科研之友
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摘要
TNF-alpha plays a mediator role in the pathogenesis of chronic heart failure contributing to cardiac remodeling and peripheral vascular disturbances. The implication of TNF-a in inflammatory responses has been shown to be mediated through up-regulation of matrix metalloproteinase-9 (MMP-9). However, the detailed mechanisms of TNF-alpha-induced MMP-9 expression in rat embryonic-heart derived H9c2 cells are largely not defined. We demonstrated that in H9c2 cells, TNF-alpha induced MMP-9 mRNA and protein expression associated with an increase in the secretion of pro-MMP-9. TNF-a-mediated responses were attenuated by pretreatment with the inhibitor of ROS (N-acetyl-L-cysteine, NAC), NADPH oxidase [apocynin (APO) or diphenyleneiodonium chloride (DPI)], MEK1/2 (U0126), p38 MAPK (SB202190), JNK1/2 (SP600125), NF-kappa B (Bayll-7082), or PYK2 (PF-431396) and transfection with siRNA of TNFR1, p47Ph, p42, p38, JNK1, p65, or PYK2. Moreover, TNF-alpha markedly induced NADPH oxidase-derived ROS generation in these cells. TNF-alpha-enhanced p42/p44 MAPK, p38 MAPK, JNK1/2, and NF-kappa B (p65) phosphorylation and in vivo binding of p65 to the MMP-9 promoter were inhibited by U0126, SB202190, SP600125, NAC, DPI, or APO. In addition, TNF-alpha-mediated PYK2 phosphorylation was inhibited by NAC, DPI, or APO. PYK2 inhibition could reduce TNF-alpha-stimulated MAPKs and NF-kappa B activation. Thus, in H9c2 cells, we are the first to show that TNF-alpha-induced MMP-9 expression is mediated through a TNFR1/NADPH oxidase/ROS/PYK2/MAPKs/NF-kappa B cascade. We demonstrated that NADPH oxidase-derived ROS generation is involved in TNF-alpha-induced PYK2 activation in these cells. Understanding the regulation of MMP-9 expression and NADPH oxidase activation by TNF-alpha on H9c2 cells may provide potential therapeutic targets of chronic heart failure.
- 出版日期2013-10-15
- 单位长春大学
