Sustained increased CaMKII phosphorylation is involved in the impaired regression of isoproterenol-induced cardiac hypertrophy in rats
Sustained increased CaMKII phosphorylation is involved in the impaired regression of isoproterenol-induced cardiac hypertrophy in rats
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DOI：
10.1016/j.jphs.2020.07.001
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发表时间：
2020-09-01
影响因子：
3.5
通讯作者：
Hao, Liying
中科院分区：
文献类型：
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作者：
Li, Jingyuan;Gao, Qinghua;Hao, Liying
为了了解心肌肥厚消退的机制，我们研究了异丙肾上腺素（ISO）停药后大鼠心肌病模型和新生儿心肌细胞的病理变化。给药2周后大鼠心肌肥厚；然而，在停用ISO （ISO-wdr组）后的自然维持三周后，肥大并未消退。ISO-wdr组的剩余肥大伴随着磷酸化Ca2+/钙调素依赖性蛋白激酶II （p-CaMKII）水平的持续增加。此外，组蛋白去乙酰化酶4 （HDAC4）和Ca(V)1.2通道的表达水平以及与HDAC4和Ca(V)1.2结合的CaMKII的数量在ISO-wdr组中没有恢复。心肌细胞模型的结果与大鼠模型相似。氯沙坦、美托洛尔或氨氯地平既不能改善心房利钠肽的增加，也不能抑制p-CaMKII和结合CaMKII的增加。相反，autocamtide-2相关抑制剂肽，一种CaMKII抑制剂，减少了这些增加。本研究首次探讨了肥厚刺激退出后CaMKII的磷酸化状态，提出CaMKII及其与Ca(V)1.2的复合物可能是实现心肌肥厚有效消退的潜在靶点。(C) 2020作者。由Elsevier B.V.代表日本药理学会制作和主办。
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however, the hypertrophy did not regress after three weeks of natural maintenance after ISO administration was withdrawn (ISO-wdr group).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 Ca2+/calmodulin-dependent protein kinase II (p-CaMKII). Additionally, the increased expression levels of histone deacetylase 4 (HDAC4) and the Ca(V)1.2 channel and amounts of CaMKII bound with HDAC4 and Ca(V)1.2 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 This study investigated the phosphorylation status of CaMKII after hypertrophic stimulus was withdrawn for the first time and proposed that CaMKII as well as its complexes with Ca(V)1.2 could be potential targets to achieve effective regression of cardiac hypertrophy. (C) 2020 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society.