Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang, 110122, China.
Department of Physiology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, 8908544, Japan; Department of Physiology, School of Life Sciences, China Medical University, Shenyang, 110001, China.
J Pharmacol Sci. 2020 Sep;144(1):30-42. doi: 10.1016/j.jphs.2020.07.001. Epub 2020 Jul 3.
To understand the mechanism underlying the regression of cardiac hypertrophy, we investigated the pathological changes after isoproterenol (ISO) withdrawal in ISO-induced cardiomyopathy models in rats and neonatal cardiomyocytes. Cardiac hypertrophy was induced in rats by two weeks of ISO administration; however, the hypertrophy did not regress after three weeks of natural maintenance after ISO administration was withdrawn (ISO-wdr group). The remaining hypertrophy in the ISO-wdr group was accompanied by a sustained increase in the level of phosphorylated Ca/calmodulin-dependent protein kinase II (p-CaMKII). Additionally, the increased expression levels of histone deacetylase 4 (HDAC4) and the Ca1.2 channel and amounts of CaMKII bound with HDAC4 and Ca1.2 were not recovered in the ISO-wdr group. The results in cardiomyocyte models were similar to those seen in rat models. Losartan, metoprolol or amlodipine neither ameliorated the increase in atrial natriuretic peptide nor inhibited the increase in p-CaMKII and bound CaMKII. In contrast, autocamtide-2-related inhibitor peptide, a CaMKII inhibitor, reduced these increases. This study investigated the phosphorylation status of CaMKII after hypertrophic stimulus was withdrawn for the first time and proposed that CaMKII as well as its complexes with Ca1.2 could be potential targets to achieve effective regression of cardiac hypertrophy.
为了理解心脏肥大消退的机制，我们研究了异丙肾上腺素（ISO）诱导的心肌病模型中 ISO 撤药后的病理变化，以及在新生大鼠心肌细胞中 ISO 撤药后的病理变化。通过两周的 ISO 给药诱导大鼠心脏肥大；然而，在 ISO 给药后三周的自然维持期间，肥大并没有消退（ISO-wdr 组）。在 ISO-wdr 组中，剩余的肥大伴随着磷酸化钙/钙调蛋白依赖性蛋白激酶 II（p-CaMKII）水平的持续增加。此外，在 ISO-wdr 组中，组蛋白去乙酰化酶 4（HDAC4）和 Ca1.2 通道的表达水平增加，以及与 HDAC4 和 Ca1.2 结合的 CaMKII 数量并未恢复。心肌细胞模型中的结果与大鼠模型中的结果相似。氯沙坦、美托洛尔或氨氯地平既不能改善心钠肽的增加，也不能抑制 p-CaMKII 和结合的 CaMKII 的增加。相比之下，CaMKII 抑制剂 Autocamtide-2 相关抑制剂肽降低了这些增加。本研究首次研究了肥大刺激物撤药后 CaMKII 的磷酸化状态，并提出 CaMKII 及其与 Ca1.2 的复合物可能是实现心脏肥大有效消退的潜在靶点。
