Inhibition of protein phosphatase 1 by inhibitor-2 gene delivery ameliorates heart failure progression in genetic cardiomyopathy
Inhibition of protein phosphatase 1 by inhibitor-2 gene delivery ameliorates heart failure progression in genetic cardiomyopathy
复制标题
DOI：
10.1096/fj.05-5299fje
复制
发表时间：
2006-06-01
期刊：
影响因子：
4.8
通讯作者：
Matsuzaki, Masunori
中科院分区：
文献类型：
--
作者：
Yamada, Michio;Ikeda, Yasuhiro;Matsuzaki, Masunori
据报道，1 型蛋白磷酸酶 (PP1) 在衰竭的心脏中过度激活，导致心脏功能下降。我们研究了抑制剂-2 (INH-2)（一种内源性 PP1 抑制剂）的心肌基因转移对体内 PP1 的抑制是否可以减轻心肌病 (CM) 仓鼠（一种成熟的 HF 模型）中的心力衰竭 (HF) 进展。腺病毒 INH-2 基因递送改善了左心室 (LV) 的缩短百分比，并在 1 周时伴随着心室尺寸的减小。体内心肌 INH-2 基因递送诱导胞质 PP1 催化亚基 α (PP1C α) 的增加，但不诱导胞质 PP1 活性的相应增加。另一方面，INH-2 递送诱导微粒体 PP1C α 的减少，导致微粒体 PP1 活性优先降低，从而增加受磷蛋白 Ser16 的磷酸化。 INH-2 基因转移减轻了脑钠尿肽的表达，可能反映了心脏功能的改善。此外，腺相关病毒介导的INH-2基因递送显着延长了3个月的生存时间。这些结果表明，PP1 活性增加是遗传性心肌病进展过程中的一个加剧因素，并且 INH-2 对 PP1 活性的调节为心力衰竭提供了一种潜在的新治疗方法，而无需激活心肌细胞中的蛋白激酶 A 信号传导。
The type 1 protein phosphatase (PP1) has been reported to be overactivated in the failing heart, leading to a depression in cardiac function. We investigated whether in vivo PP1 inhibition by myocardial gene transfer of inhibitor-2 (INH-2), an endogenous PP1 inhibitor, alleviates heart failure (HF) progression in the cardiomyopathic (CM) hamster, a well-established HF model. Adenoviral INH-2 gene delivery improved % fractional shortening of the left ventricle (LV) accompanied by reduced chamber size at 1 wk. In vivo myocardial INH-2 gene delivery induced an increase in cytosolic PP1 catalytic subunit alpha (PP1C alpha) without inducing the corresponding increase in cytosolic PP1 activity. On the other hand, INH-2 delivery induced a decrease in microsomal PP1C alpha, resulting in a preferential decrease in microsomal PP1 activity, thereby increasing in phospholamban phosphorylation at Ser16. INH-2 gene transfer alleviated brain natriuretic peptide expression, presumably reflecting improved cardiac function. Moreover, adeno-associated virus-mediated INH-2 gene delivery significantly extended the survival time for 3 mo. These results indicate that increased PP1 activity is an exacerbating factor during progression of genetic cardiomyopathy and modulation of PP1 activity by INH-2 provides a potential new treatment for HF without activating protein kinase A signaling in cardiomyocytes.