VENTRICULAR EXPRESSION OF A MLC-2V-RAS FUSION GENE INDUCES CARDIAC-HYPERTROPHY AND SELECTIVE DIASTOLIC DYSFUNCTION IN TRANSGENIC MICE
VENTRICULAR EXPRESSION OF A MLC-2V-RAS FUSION GENE INDUCES CARDIAC-HYPERTROPHY AND SELECTIVE DIASTOLIC DYSFUNCTION IN TRANSGENIC MICE
复制标题
DOI：
10.1074/jbc.270.39.23173
复制
发表时间：
1995-09-29
影响因子：
4.8
通讯作者：
CHIEN, KR
中科院分区：
文献类型：
--
作者：
HUNTER, JJ;TANAKA, N;CHIEN, KR
p21（ras）与培养的心肌细胞对特定生长刺激的肥厚反应有关。为了确定ras依赖的细胞内信号通路的激活是否足以诱导体内肥厚，我们创建了在心室中表达致癌ras的转基因小鼠。转基因纯合子小鼠表现出心肌肥大的形态、生理和遗传标记。小型化导管技术记录了心脏舒张的选择性延长，类似于早期人类肥厚性心脏病，左心房肿块增加，在没有转基因表达的情况下，进一步支持了左心室舒张功能的生理异常。组织学分析显示心肌纤维紊乱，与人类肥厚性心肌病无法区分。这些研究建立了肥厚性心脏病的ras依赖通路，并通过对基因操纵小鼠进行体内微生理分析，证明了绘制心脏肥厚和功能障碍的体内信号通路的可行性。ras依赖通路也可能是开发新方法来抑制某些病理条件下肥厚发生的合理目标。
p21(ras) has been implicated in the hypertrophic response of cultured cardiac myocytes to defined growth stimuli, To determine if activation of ras-dependent intracellular signaling pathways is sufficient to induce in vivo hypertrophy, transgenic mice were created that express oncogenic ras in the cardiac ventricular chamber. Mice homozygous for the transgene displayed morphological, physiological, and genetic markers of marked cardiac muscle hypertrophy. Miniaturized catheterization technology documented a selective prolongation of cardiac relaxation, similar to that seen in early human hypertrophic heart disease, An increase in left atrial mass, in the absence of transgene expression in that chamber, further supported physiologically abnormal left ventricular diastolic function. Histological analysis revealed myofibrillar disarray, indistinguishable from that in hypertrophic cardiomyopathy in man, These studies establish a ras-dependent pathway for hypertrophic heart disease and document the feasibility of mapping in vivo signaling pathways for cardiac hypertrophy and dysfunction by applying in vivo micro-physiological assays to genetically manipulated mice, ras-dependent pathways may also be a rational target for developing new approaches to inhibit the genesis of hypertrophy in certain pathological settings.