Involvement of the NF-kappa B/matrix metalloproteinase pathway in cardiac fibrosis of mice lacking guanylyl cyclase/natriuretic peptide receptor A.
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-beta1, 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-beta1, 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.
Vellaichamy
Elangovan
E
Department of Physiology and Hypertension and Renal Center of Excellence, Tulane University Health Sciences Center, School of Medicine, New Orleans, Louisiana 70112, USA.
Khurana
Madan L
ML
Fink
Jude
J
Pandey
Kailash N
KN
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure; D015152:Blotting, Northern; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D003094:Collagen / Q000737:chemistry / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D003720:Densitometry; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005109:Extracellular Matrix / Q000378:metabolism; D005355:Fibrosis; D005819:Genetic Markers; D005838:Genotype; D006162:Guanylate Cyclase / Q000235:genetics* / Q000502:physiology*; D006352:Heart Ventricles / Q000378:metabolism; D006720:Homozygote; D006909:Hydroxyproline / Q000737:chemistry; D051550:I-kappa B Kinase; D007249:Inflammation; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009154:Mutation; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology*; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics* / Q000502:physiology*; D011995:Recombination, Genetic; D012260:Ribonucleases / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
D000959:Antihypertensive Agents; D004791:Enzyme Inhibitors; D005819:Genetic Markers; D016328:NF-kappa B; D020033:Protein Isoforms; D014409:Tumor Necrosis Factor-alpha; D003094:Collagen; D017346:Protein Serine-Threonine Kinases; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse; D012260:Ribonucleases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A; D006152:Cyclic GMP; D006909:Hydroxyproline