c-kit dysfunction impairs myocardial healing after infarction
c-kit dysfunction impairs myocardial healing after infarction
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DOI：
10.1161/circulationaha.107.708107
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发表时间：
2007-09-11
期刊：
影响因子：
37.8
通讯作者：
Li, Ren-Ke
中科院分区：
文献类型：
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作者：
Cimini, Massimo;Fazel, Shafie;Li, Ren-Ke
背景 - 我们假设骨髓中的 c-kit 受体功能对于促进愈合非常重要，从而导致心肌梗死 (MI) 后有效的心脏修复。方法和结果 - 我们使用 Kit(W)/Kit(W-v) c-kit 突变小鼠及其野生型同窝小鼠来评估 c-kit 功能在冠状动脉结扎后心脏重塑中的重要性。我们发现突变小鼠的心室扩张增加了 1.6 倍（P = 0.008），这归因于 MI 后第 14 天梗塞扩张增加了 1.3 倍（P = 0.01）。第3天，突变小鼠中增殖的平滑肌α-肌动蛋白表达细胞的数量减少了1.8倍（P < 0.01），导致通过显微镜和流式细胞术检测，区域非血管平滑肌α-肌动蛋白表达细胞总数减少了1.6至1.8倍（两者均P < 0.001）。这种减少伴随着表达 CD31 的血管数量减少 1.4 倍 (P < 0.05)。先前将野生型骨髓细胞移植到突变小鼠体内，通过诱导非血管平滑肌α-肌动蛋白表达细胞和表达CD31的血管增加1.5倍，挽救了富含血管的修复组织的有效建立（两者P <0.05）。与野生型水平相比，嵌合小鼠梗塞区域中细胞募集的增加与梗塞扩张的减少相关（P < 0.03）。 结论 - 骨髓 c-kit 功能严重影响梗塞心脏中的肌成纤维细胞修复反应。增加 c-kit(+) 细胞对梗塞心脏的浸润的干预措施可能会增强这种内源性修复反应，防止梗塞扩大，并改善 MI 后心功能的恢复。
Background - We hypothesized that c-kit receptor function in the bone marrow is important for facilitating healing, leading to efficient cardiac repair after myocardial infarction (MI).Methods and Results - We used Kit(W)/Kit(W-v) c-kit mutant mice and their wild-type littermates to assess the importance of c-kit function in cardiac remodeling after coronary ligation. We found that mutant mice developed 1.6-fold greater ventricular dilation (P = 0.008) attributable to a 1.3-fold greater infarct expansion by day 14 after MI (P = 0.01). The number of proliferating smooth muscle alpha-actin expressing cells was 1.8-fold lower in mutant mice at day 3 (P < 0.01), resulting in a 1.6 to 1.8-fold reduction in total regional nonvascular smooth muscle alpha-actin expressing cells by both microscopy and flow cytometry (P < 0.001 for both). This decrease was accompanied by a 1.4-fold reduction in the number of CD31 expressing blood vessels (P < 0.05). Prior transplantation of wild-type bone marrow cells into mutant mice rescued the efficient establishment of vessel-rich repair tissue by inducing a 1.5-fold increase in nonvascular smooth muscle alpha-actin expressing cells and CD31 expressing blood vessels (P < 0.05 for both). The increased recruitment of cells into the infarct region in the chimeric mice was associated with reduced infarct expansion (P < 0.03) compared to wild-type levels.Conclusions - Bone marrow c-kit function critically impacts the myofibroblast repair response in infarcted hearts. Interventions that increase the infiltration of c-kit(+) cells to the infarcted heart may potentiate this endogenous repair response, prevent infarct expansion, and improve the recovery of cardiac function after MI.