Inducible cardiomyocyte-specific deletion of CaM kinase II protects from pressure overload-induced heart failure
Inducible cardiomyocyte-specific deletion of CaM kinase II protects from pressure overload-induced heart failure
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DOI：
10.1007/s00395-016-0581-2
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发表时间：
2016-11-01
影响因子：
9.5
通讯作者：
Backs, Johannes
中科院分区：
文献类型：
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作者：
Kreusser, Michael M.;Lehmann, Lorenz H.;Backs, Johannes
CaM激酶II（CaMKII）已被认为驱动病理性心脏重塑和心力衰竭。然而，迄今为止提供的证据是基于使用化合物和肽的抑制策略，这些化合物和肽也发挥脱靶效应，并遵循专门的预防策略。因此，本研究的目的是调查是否特异性CaMKII抑制后，心脏应激延迟或逆转适应不良的心脏重塑和功能障碍。两个冗余的CaMKII基因δ和γ的组合基因缺失在明显心力衰竭发作后诱导，这是由横主动脉缩窄（TAC）诱导的病理性压力超负荷的结果。我们使用两种不同的策略来设计诱导型心肌细胞特异性CaMK II delta/CaMK II gamma双敲除小鼠模型（DKO）：一种模型基于在心脏特异性α MHC启动子控制下的他莫昔芬诱导型mER/Cre/mER表达;另一种策略基于在心脏特异性肌球蛋白轻链启动子控制下通过腺相关病毒（AAV 9）通过心脏特异性基因转移过表达Cre重组酶。这两种模型都导致了衰竭心脏中CaMKII的大量缺失。为了接近临床情况，在TAC手术后3周诱导CaMKII缺失。在两种DKO模型中，与对照动物相比，心脏功能障碍和间质纤维化的进展可以减缓。综上所述，我们第一次表明，心脏损伤后的“治疗性”CaMKII缺失足以减弱适应不良的心脏重塑，并逆转心力衰竭的迹象。这些数据表明，CaMKII抑制是对抗心力衰竭的有前景的治疗方法。
CaM kinase II (CaMKII) has been suggested to drive pathological cardiac remodeling and heart failure. However, the evidence provided so far is based on inhibitory strategies using chemical compounds and peptides that also exert off-target effects and followed exclusively preventive strategies. Therefore, the aim of this study was to investigate whether specific CaMKII inhibition after the onset of cardiac stress delays or reverses maladaptive cardiac remodeling and dysfunction. Combined genetic deletion of the two redundant CaMKII genes delta and gamma was induced after the onset of overt heart failure as the result of pathological pressure overload induced by transverse aortic constriction (TAC). We used two different strategies to engineer an inducible cardiomyocytespecific CaMKII delta/CaMKII gamma double knockout mouse model (DKO): one model bases on tamoxifen-inducible mER/Cre/mER expression under control of the cardiac-specific alpha MHC promoter; the other strategy bases on overexpression of Cre recombinase via cardiac-specific gene transfer through adenoassociated virus (AAV9) under control of the cardiac-specific myosin light chain promoter. Both models led to a substantial deletion of CaMKII in failing hearts. To approximate the clinical situation, CaMKII deletionwas induced 3 weeks after TAC surgery. In both models of DKO, the progression of cardiac dysfunction and interstitial fibrosis could be slowed down as compared to control animals. Taken together, we show for the first time that "therapeutic'' CaMKII deletion after cardiac damage is sufficient to attenuate maladaptive cardiac remodeling and to reverse signs of heart failure. These data suggest that CaMKII inhibition is a promising therapeutic approach to combat heart failure.