PDF(Pubmed)
Abstract：
ERK3/MAPK6 activates MAP kinase-activated protein kinase (MK)-5 in selected cell types. Male MK5 haplodeficient mice show reduced hypertrophy and attenuated increase in Col1a1 mRNA in response to increased cardiac afterload. In addition, MK5 deficiency impairs cardiac fibroblast function. This study determined the effect of reduced ERK3 on cardiac hypertrophy following transverse aortic constriction (TAC) and fibroblast biology in male mice. Three weeks post-surgery, ERK3, but not ERK4 or p38α, co-immunoprecipitated with MK5 from both sham and TAC heart lysates. The increase in left ventricular mass and myocyte diameter was lower in TAC-ERK3+/- than TAC-ERK3+/+ hearts, whereas ERK3 haploinsufficiency did not alter systolic or diastolic function. Furthermore, the TAC-induced increase in Col1a1 mRNA abundance was diminished in ERK3+/- hearts. ERK3 immunoreactivity was detected in atrial and ventricular fibroblasts but not myocytes. In both quiescent fibroblasts and \"activated\" myofibroblasts isolated from adult mouse heart, siRNA-mediated knockdown of ERK3 reduced the TGF-β-induced increase in Col1a1 mRNA. In addition, intracellular type 1 collagen immunoreactivity was reduced following ERK3 depletion in quiescent fibroblasts but not myofibroblasts. Finally, knocking down ERK3 impaired motility in both atrial and ventricular myofibroblasts. These results suggest that ERK3 plays an important role in multiple aspects of cardiac fibroblast biology.
摘要：
ERK3/MAPK6在选定的细胞类型中激活MAP激酶激活的蛋白激酶(MK)-5。雄性MK5单倍体缺陷小鼠对心脏后负荷增加的反应显示出减少的肥大和减少的Col1a1mRNA增加。此外,MK5缺乏损害心脏成纤维细胞功能。这项研究确定了减少的ERK3对雄性小鼠中横主动脉缩窄（TAC）和成纤维细胞生物学后心脏肥大的影响。手术后三周,ERK3，但不是ERK4或p38α，与来自假手术和TAC心脏裂解物的MK5共免疫沉淀。TAC-ERK3+/-心脏左心室质量和心肌细胞直径的增加低于TAC-ERK3+/+心脏，而ERK3单倍功能不全不改变收缩或舒张功能。此外，在ERK3+/-心脏中，TAC诱导的Col1a1mRNA丰度增加减少。在心房和心室成纤维细胞中检测到ERK3免疫反应性，但在肌细胞中未检测到。在从成年小鼠心脏分离的静止成纤维细胞和“活化成肌成纤维细胞中，siRNA介导的ERK3敲低降低了TGF-β诱导的Col1a1mRNA的增加。此外,在静止的成纤维细胞而不是肌成纤维细胞中的ERK3消耗后，细胞内1型胶原免疫反应性降低。最后,敲除ERK3受损的心房和心室肌成纤维细胞的运动。这些结果表明，ERK3在心脏成纤维细胞生物学的多个方面发挥着重要作用。
