，在TAC后5d，CaMKIIδC在细胞核和核周与胞液中的激活和积聚不成比例。这种CaMKIIδ的激活导致肌浆网钙含量、钙瞬变幅度和[钙]下降速率代偿性增加，而磷蛋白表达降低，所有这些都在胞核附近和胞核内最为显著。TAC的这些早期适应效应在年轻的CaMKIIδTG小鼠(6-8周)中完全模拟，在这些小鼠中没有明显的心功能障碍。(周边型)核内CaMKII的积聚也与HDAC4(组蛋白脱乙酰酶)核输出增强相关，为转录调控创造了一个微域。在更长的时间内，TAC和TG小鼠都进展到显性心衰(分别在45天和11-13周)，在此期间，代偿性钙瞬变效应逆转，但核和时间平均[Ca~(2+)]和CaMKII活性进一步增加。缺乏δB的CaMKIIδTg小鼠表现出更严重的心衰、心肌细胞偏心性生长和核改变。患者心衰组织中CaMKIIδ的表达也显著增加，尤其是核组织中CaMKIIδC的表达。我们的结论是，在TAC早期，核周CaMKIIδC的激活促进了心肌细胞Ca~(2+)瞬变和核转录反应的适应性增加，但这种核Ca~(2+)-CaMKⅡδC轴的慢性进展导致了离心性肥厚和心衰。
Supplemental Digital Content is available in the text. CaMKII (Ca2+-Calmodulin dependent protein kinase) δC activation is implicated in pathological progression of heart failure (HF) and CaMKIIδC transgenic mice rapidly develop HF and arrhythmias. However, little is known about early spatio-temporal Ca2+ handling and CaMKII activation in hypertrophy and HF. To measure time- and location-dependent activation of CaMKIIδC signaling in adult ventricular cardiomyocytes, during transaortic constriction (TAC) and in CaMKIIδC transgenic mice. We used human tissue from nonfailing and HF hearts, 4 mouse lines: wild-type, KO (CaMKIIδ-knockout), CaMKIIδC transgenic in wild-type (TG), or KO background, and wild-type mice exposed to TAC. Confocal imaging and biochemistry revealed disproportional CaMKIIδC activation and accumulation in nuclear and perinuclear versus cytosolic regions at 5 days post-TAC. This CaMKIIδ activation caused a compensatory increase in sarcoplasmic reticulum Ca2+ content, Ca2+ transient amplitude, and [Ca2+] decline rates, with reduced phospholamban expression, all of which were most prominent near and in the nucleus. These early adaptive effects in TAC were entirely mimicked in young CaMKIIδ TG mice (6–8 weeks) where no overt cardiac dysfunction was present. The (peri)nuclear CaMKII accumulation also correlated with enhanced HDAC4 (histone deacetylase) nuclear export, creating a microdomain for transcriptional regulation. At longer times both TAC and TG mice progressed to overt HF (at 45 days and 11–13 weeks, respectively), during which time the compensatory Ca2+ transient effects reversed, but further increases in nuclear and time-averaged [Ca2+] and CaMKII activation occurred. CaMKIIδ TG mice lacking δB exhibited more severe HF, eccentric myocyte growth, and nuclear changes. Patient HF samples also showed greatly increased CaMKIIδ expression, especially for CaMKIIδC in nuclear fractions. We conclude that in early TAC perinuclear CaMKIIδC activation promotes adaptive increases in myocyte Ca2+ transients and nuclear transcriptional responses but that chronic progression of this nuclear Ca2+-CaMKIIδC axis contributes to eccentric hypertrophy and HF.