Left ventricular response in the transition from hypertrophy to failure recapitulates distinct roles of Akt, β-arrestin-2, and CaMKII in mice with aortic regurgitation
Left ventricular response in the transition from hypertrophy to failure recapitulates distinct roles of Akt, β-arrestin-2, and CaMKII in mice with aortic regurgitation
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从肥大到衰竭转变过程中的左心室反应概括了 Akt、β-arrestin-2 和 CaMKII 在主动脉瓣反流小鼠中的不同作用。
DOI：
10.21037/atm.2020.01.51
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发表时间：
2020-03-01
影响因子：
--
通讯作者：
Zou, Yunzeng
中科院分区：
文献类型：
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作者：
Wu, Jian;You, Jieyun;Zou, Yunzeng
背景资料：虽然主动脉瓣返流（AR）是一种临床上重要的疾病，变得越来越常见，但这种疾病的相关小鼠模型和机制研究很少。在这项研究中，我们试图描绘病理和分子变化，并解决一些潜在的相关分子在手术诱导的AR动物模型中的作用。方法：在超声心动图引导下，通过穿刺C57 BL/6 J小鼠的主动脉瓣叶诱导AR。早在AR后1周，左心室（LV）显示舒张功能和冠状动脉血流储备（CFR）明显受损，以及在收缩末期和舒张末期的心脏肥大和腔室扩张。AR后2周观察到LV游离壁增厚和LV心肌细胞肥大，而射血分数下降直到4周后才观察到。Nppa（利钠肽A）和NppB（尖塔C肽B）随时间增加，与突出的Akt激活以及轻微的CaMKII（Ca 2 +/钙调蛋白依赖性蛋白激酶II）激活和双相变化-arrestin-2表达。治疗AR小鼠Akt抑制加剧了离心性肥大，而既不抑制CaMKII也不β-arrestin-2过表达的影响，以AR的反应。结论：我们的结构，功能，分子和治疗分析表明，Akt，但不是CaMKII或β-arrestin-2，在小鼠AR后左室重构的发展中起着调节作用。这些结果可能为容量超负荷心肌病的治疗靶点提供重要线索。
Background: Although aortic regurgitation (AR) is a clinically important condition that is becoming increasingly common, few relevant murine models and mechanistic studies exist for this condition. In this study, we attempted to delineate the pathological and molecular changes and address the roles of some potentially relevant molecules in an animal model of surgically induced AR.Methods: AR was induced by puncturing the aortic valve leaflets in C57BL/6J mice under echocardiographic guidance.Results: As early as 1 week following AR, the left ventricles (LV) displayed marked impairments in diastolic function and coronary flow reserve (CFR), as well as cardiac hypertrophy and chamber dilatation at both end-systole and end-diastole. LV free wall thickening and cardiomyocyte hypertrophy in LV were observed 2 weeks following of AR while a decline in ejection fraction was not seen until after 4 weeks. Nppa (natriuretic peptide A) and Nppb (minaret c peptide B) increased over time, in conjunction with prominent Akt activation as well as slight CaMKII (Ca2+/calmodulin-dependent protein kinase II) activation and biphasic changes in -arrestin-2 expression. Treatment of AR mice with Akt inhibition exacerbated the eccentric hypertrophy, while neither inhibition of CaMKII nor beta-arrestin-2 overexpression influenced the response to AR.Conclusions: Our structural, functional, molecular and therapeutic analyses reveal that Akt, but not CaMKII or beta-arrestin-2, plays a regulatory role in the development of LV remodeling after AR in Mice. These results may shed important light on therapeutic targets for volume overloaded cardiomyopathy.