Stretch-induced hypertrophy activates NFkB-mediated VEGF secretion in adult cardiomyocytes.
Stretch-induced hypertrophy activates NFkB-mediated VEGF secretion in adult cardiomyocytes.
复制标题
DOI：
10.1371/journal.pone.0029055
复制
发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Matter ML
中科院分区：
文献类型：
--
作者：
Leychenko A;Konorev E;Jijiwa M;Matter ML
高血压和心肌梗死与心肌肥厚的发生有关。肥厚是由于压力或体积过载引起的机械负荷增加的代偿反应机制。它的特点是细胞外基质重塑和成人心肌细胞肥厚生长。血管内皮生长因子（VEGF）是一种血管生成因子和心肌细胞功能调节剂，其产生受机械拉伸的调节。机械拉伸促进新生心肌细胞VEGF分泌。这种作用是否在成人细胞中保留，以及介导拉伸诱导的VEGF分泌的分子机制尚未阐明。我们的目的是研究循环机械拉伸是否诱导成人心肌细胞中VEGF的分泌，并确定在这些细胞中介导VEGF分泌的分子机制。分离的成年大鼠原代心肌细胞（ARCMs）以30周期/分钟的速度以10%的拉伸水平进行循环机械拉伸，诱导肥厚反应。与非拉伸对照组相比，循环机械拉伸诱导ARCMs中VEGF分泌增加3倍。拉伸诱导的VEGF分泌增加与NFkB激活相关。循环机械拉伸介导的VEGF分泌被NFkB肽抑制剂和显性阴性突变体IkBα的表达阻断，但不被MAPK/ERK1/2或PI3K途径的抑制剂阻断。染色质免疫沉淀试验表明，在拉伸的原代心肌细胞中，NFkB与VEGF启动子相互作用。此外，在压力超载引起的肥大过程中，被拉伸的心肌中VEGF的分泌增加。这些发现首次证明了NFkB激活在成人心肌细胞循环机械拉伸时介导VEGF分泌中起作用。因此，在成人心肌细胞中，由NFkB发起的响应周期性机械拉伸的信号传导可能会协调肥厚反应。这一新机制的阐明可能为开发未来治疗高血压和心脏病的药物治疗提供一个靶点。
Hypertension and myocardial infarction are associated with the onset of hypertrophy. Hypertrophy is a compensatory response mechanism to increases in mechanical load due to pressure or volume overload. It is characterized by extracellular matrix remodeling and hypertrophic growth of adult cardiomyocytes. Production of Vascular Endothelial Growth Factor (VEGF), which acts as an angiogenic factor and a modulator of cardiomyocyte function, is regulated by mechanical stretch. Mechanical stretch promotes VEGF secretion in neonatal cardiomyocytes. Whether this effect is retained in adult cells and the molecular mechanism mediating stretch-induced VEGF secretion has not been elucidated. Our objective was to investigate whether cyclic mechanical stretch induces VEGF secretion in adult cardiomyocytes and to identify the molecular mechanism mediating VEGF secretion in these cells. Isolated primary adult rat cardiomyocytes (ARCMs) were subjected to cyclic mechanical stretch at an extension level of 10% at 30 cycles/min that induces hypertrophic responses. Cyclic mechanical stretch induced a 3-fold increase in VEGF secretion in ARCMs compared to non-stretch controls. This increase in stretch-induced VEGF secretion correlated with NFkB activation. Cyclic mechanical stretch-mediated VEGF secretion was blocked by an NFkB peptide inhibitor and expression of a dominant negative mutant IkBα, but not by inhibitors of the MAPK/ERK1/2 or PI3K pathways. Chromatin immunoprecipitation assays demonstrated an interaction of NFkB with the VEGF promoter in stretched primary cardiomyocytes. Moreover, VEGF secretion is increased in the stretched myocardium during pressure overload-induced hypertrophy. These findings are the first to demonstrate that NFkB activation plays a role in mediating VEGF secretion upon cyclic mechanical stretch in adult cardiomyocytes. Signaling by NFkB initiated in response to cyclic mechanical stretch may therefore coordinate the hypertrophic response in adult cardiomyocytes. Elucidation of this novel mechanism may provide a target for developing future pharmacotherapy to treat hypertension and heart disease.
登录
查看更多内容
影响因子：
3.7
作者：
Gawecka JE;Griffiths GS;Ek-Rylander B;Ramos JW;Matter ML
通讯作者：
Matter ML
影响因子：
3.3
作者：
Ramanathan, Madhuri;Pinhal-Enfield, Grace;Leibovich, Samuel Joseph
通讯作者：
Leibovich, Samuel Joseph
DOI：
10.3109/10799899309073692
发表时间：
1993-01-01
期刊：
JOURNAL OF RECEPTOR RESEARCH
影响因子：
--
作者：
SADOSHIMA, J;IZUMO, S
通讯作者：
IZUMO, S
影响因子：
64.5
作者：
Rahl PB;Lin CY;Seila AC;Flynn RA;McCuine S;Burge CB;Sharp PA;Young RA
通讯作者：
Young RA
影响因子：
6
作者：
Seko, Y;Imai, Y;Yazaki, Y
通讯作者：
Yazaki, Y