Impaired heart Contractility in apelin gene-deficient mice associated with aging and pressure overload
Impaired heart Contractility in apelin gene-deficient mice associated with aging and pressure overload
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DOI：
10.1161/circresaha.107.158659
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发表时间：
2007-08-17
影响因子：
20.1
通讯作者：
Penninger, Josef M.
中科院分区：
文献类型：
--
作者：
Kuba, Keiji;Zhang, Liyong;Penninger, Josef M.
爱帕琳肽是一种新型的内源性肽系统，被认为参与广泛的生理功能，包括心血管功能、心脏发育、流体稳态控制和肥胖。爱帕琳也是严重急性呼吸综合征的关键受体血管紧张素转换酶2的催化底物。爱帕琳的体内生理作用仍然是难以捉摸的。在这里，我们报告了Apelin基因靶向小鼠的产生。爱帕琳突变小鼠是存活的和可生育的，看起来健康，并且表现出正常的体重、水和食物摄入、心率和心脏形态。有趣的是，老年Apelin基因敲除小鼠在没有组织学异常的情况下发生了与收缩功能障碍相关的心脏收缩力的进行性损害。我们还报道了压力超负荷诱导心脏Apelin表达上调。重要的是，在压力超负荷诱导的心力衰竭中，爱帕琳蛋白的缺失并不显著影响肥大反应，但爱帕琳蛋白突变小鼠发展为进行性心力衰竭。在带状Apelin（-/y）和Apelin（-/y）小鼠心脏中差异表达基因的全局基因表达阵列和层次聚类显示参与细胞外基质重塑和肌肉收缩的基因一致上调。这些遗传数据表明，内源性肽Apelin对维持压力超负荷和衰老的心脏收缩力至关重要。
Apelin constitutes a novel endogenous peptide system suggested to be involved in a broad range of physiological functions, including cardiovascular function, heart development, control of fluid homeostasis, and obesity. Apelin is also a catalytic substrate for angiotensin- converting enzyme 2, the key severe acute respiratory syndrome receptor. The in vivo physiological role of Apelin is still elusive. Here we report the generation of Apelin gene -targeted mice. Apelin mutant mice are viable and fertile, appear healthy, and exhibit normal body weight, water and food intake, heart rates, and heart morphology. Intriguingly, aged Apelin knockout mice developed progressive impairment of cardiac contractility associated with systolic dysfunction in the absence of histological abnormalities. We also report that pressure overload induces upregulation of Apelin expression in the heart. Importantly, in pressure overload -induced heart failure, loss of Apelin did not significantly affect the hypertrophy response, but Apelin mutant mice developed progressive heart failure. Global gene expression arrays and hierarchical clustering of differentially expressed genes in hearts of banded Apelin(-/y) and Apelin(-/y) mice showed concerted upregulation of genes involved in extracellular matrix remodeling and muscle contraction. These genetic data show that the endogenous peptide Apelin is crucial to maintain cardiac contractility in pressure overload and aging.