MK5 haplodeficiency decreases collagen deposition and scar size during post-myocardial infarction wound repair
MK5 haplodeficiency decreases collagen deposition and scar size during post-myocardial infarction wound repair
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DOI：
10.1152/ajpheart.00532.2017
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发表时间：
2019-06-01
影响因子：
4.8
通讯作者：
Allen, Bruce G.
中科院分区：
文献类型：
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作者：
Nawaito, Sherin Ali;Sahadevan, Pramod;Allen, Bruce G.
MK5 是一种由 p38、ERK3 和 ERK4 MAPK 激活的蛋白丝氨酸/苏氨酸激酶。在小鼠心脏成纤维细胞中检测到 MK5 mRNA 和免疫反应性。 MK5 单倍体缺陷会减弱压力超负荷引起的胶原蛋白 1-al mRNA 的增加。本研究探讨了 MK5 单倍体缺陷对心肌梗死 (MI) 后修复性纤维化的影响。十二周大的 MK5(+/-) 和野生型同窝小鼠 (MK5(+/+)) 接受左冠状动脉前降支 (LADL) 结扎。存活的小鼠在 MI 后 8 或 21 天被安乐死。 MK5+/- 和 MK5(+/-) 小鼠的存活率没有显着差异，左心室壁破裂是死亡的主要原因。超声心动图显示 LADL-MK5(+/+) 和 LADL:MK5(+/+) 小鼠的 LV 舒张末期直径、心肌性能指数和室壁运动评分指数有类似的增加。 LADL-MK5(+/+) 和 LADL-MK5(+/-) 心脏之间的风险面积没有差异。相比之下，LADL-MK5(+/-) 心脏中的梗塞面积、疤痕面积和疤痕胶原含量均减少。对经历心脏破裂的小鼠进行的免疫组织化学分析显示，与 LADL-MK5(+/+) 相比，LADL-MK5(+/-) 心脏梗塞边缘区的 MMP-9 免疫反应性增加。尽管LADL-MK5(+/+)和LADL-MK5(+/-)心脏中的炎症细胞浸润相似，但血管生成在LADL-MK5(+/-)小鼠的梗塞边界区更为明显。心室成纤维细胞的表征显示，与野生型和单倍体缺陷小鼠相比，从 MK5(-/-) 小鼠中分离的成纤维细胞的运动性和增殖能力降低。野生型小鼠成纤维细胞中 siRNA 介导的 MK5 敲除也会损害运动性。因此，MK5 表达减少会改变成纤维细胞功能和疤痕形态，但不会改变 MI 后的死亡率。新的和值得注意的 MK5/PRAK 是一种由 p38 MAPK 和/或非典型 MAPK ERK3/4 激活的蛋白丝氨酸/苏氨酸激酶。 MK5 单倍体缺陷减少了心肌梗塞后的梗塞面积、疤痕面积和疤痕胶原含量。培养的 MK5 缺失的心肌成纤维细胞的运动和增殖均降低。
MK5 is a protein serine/threonine kinase activated by p38, ERK3, and ERK4 MAPKs. MK5 mRNA and immunoreactivity are detected in mouse cardiac fibroblasts. and MK5 haplodeficiency attenuates the increase in collagen 1-al mRNA evoked by pressure overload. The present study examined the effect of MK5 haplodeficiency on reparative fibrosis following myocardial infarction (MI). Twelve-week-old MK5(+/-) and wild-type littermate (MK5(+/+)) mice underwent ligation of the left anterior descending coronary artery (LADL). Surviving mice were euthanized 8 or 21 days post-MI. Survival rates did not differ significantly between MK5+/ - and MK5(+/-) mice, with rupture of the LV wall being the primary cause of death. Echocardiographic imaging revealed similar increases in LV end-diastolic diameter, myocardial performance index, and wall motion score index in LADL-MK5(+/+) and LADL: MK5(+/+) mice. Area at risk did not differ between LADL-MK5(+/+) and LADL-MK5(+/-) hearts. In contrast, infarct size, scar area, and scar collagen content were reduced in LADL-MK5(+/-) hearts. Immunohistochemical analysis of mice experiencing heart rupture revealed increased MMP-9 immunoreactivity in the infarct border zone of LADL-MK5(+/-) hearts compared with LADL-MK5(+/+). Although inflammatory cell infiltration was similar in LADL-MK5(+/+) and LADL-MK5(+/-) hearts, angiogenesis was more pronounced in the infarct border zone of LADL-MK5(+/-) mice. Characterization of ventricular fibroblasts revealed reduced motility and proliferation in fibroblasts isolated from MK5(-/-) mice compared with those from both wild-type and haplodeficient mice. siRNA-mediated knockdown of MK5 in fibroblasts from wild-type mice also impaired motility. Hence, reduced MK5 expression alters fibroblast function and scar morphology but not mortality post-MI.NEW & NOTEWORTHY MK5/PRAK is a protein serine/threonine kinase activated by p38 MAPK and/or atypical MAPKs ERK3/4. MK5 haplodeficiency reduced infarct size, scar area, and scar collagen content post-myocardial infarction. Motility and proliferation were reduced in cultured MK5-null cardiac myofibroblasts.