School of Life Sciences and Systems Biology Research Center, Gwangju Institute of Science and Technology (GIST), 123 Cheomdan-gwagiro, Buk-gu, Gwangju, 500-712, Republic of Korea.
Basic Res Cardiol. 2013 May;108(3):344. doi: 10.1007/s00395-013-0344-2. Epub 2013 Apr 4.
The histidine-rich Ca(2+)-binding protein (HRC) is located in the lumen of the sarcoplasmic reticulum (SR) and exhibits high-capacity Ca(2+)-binding properties. Overexpression of HRC in the heart resulted in impaired SR Ca(2+) uptake and depressed relaxation through its interaction with SERCA2a. However, the functional significance of HRC in overall regulation of calcium cycling and contractility is not currently well defined. To further elucidate the role of HRC in vivo under physiological and pathophysiological conditions, we generated and characterized HRC-knockout (KO) mice. The KO mice were morphologically and histologically normal compared to wild-type (WT) mice. At the cellular level, ablation of HRC resulted in significantly enhanced contractility, Ca(2+) transients, and maximal SR Ca(2+) uptake rates in the heart. However, after-contractions were developed in 50 % of HRC-KO cardiomyocytes, compared to 11 % in WT mice under stress conditions of high-frequency stimulation (5 Hz) and isoproterenol application. A parallel examination of the electrical activity revealed significant increases in the occurrence of Ca(2+) spontaneous SR Ca(2+) release and delayed afterdepolarizations with ISO in HRC-KO, compared to WT cells. The frequency of Ca(2+) sparks was also significantly higher in HRC-KO cells with ISO, consistent with the elevated SR Ca(2+) load in the KO cells. Furthermore, HRC-KO cardiomyocytes showed significantly deteriorated cell contractility and Ca(2+)-cycling caused possibly by depressed SERCA2a expression after transverse-aortic constriction (TAC). Also HRC-null mice exhibited severe cardiac hypertrophy, fibrosis, pulmonary edema and decreased survival after TAC. Our results indicate that ablation of HRC is associated with poorly regulated SR Ca(2+)-cycling, and severe pathology under pressure-overload stress, suggesting an essential role of HRC in maintaining the integrity of cardiac function.
富含组氨酸的 Ca(2+)-结合蛋白（HRC）位于肌浆网（SR）的腔室中，具有高容量的 Ca(2+)-结合特性。在心脏中过度表达 HRC 会通过与 SERCA2a 的相互作用导致 SR Ca(2+)摄取受损和舒张功能下降。然而，HRC 在整体调节钙循环和收缩性方面的功能意义目前还没有很好地定义。为了进一步阐明 HRC 在生理和病理生理条件下体内的作用，我们生成并表征了 HRC 敲除（KO）小鼠。与野生型（WT）小鼠相比，KO 小鼠在形态和组织学上均正常。在细胞水平上，HRC 的缺失导致心脏的收缩性、Ca(2+)瞬变和最大 SR Ca(2+)摄取率显著增强。然而，在高频率刺激（5 Hz）和异丙肾上腺素应用的应激条件下，50%的 HRC-KO 心肌细胞发生继收缩，而 WT 小鼠仅为 11%。平行检查电活动发现，与 WT 细胞相比，HRC-KO 中 Ca(2+)自发性 SR Ca(2+)释放和延迟后去极化的发生显著增加。在 ISO 存在的情况下，HRC-KO 细胞中的 Ca(2+)火花频率也显著升高，与 KO 细胞中升高的 SR Ca(2+)负荷一致。此外，在横主动脉缩窄（TAC）后，HRC-KO 心肌细胞的细胞收缩性和 Ca(2+)-循环明显恶化，可能是由于 SERCA2a 表达下调。HRC 缺失的小鼠在 TAC 后也表现出严重的心脏肥大、纤维化、肺水肿和存活率降低。我们的结果表明，HRC 的缺失与 SR Ca(2+)-循环调控不良以及压力超负荷应激下的严重病理学有关，提示 HRC 在维持心脏功能完整性方面的重要作用。
