Department of Cell and Molecular Biology and Center for Cardiovascular Research, John A Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, United States of America.
PLoS One. 2011;6(12):e29055. doi: 10.1371/journal.pone.0029055. Epub 2011 Dec 13.
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.
高血压和心肌梗死与肥大的发生有关。肥大是一种对压力或容量超负荷引起的机械负荷增加的代偿反应机制。其特征是细胞外基质重塑和成年心肌细胞的肥大生长。血管内皮生长因子（VEGF）的产生受机械拉伸调节，VEGF 作为一种血管生成因子和心肌细胞功能的调节剂。机械拉伸促进新生儿心肌细胞中 VEGF 的分泌。这种效应是否在成年细胞中保留，以及介导拉伸诱导的 VEGF 分泌的分子机制尚未阐明。我们的目的是研究周期性机械拉伸是否诱导成年心肌细胞中 VEGF 的分泌，并确定介导这些细胞中 VEGF 分泌的分子机制。将分离的原代成年大鼠心肌细胞（ARCMs）在 30 个循环/分钟的 10%伸展水平下进行周期性机械拉伸，以诱导肥大反应。与非拉伸对照相比，周期性机械拉伸使 ARCMs 中的 VEGF 分泌增加了 3 倍。这种拉伸诱导的 VEGF 分泌增加与 NFkB 激活相关。NFkB 肽抑制剂和显性负突变 IkBα的表达阻断了周期性机械拉伸介导的 VEGF 分泌，但 MAPK/ERK1/2 或 PI3K 途径的抑制剂则没有。染色质免疫沉淀分析表明，NFkB 与伸展的原代心肌细胞中 VEGF 启动子相互作用。此外，在压力超负荷诱导的肥大期间，伸展的心肌中的 VEGF 分泌增加。这些发现首次证明，NFkB 激活在成年心肌细胞中周期性机械拉伸时介导 VEGF 分泌中起作用。因此，对 NFkB 的信号转导可能在成年心肌细胞的肥大反应中起协调作用。阐明这种新的机制可能为开发未来治疗高血压和心脏病的药物治疗提供靶点。
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