Intermittent pressure overload triggers hypertrophy-independent cardiac dysfunction and vascular rarefaction
Intermittent pressure overload triggers hypertrophy-independent cardiac dysfunction and vascular rarefaction
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DOI：
10.1172/jci25397
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发表时间：
2006-06-01
影响因子：
15.9
通讯作者：
Rockman, Howard A.
中科院分区：
文献类型：
--
作者：
Perrino, Cinzia;Prasad, Sathyamangla V. Naga;Rockman, Howard A.
一个多世纪以来，关于为什么有些心脏压力是病理性的，有些是生理性的，一直存在激烈的争论。一个长期存在的理论是，运动等生理负荷是间歇性的，而高血压等病理性负荷是慢性的。在这项研究中，我们假设心脏压力的性质，而不是持续时间，是适应不良表型的关键决定因素。为了验证这一点，我们对小鼠的心脏施加了间歇性压力过载，并测试了压力持续时间和性质对心力衰竭发展的作用。尽管有轻微的肥厚反应、保留的收缩功能和有利的胎儿基因表达谱，暴露于间歇性压力过载的心脏表现出病理特征。重要的是，间歇性压力过载导致舒张功能障碍，β -肾上腺素能受体（β AR）功能改变，以及心脏肥厚发生前血管稀疏，这些在很大程度上通过阻止β AR激酶1向配体激活受体募集PI3K而正常化。因此，应激诱导的致病信号通路的激活，而不是应激持续时间或肥厚生长本身，是心功能障碍的分子触发因素。
For over a century, there has been intense debate as to the reason why some cardiac stresses are pathological and others are physiological. One long-standing theory is that physiological overloads such as exercise are intermittent, while pathological overloads such as hypertension are chronic. In this study, we hypothesized that the nature of the stress on the heart, rather than its duration, is the key determinant of the maladaptive phenotype. To test this, we applied intermittent pressure overload on the hearts of mice and tested the roles of duration and nature of the stress on the development of cardiac failure. Despite a mild hypertrophic response, preserved systolic function, and a favorable fetal gene expression profile, hearts exposed to intermittent pressure overload displayed pathological features. Importantly, intermittent pressure overload caused diastolic dysfunction, altered beta-adrenergic receptor (beta AR) function, and vascular rarefaction before the development of cardiac hypertrophy, which were largely normalized by preventing the recruitment of PI3K by beta AR kinase 1 to ligand-activated receptors. Thus stress-induced activation of pathogenic signaling pathways, not the duration of stress or the hypertrophic growth per se, is the molecular trigger of cardiac dysfunction.