Novel roles of cardiac-derived erythropoietin in cardiac development and function

IF 4.9 2区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS
Melissa A. Allwood , Brittany A. Edgett , Mathew J. Platt , Jade P. Marrow , Bridget Coyle-Asbil , Emma J.B. Holjak , Victoria L. Nelson , Swara Bangali , Razan Alshamali , Kathy Jacyniak , Jorden M. Klein , Laura Farquharson , Nadya Romanova , Victoria Northrup , Leslie M. Ogilvie , Anmar Ayoub , Kjetil Ask , Matthew K. Vickaryous , Gregory M.T. Hare , Keith R. Brunt , Jeremy A. Simpson
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引用次数: 0

Abstract

The role of erythropoietin (EPO) has extended beyond hematopoiesis to include cytoprotection, inotropy, and neurogenesis. Extra-renal EPO has been reported for multiple tissue/cell types, but the physiological relevance remains unknown. Although the EPO receptor is expressed by multiple cardiac cell types and human recombinant EPO increases contractility and confers cytoprotection against injury, whether the heart produces physiologically meaningful amounts of EPO in vivo is unclear. We show a distinct circadian rhythm of cardiac EPO mRNA expression in adult mice and increased mRNA expression during embryogenesis, suggesting physiological relevance to cardiac EPO production throughout life. We then generated constitutive, cardiomyocyte-specific EPO knockout mice driven by the Mlc2v promoter (EPOfl/fl:Mlc2v-cre+/−; EPOΔ/Δ-CM). During cardiogenesis, cardiac EPO mRNA expression and cellular proliferation were reduced in EPOΔ/Δ-CM hearts. However, in adult EPOΔ/Δ- CM mice, total heart weight was preserved through increased cardiomyocyte cross-sectional area, indicating the reduced cellular proliferation was compensated for by cellular hypertrophy. Echocardiography revealed no changes in cardiac dimensions, with modest reductions in ejection fraction, stroke volume, and tachycardia, whereas invasive hemodynamics showed increased cardiac contractility and lusitropy. Paradoxically, EPO mRNA expression in the heart was elevated in adult EPOΔ/Δ-CM, along with increased serum EPO protein content and hematocrit. Using RNA fluorescent in situ hybridization, we found that Epo RNA colocalized with endothelial cells in the hearts of adult EPOΔ/Δ-CM mice, identifying the endothelial cells as a cell responsible for the EPO hyper-expression. Collectively, these data identify the first physiological roles for cardiomyocyte-derived EPO. We have established cardiac EPO mRNA expression is a complex interplay of multiple cell types, where loss of embryonic cardiomyocyte EPO production results in hyper-expression from other cells within the adult heart.

Abstract Image

心源性促红细胞生成素在心脏发育和功能中的新作用
促红细胞生成素(EPO)的作用已从造血扩展到细胞保护、肌力和神经发生。据报道,肾外 EPO 可用于多种组织/细胞类型,但其生理相关性仍不清楚。虽然多种心脏细胞类型都表达 EPO 受体,而且人重组 EPO 能增强收缩力并赋予细胞抗损伤保护作用,但心脏是否会在体内产生有生理意义的 EPO 尚不清楚。我们发现成年小鼠心脏 EPO mRNA 表达有明显的昼夜节律,胚胎发育过程中 mRNA 表达增加,这表明心脏在整个生命过程中产生 EPO 与生理有关。随后,我们生成了由 Mlc2v 启动子驱动的组成型、心肌细胞特异性 EPO 基因敲除小鼠(EPOfl/fl:Mlc2v-cre+/-;EPOΔ/Δ-CM)。在心脏生成过程中,EPOΔ/Δ-CM心脏的心脏EPO mRNA表达和细胞增殖减少。然而,在成年 EPOΔ/Δ- CM 小鼠中,心脏总重量通过心肌细胞横截面积的增加而得以保持,这表明细胞增殖的减少通过细胞肥大得到了补偿。超声心动图显示心脏尺寸没有变化,射血分数、每搏量和心动过速略有减少,而有创血液动力学显示心脏收缩力和嗜酸性增加。矛盾的是,成年 EPOΔ/Δ-CM 患者心脏中 EPO mRNA 表达升高,同时血清 EPO 蛋白含量和血细胞比容增加。利用 RNA 荧光原位杂交技术,我们发现在成年 EPOΔ/Δ-CM 小鼠的心脏中,Epo RNA 与内皮细胞共聚焦,从而确定内皮细胞是导致 EPO 高表达的细胞。总之,这些数据首次确定了心肌细胞源性 EPO 的生理作用。我们已经确定心脏 EPO mRNA 的表达是多种细胞类型的复杂相互作用,其中胚胎心肌细胞 EPO 生成的缺失会导致成人心脏中其他细胞的高表达。
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来源期刊
CiteScore
10.70
自引率
0.00%
发文量
171
审稿时长
42 days
期刊介绍: The Journal of Molecular and Cellular Cardiology publishes work advancing knowledge of the mechanisms responsible for both normal and diseased cardiovascular function. To this end papers are published in all relevant areas. These include (but are not limited to): structural biology; genetics; proteomics; morphology; stem cells; molecular biology; metabolism; biophysics; bioengineering; computational modeling and systems analysis; electrophysiology; pharmacology and physiology. Papers are encouraged with both basic and translational approaches. The journal is directed not only to basic scientists but also to clinical cardiologists who wish to follow the rapidly advancing frontiers of basic knowledge of the heart and circulation.
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