Smooth muscle cell-extrinsic vascular spasm arises from cardiomyocyte degeneration in sarcoglycan-deficient cardiomyopathy.
Smooth muscle cell-extrinsic vascular spasm arises from cardiomyocyte degeneration in sarcoglycan-deficient cardiomyopathy.
复制标题
平滑肌细胞外源性血管痉挛是由肌聚糖缺陷型心肌病中的心肌细胞变性引起的。
DOI：
10.1172/jci20410
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发表时间：
2004
期刊：
影响因子：
--
通讯作者：
McNally,ElizabethM
中科院分区：
文献类型：
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作者：
Wheeler,MatthewT;Allikian,MichaelJ;Heydemann,Ahlke;Hadhazy,Michele;Zarnegar,Sara;McNally,ElizabethM
血管痉挛是一个知之甚少，但关键的生物医学过程，因为它 会严重减少血液供应和组织氧合。小鼠心肌病 缺乏γ-肌聚糖或δ-肌聚糖的特征在于 局部损伤在心脏中，肌聚糖基因突变产生区域性 膜通透性和局灶性变性的缺陷，并假设 血管痉挛导致了局灶性坏死支持这一 概念，在冠状动脉中观察到血管痉挛， 在血管平滑肌中观察到肌聚糖复合物， 痉挛的机制使用转基因拯救策略， 在肌聚糖缺失小鼠中，我们替换了心肌细胞肌聚糖表达。 心肌细胞特异性肌聚糖的表达足以纠正心脏 局灶性变性有趣的是，心肌细胞的成功恢复 肌聚糖复合物也消除冠状动脉血管痉挛， 肌聚糖缺失背景下平滑肌肌聚糖的恢复 等位基因则没有。组织损伤导致血管痉挛的机制， 可以通过NO合酶抑制剂部分纠正。因此，我们建议 从受损心肌细胞释放的细胞因子可以反馈到产生血管 痉挛此外，血管痉挛会产生额外的心脏 损害
Vascular spasm is a poorly understood but critical biomedical process because it can acutely reduce blood supply and tissue oxygenation. Cardiomyopathy in mice lacking γ-sarcoglycan or δ-sarcoglycan is characterized by focal damage. In the heart, sarcoglycan gene mutations produce regional defects in membrane permeability and focal degeneration, and it was hypothesized that vascular spasm was responsible for this focal necrosis. Supporting this notion, vascular spasm was noted in coronary arteries, and disruption of the sarcoglycan complex was observed in vascular smooth muscle providing a molecular mechanism for spasm. Using a transgene rescue strategy in the background of sarcoglycan-null mice, we replaced cardiomyocyte sarcoglycan expression. Cardiomyocyte-specific sarcoglycan expression was sufficient to correct cardiac focal degeneration. Intriguingly, successful restoration of the cardiomyocyte sarcoglycan complex also eliminated coronary artery vascular spasm, while restoration of smooth muscle sarcoglycan in the background of sarcoglycan-null alleles did not. This mechanism, whereby tissue damage leads to vascular spasm, can be partially corrected by NO synthase inhibitors. Therefore, we propose that cytokine release from damaged cardiomyocytes can feed back to produce vascular spasm. Moreover, vascular spasm feeds forward to produce additional cardiac damage.