Cardiac Progenitor Cells Engineered With βARKct Have Enhanced β-Adrenergic Tolerance
Cardiac Progenitor Cells Engineered With βARKct Have Enhanced β-Adrenergic Tolerance
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DOI：
10.1038/mt.2013.200
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发表时间：
2014-01-01
影响因子：
12.4
通讯作者：
Sussman, Mark A.
中科院分区：
文献类型：
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作者：
Khan, Mohsin;Mohsin, Sadia;Sussman, Mark A.
过继移植后干细胞在损伤心肌中的存活率和存留率较低。儿茶酚胺水平升高与心肌损伤相一致，对心脏祖细胞(CPC)的存活产生不利影响。G蛋白偶联受体激酶2(GRK2)衍生的抑制性多肽βARKct可增强心衰时心肌细胞的收缩能力，延长存活时间，并使神经激素轴正常化，但对CPC存活和增殖的有益作用尚不清楚。在这里，我们调查了在衰竭心脏中看到的βARKct表达的保护作用是否与CPC有关。表达β-ARKct的修饰细胞通过保护β2-肾上腺素能受体(β2-ARs)增强AKT/eNOS信号转导。此外，除了βARKct表达对β2-AR信号转导的作用外，GRK2的药物抑制也增加了非工程细胞(缺乏βARKct)中的β2-AR信号转导，但对βARKct工程细胞的作用有限，这为βARKct抑制GRK2的作用提供了证据。在儿茶酚胺刺激后，观察到βARKct工程的CPC的增殖和代谢活性增加，表明肾上腺素能耐受性得到改善。在急性心肌梗死模型中，β-ARKct修饰的CPC可提高过继移植后的存活率和增殖能力，同时增加β-AR的表达。因此，CPC的βARKct工程可以促进心肌梗死后注射细胞的存活和增殖，其中包括改善干细胞生存所必需的β-肾上腺素能耐受。
Stem cell survival and retention in myocardium after injury following adoptive transfer is low. Elevated catecholamine levels coinciding with myocardial injury adversely affect cardiac progenitor cell (CPC) survival. The G protein-coupled receptor kinase 2 (GRK2)-derived inhibitory peptide, beta ARKct, enhance myocyte contractility, survival, and normalize the neurohormonal axis in failing heart, however salutary effects of beta ARKct on CPC survival and proliferation are unknown. Herein, we investigated whether the protective effects of beta ARKct expression seen in the failing heart relate to CPCs. Modified CPCs expressing beta ARKct enhanced AKT/eNOS signaling through protective beta 2-adrenergic receptors (beta 2-ARs). In addition, to the actions of beta ARKct expression on beta 2- AR signaling, pharmacologic inhibition of GRK2 also increased beta 2-AR signaling in nonengineered CPCs (lacking beta ARKct) but had limited effects in beta ARKct engineered CPCs providing evidence for the strength of the beta ARKct in inhibiting GRK2 in these cells. Increased proliferation and metabolic activity were observed in beta ARKct-engineered CPCs following catecholamine stimulation indicating improved adrenergic tolerance. beta ARKct modification of CPCs increased survival and proliferation following adoptive transfer in an acute myocardial infarction model concomitant with increased expression of beta-AR. Thus, beta ARKct engineering of CPCs promotes survival and proliferation of injected cells following myocardial infarction, which includes improved beta-adrenergic tolerance essential for stem cell survival.