Endogenous regulation of cardiovascular function by apelin-APJ
Endogenous regulation of cardiovascular function by apelin-APJ
复制标题
DOI：
10.1152/ajpheart.00686.2009
复制
发表时间：
2009-11-01
影响因子：
4.8
通讯作者：
Quertermous, Thomas
中科院分区：
文献类型：
--
作者：
Charo, David N.;Ho, Michael;Quertermous, Thomas
Charo DN，Ho M，法哈尔多G，Kawana M，Kundu RK，Sheikh AY，Finsterbach TP，Leeper NJ，Ernst KV，Chen MM，Ho YD，Chun HJ，伯恩斯坦D，阿什利EA，Quertermous T. Apelin-APJ对心血管功能的内源性调节。Am J Physiol Heart Circ Physiol 297：H1904-H1913，2009.首次发表于2009年9月18日; doi：10.1152/ajpheart.00686.2009。研究已经显示外源性爱帕琳施用的显著心血管作用，包括心脏收缩的有效激活。然而，内源性apelin-APJ通路的作用尚不清楚。为了研究内源性爱帕琳-APJ信号传导的损失，我们产生了缺乏配体（爱帕琳）或受体（APJ）的小鼠。Apelin缺陷小鼠存活，可生育，并显示正常发育。相比之下，APJ缺陷小鼠并没有按照预期的孟德尔比率出生，许多小鼠表现出心血管发育缺陷。在基础条件下，存活至成年期的爱帕琳和APJ缺失小鼠均表现出收缩功能的适度下降。然而，与运动应激两个突变株系表现出一致的和显着的运动能力下降。为了解释这些发现，我们探索了自分泌信号的作用，在体外使用缺乏爱帕琳或APJ的离体左心室心肌细胞的场刺激。两组均表现出较少的肌节缩短和收缩和舒张速度受损，钙瞬变无差异。总之，这些结果表明，内源性apelin-APJ信号传导在维持成年小鼠的基础心脏功能中发挥适度的作用，在应激条件下发挥更实质性的作用。此外，自分泌途径似乎存在于心肌细胞中，其消融减少细胞收缩而不改变钙瞬变。最后，apelin和APJ基因敲除小鼠之间发育表型的差异表明可能存在未发现的APJ配体或APJ的配体非依赖性效应。
Charo DN, Ho M, Fajardo G, Kawana M, Kundu RK, Sheikh AY, Finsterbach TP, Leeper NJ, Ernst KV, Chen MM, Ho YD, Chun HJ, Bernstein D, Ashley EA, Quertermous T. Endogenous regulation of cardiovascular function by apelin-APJ. Am J Physiol Heart Circ Physiol 297: H1904-H1913, 2009. First published September 18, 2009; doi:10.1152/ajpheart.00686.2009.-Studies have shown significant cardiovascular effects of exogenous apelin administration, including the potent activation of cardiac contraction. However, the role of the endogenous apelin-APJ pathway is less clear. To study the loss of endogenous apelin-APJ signaling, we generated mice lacking either the ligand (apelin) or the receptor (APJ). Apelin-deficient mice were viable, fertile, and showed normal development. In contrast, APJ-deficient mice were not born in the expected Mendelian ratio, and many showed cardiovascular developmental defects. Under basal conditions, both apelin and APJ null mice that survived to adulthood manifested modest decrements in contractile function. However, with exercise stress both mutant lines demonstrated consistent and striking decreases in exercise capacity. To explain these findings, we explored the role of autocrine signaling in vitro using field stimulation of isolated left ventricular cardiomyocytes lacking either apelin or APJ. Both groups manifested less sarcomeric shortening and impaired velocity of contraction and relaxation with no difference in calcium transient. Taken together, these results demonstrate that endogenous apelin-APJ signaling plays a modest role in maintaining basal cardiac function in adult mice with a more substantive role during conditions of stress. In addition, an autocrine pathway seems to exist in myocardial cells, the ablation of which reduces cellular contraction without change in calcium transient. Finally, differences in the developmental phenotype between apelin and APJ null mice suggest the possibility of undiscovered APJ ligands or ligand-independent effects of APJ.