Kern Christine B, Norris Russell A, Thompson Robert P, Argraves W Scott, Fairey Sarah E, Reyes Leticia, Hoffman Stanley, Markwald Roger R, Mjaatvedt Corey H
Department of Cell Biology and Anatomy, Medical University of South Carolina, Charleston, SC 29425-2204, USA.
Dev Dyn. 2007 Mar;236(3):671-83. doi: 10.1002/dvdy.21059.
An important phase of cardiac outflow tract (OFT) formation is the remodeling of the distal region of the common outlet in which the myocardial sleeve is replaced by with smooth muscle. Here we demonstrate that expression of the proteoglycan versican is reduced before the loss of myocardium from the distal cardiac outlet concomitant with an increase in production of the N-terminal cleavage fragment of versican. To test whether versican proteolysis plays a role in OFT remodeling, we determined the effects of adenoviral-mediated expression of a versican isoform devoid of known matrix metalloproteinase cleavage sites (V3) and an N-terminal fragment of versican (G1). V3 expression promoted an increase in thickness of the proximal OFT myocardial layer independent of proliferation. In contrast, the G1 domain caused thinning and interruptions of the OFT myocardium. These in vivo findings were consistent with findings using cultured primary cardiomyocytes showing that the V3 promoted myocardial cell-cell association while the G1 domain caused a loss of myocardial cell-cell association. Taken together, we conclude that intact versican and G1-containing versican cleavage products have opposing effects on myocardial cells and that versican proteolysis may facilitate the loss of distal myocardium during OFT remodeling.
心脏流出道（OFT）形成的一个重要阶段是共同出口远端区域的重塑，在此过程中，心肌套被平滑肌所取代。我们在此证明，在远端心脏出口处心肌丧失之前，蛋白聚糖多功能蛋白聚糖的表达降低，同时多功能蛋白聚糖N端裂解片段的产生增加。为了测试多功能蛋白聚糖蛋白水解是否在OFT重塑中起作用，我们确定了腺病毒介导的缺乏已知基质金属蛋白酶裂解位点的多功能蛋白聚糖异构体（V3）和多功能蛋白聚糖N端片段（G1）表达的影响。V3表达促进近端OFT心肌层厚度增加，且与增殖无关。相反，G1结构域导致OFT心肌变薄和中断。这些体内研究结果与使用原代培养心肌细胞得到的结果一致，即V3促进心肌细胞间结合，而G1结构域导致心肌细胞间结合丧失。综上所述，我们得出结论，完整的多功能蛋白聚糖和含G1的多功能蛋白聚糖裂解产物对心肌细胞具有相反的作用，并且多功能蛋白聚糖蛋白水解可能有助于OFT重塑过程中远端心肌的丧失。
