Cardiac function in mice lacking the glucagon-like peptide-1 receptor
Cardiac function in mice lacking the glucagon-like peptide-1 receptor
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DOI：
10.1210/en.2003-0007
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发表时间：
2003-06-01
期刊：
影响因子：
4.8
通讯作者：
Husain, M
中科院分区：
文献类型：
--
作者：
Gros, R;You, XM;Husain, M
胰高血糖素样肽-1（GLP-1）通过其G蛋白偶联受体（GLP-1 R）调节血糖。尽管GLP-1 R在外周组织（包括心脏）中广泛表达，并且外源性GLP-1给药可增加啮齿动物的心率和血压，但GLP-1 R在心血管系统中作用的生理重要性仍不清楚。我们现在发现，与CD-1野生型对照组相比，GLP-1 R基因缺失（GLP-1 R（-/-））的2月龄小鼠表现出静息心率降低和左心室（LV）舒张末期压升高。5月龄时，超声心动图和组织学检查显示GLP-1 R（-/-）小鼠的LV厚度增加。尽管GLP-1 R（-/-）的基线血流动力学参数与野生型无显著差异，但GLP-1 R（-/-）小鼠在胰岛素给药后显示LV收缩力和舒张功能受损。对胰岛素的心血管反应缺陷不能归因于应激反应的一般性缺陷，因为GLP-1 R（-/-）小鼠对胰岛素有适当的反应，下丘脑中c-fos表达增加，胰高血糖素和肾上腺素的循环水平增加。此外，GLP-1 R（-/-）小鼠输注外源性肾上腺素后的LV收缩性也降低。这些发现提供了新的证据，表明GLP-1 R在体内控制小鼠心脏结构和功能中具有重要作用。
Glucagon-like peptide-1 (GLP-1) acts via its G protein-coupled receptor (GLP-1R) to regulate blood glucose. Although the GLP-1R is widely expressed in peripheral tissues, including the heart, and exogenous GLP-1 administration increases heart rate and blood pressure in rodents, the physiological importance of GLP-1R action in the cardiovascular system remains unclear. We now show that 2-month-old mice with genetic deletion of the GLP-1R (GLP-1R(-/-)) exhibit reduced resting heart rate and elevated left ventricular (LV) end diastolic pressure compared with CD-1 wild-type controls. At the age of 5 months, echocardiography and histology demonstrate increased LV thickness in GLP-1R(-/-) mice. Although baseline hemodynamic parameters of GLP-1R(-/-) did not differ significantly from those of wild type, GLP-1R(-/-) mice displayed impaired LV contractility and diastolic function after insulin administration. The defective cardiovascular response to insulin was not attributable to a generalized defect in the stress response, because GLP-1R(-/-) mice responded appropriately to insulin with increased c-fos expression in the hypothalamus and increased circulating levels of glucagon and epinephrine. Furthermore, LV contractility after exogenous epinephrine infusion was also reduced in GLP-1R(-/-) mice. These findings provide new evidence implicating an essential role for GLP-1R in the control of murine cardiac structure and function in vivo.