Involvement of the NF-κB/matrix metalloproteinase pathway in cardiac fibrosis of mice lacking guanylyl cyclase/natriuretic peptide receptor A
Involvement of the NF-κB/matrix metalloproteinase pathway in cardiac fibrosis of mice lacking guanylyl cyclase/natriuretic peptide receptor A
复制标题
DOI：
10.1074/jbc.m411373200
复制
发表时间：
2005-05-13
影响因子：
4.8
通讯作者：
Pandey, KN
中科院分区：
文献类型：
--
作者：
Vellaichamy, E;Khurana, ML;Pandey, KN
携带 Npr1 基因（编码鸟苷酸环化酶/利钠肽受体 A (NPRA)）的靶向破坏的小鼠表现出血压升高、心脏肥大和充血性心力衰竭，与未经治疗的人类高血压患者相似。本研究的目的是确定小鼠中 NPRA 信号传导的永久消除是否会改变基质金属蛋白酶 (MMP)-2 和 MMP-9 以及肿瘤坏死因子-α (TNF-α) 等促炎介质的表达，从而导致心肌胶原重塑。在这里，我们报告，与野生型（Npr1（+/+））对照小鼠心脏相比，Npr1纯合无效突变体（Npr1（-/-））小鼠心脏中MMP-2和MMP-9基因的表达水平增加了3-5倍，TNF-α基因的表达水平增强了8倍。与年龄匹配的野生型小鼠相比，成年 Npr1(-/-) 小鼠的心肌纤维化、总胶原蛋白和 I/III 型胶原蛋白比率 (p < 0.01) 显着增加。肥大标记基因，包括β-肌球蛋白重链和转化生长因子-β1，在年轻和成年Npr1(-/-)小鼠心脏中显着上调（3-5倍）。在 Npr1(-/-) 小鼠中，随着 p65 亚基从细胞质到核部分的易位增加，心室组织中的 NF-κ B 结合活性增强了 4 倍。我们的结果表明，减少 NPRA 信号传导会激活 Npr1(-/-) 小鼠心脏中的 MMP、转化生长因子-β 1 和 TNF-α 表达。这项研究的结果表明，NPRA/cGMP 信号传导的破坏会促进肥厚性生长和细胞外基质重塑，从而导致心脏肥大、心肌纤维化和充血性心力衰竭的发展。
Mice carrying a targeted disruption of the Npr1 gene (coding for guanylyl cyclase/natriuretic peptide receptor A (NPRA)) exhibit increased blood pressure, cardiac hypertrophy, and congestive heart failure, similar to untreated human hypertensive patients. The objective of this study was to determine whether permanent ablation of NPRA signaling in mice alters the expression of matrix metalloproteinase (MMP)-2 and MMP-9 and pro-inflammatory mediators such as tumor necrosis factor-alpha (TNF-alpha), leading to myocardial collagen remodeling. Here, we report that expression levels of the MMP-2 and MMP-9 genes were increased by 3-5-fold and that the expression of the TNF-alpha gene was enhanced by 8-fold in Npr1 homozygous null mutant (Npr1(-/-)) mouse hearts compared with wild-type (Npr1(+/+)) control mouse hearts. Myocardial fibrosis, total collagen, and the collagen type I/III ratio (p < 0.01) were dramatically increased in adult Npr1(-/-) mice compared with age-matched wild-type counterparts. Hypertrophic marker genes, including the beta-myosin heavy chain and transforming growth factor-beta 1, were significantly up-regulated (3-5-fold) in both young and adult Npr1(-/-) mouse hearts. NF-kappa B binding activity in ventricular tissues was enhanced by 4-fold with increased translocation of the p65 subunit from the cytoplasmic to nuclear fraction in Npr1(-/-) mice. Our results show that reduced NPRA signaling activates MMP, transforming growth factor-beta 1, and TNF-alpha expression in Npr1(-/-) mouse hearts. The findings of this study demonstrate that disruption of NPRA/cGMP signaling promotes hypertrophic growth and extracellular matrix remodeling, leading to the development of cardiac hypertrophy, myocardial fibrosis, and congestive heart failure.