The role of phospholamban and SERCA3 in regulation of smooth muscle-endothelial cell signalling mechanisms: evidence from gene-ablated mice.
The role of phospholamban and SERCA3 in regulation of smooth muscle-endothelial cell signalling mechanisms: evidence from gene-ablated mice.
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受磷蛋白和 SERCA3 在平滑肌内皮细胞信号传导机制调节中的作用：来自基因消除小鼠的证据。
DOI：
10.1111/j.1365-201x.1998.tb10704.x
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发表时间：
1998
期刊：
影响因子：
--
通讯作者：
Paul,RJ
中科院分区：
文献类型：
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作者：
Paul,RJ
人们普遍认为，细胞内 Ca2+ 储存，即肌（内）质网 (SER)，影响 Ca2+ 稳态，从而影响血管平滑肌的收缩性。然而，对于 SER 对 Ca2+ 处理的贡献程度、SER Ca2+-ATP 酶 (SERCA) 亚型的基础或 SER 相关调节蛋白受磷蛋白 (PLB) 的作用，尚未达成普遍共识。尽管 SER 的生化和细胞生物学作用已在体外得到深入研究，但基因靶向和转基因小鼠模型的发展使我们能够将我们的信息扩展到体内水平。简要回顾了 PLB 和 SERCA 功能在血管和内皮细胞功能中的作用。对 PLB 基因缺失小鼠的研究表明，血管收缩力发生了显着改变。这反映在细胞内 Ca2+ 的变化上。此外，通过环匹阿尼酸治疗消除了基因消除组织的收缩性差异，环匹阿尼酸通过抑制 Ca2+-ATP 酶在药理学上消除了 SER 功能。因此，PLB 对肌浆网 (SR) Ca2+ 摄取的调节在调节血管收缩性中起着重要作用。有趣的是，在 PLB 缺陷的主动脉中，内皮依赖性舒张减少了。鉴于 PLB 分布被认为仅限于心脏、慢骨骼肌和平滑肌，这是令人惊讶的。我们的数据表明内皮细胞中存在 PLB，并指出了一条未被识别的内皮细胞 [Ca2+] 和血管收缩性调节途径。来自 SERCA3 基因消除小鼠平滑肌组织的数据表明，这种异构体影响内皮依赖性功能，但不影响平滑肌功能，与其已知的分布一致。该异构体似乎执行调节功能，而不是 SERCA2 更重要的作用。基因靶向和转基因模型为理解 SER 在血管信号传导中的作用提供了重要途径。
It is generally agreed that intracellular Ca2+stores, the sarco(endo)plasmic‐reticulum (SER), affect Ca2+homeostasis and thus contractility of vascular smooth muscle. There is, however, no general consensus as to the magnitude of the SER contribution to Ca2+handling, the basis for isoforms of the SER Ca2+‐ATPases (SERCAs) or the role of an SER‐associated regulatory protein, phospholamban (PLB). Although the biochemical and cell biological roles of the SER have been intensely studiedin vitro, the development of gene‐targeted and transgenic mouse models enables one to extend our information to thein vivolevels. A brief review of the role of PLB and SERCA function in vascular and endothelial cell function is presented. Studies on the PLB gene‐ablated mouse indicate that vascular contractility is considerably altered. This is mirrored by changes in intracellular Ca2+. Moreover, differences in contractility of the gene‐ablated tissues are eliminated by treatment with cyclopiazonic acid, which pharmacologically abolishes SER function by inhibiting the Ca2+‐ATPase. Thus PLB modulation of sarcoplasmic reticulum (SR) Ca2+uptake plays a major role in modulating vascular contractility. It is interesting that endothelium‐dependent relaxation was decreased in the PLB‐deficient aorta. This is surprising in light of the PLB distribution, thought to be limited to cardiac, slow skeletal and smooth muscle. Our data indicate the presence of PLB in endothelial cells and point to an unrecognized pathway for modulation of endothelial cell [Ca2+]iand vascular contractility. Data from smooth muscle tissues of the SERCA3 gene‐ablated mouse demonstrate that this isoform affects endothelium‐dependent function, but not that of smooth muscle, consistent with its known distribution. This isoform appears to perform a modulatory function, rather than the more essential role of SERCA2. Gene‐targeted and transgenic models provide an important avenue for understanding the role of SER in vascular signalling.