Abteilung Kardiologie und Pneumologie/Herzzentrum, Georg August Universität Göttingen, Robert-Koch-Strasse 40, Göttingen, Germany.
Circulation. 2013 Aug 27;128(9):970-81. doi: 10.1161/CIRCULATIONAHA.113.001746. Epub 2013 Jul 19.
Sarcoplasmic reticulum (SR) Ca(2+) leak through ryanodine receptor type 2 (RyR2) dysfunction is of major pathophysiological relevance in human heart failure (HF); however, mechanisms underlying progressive RyR2 dysregulation from cardiac hypertrophy to HF are still controversial.
We investigated healthy control myocardium (n=5) and myocardium from patients with compensated hypertrophy (n=25) and HF (n=32). In hypertrophy, Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and protein kinase A (PKA) both phosphorylated RyR2 at levels that were not different from healthy myocardium. Accordingly, inhibitors of these kinases reduced the SR Ca(2+) leak. In HF, however, the SR Ca(2+) leak was nearly doubled compared with hypertrophy, which led to reduced systolic Ca(2+) transients, a depletion of SR Ca(2+) storage and elevated diastolic Ca(2+) levels. This was accompanied by a significantly increased CaMKII-dependent phosphorylation of RyR2. In contrast, PKA-dependent RyR2 phosphorylation was not increased in HF and was independent of previous β-blocker treatment. In HF, CaMKII inhibition but not inhibition of PKA yielded a reduction of the SR Ca(2+) leak. Moreover, PKA inhibition further reduced SR Ca(2+) load and systolic Ca(2+) transients.
In human hypertrophy, both CaMKII and PKA functionally regulate RyR2 and may induce SR Ca(2+) leak. In the transition from hypertrophy to HF, the diastolic Ca(2+) leak increases and disturbed Ca(2+) cycling occurs. This is associated with an increase in CaMKII- but not PKA-dependent RyR2 phosphorylation. CaMKII inhibition may thus reflect a promising therapeutic target for the treatment of arrhythmias and contractile dysfunction.
肌浆网（SR）Ca2+ 通过兰尼碱受体 2（RyR2）功能障碍渗漏与人类心力衰竭（HF）的主要病理生理相关；然而，从心脏肥大到 HF 时 RyR2 调节逐渐失常的机制仍存在争议。
我们研究了健康对照组心肌（n=5）和代偿性肥大患者心肌（n=25）和 HF 患者心肌（n=32）。在肥大中，Ca2+/钙调蛋白依赖性蛋白激酶 II（CaMKII）和蛋白激酶 A（PKA）均使 RyR2 磷酸化，磷酸化水平与健康心肌无差异。因此，这些激酶的抑制剂降低了 SR Ca2+渗漏。然而，HF 中的 SR Ca2+ 渗漏几乎是肥大的两倍，这导致收缩期 Ca2+ 瞬变减少、SR Ca2+ 储存耗竭和舒张期 Ca2+ 水平升高。这伴随着 RyR2 的 CaMKII 依赖性磷酸化显著增加。相比之下，HF 中 PKA 依赖性 RyR2 磷酸化没有增加，并且与之前的β受体阻滞剂治疗无关。HF 中，CaMKII 抑制而非 PKA 抑制可降低 SR Ca2+ 渗漏。此外，PKA 抑制进一步降低了 SR Ca2+ 负荷和收缩期 Ca2+ 瞬变。
在人类肥大中，CaMKII 和 PKA 均可调节 RyR2 的功能，并可能诱导 SR Ca2+ 渗漏。在从肥大到 HF 的过渡中，舒张期 Ca2+ 渗漏增加，Ca2+ 循环紊乱发生。这与 CaMKII-而非 PKA-依赖性 RyR2 磷酸化增加相关。因此，CaMKII 抑制可能反映了心律失常和收缩功能障碍治疗的有前途的治疗靶点。
