Brain Natriuretic Peptide Is Produced in Cardiac Fibroblasts and Induces Matrix Metalloproteinases

• Published in: Circulation research Vol. 91; no. 12; pp. 1127 - 1134
• Main Authors: Tsuruda, Toshihiro, Boerrigter, Guido, Huntley, Brenda K, Noser, Josh A, Cataliotti, Alessandro, Costello-Boerrigter, Lisa C, Chen, Horng H, Burnett, John C
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 13.12.2002; Lippincott; Lippincott Williams & Wilkins Ovid Technologies
• Subjects: Animals; Biological and medical sciences; Cells, Cultured; Collagen - biosynthesis; Culture Media, Conditioned - chemistry; Culture Media, Conditioned - metabolism; Cyclic GMP - analogs & derivatives; Cyclic GMP - metabolism; Cyclic GMP - pharmacology; Cyclic GMP-Dependent Protein Kinases - antagonists & inhibitors; Cyclic GMP-Dependent Protein Kinases - metabolism; Dogs; Enzyme Induction - drug effects; Enzyme Induction - physiology; Enzyme Inhibitors - pharmacology; Fibroblasts - cytology; Fibroblasts - drug effects; Fibroblasts - metabolism; Fundamental and applied biological sciences. Psychology; Heart; Heart Ventricles - cytology; Immunohistochemistry; Matrix Metalloproteinases - metabolism; Natriuretic Peptide, Brain - genetics; Natriuretic Peptide, Brain - metabolism; Natriuretic Peptide, Brain - pharmacology; Nerve Tissue Proteins - analysis; Nerve Tissue Proteins - metabolism; Proline - metabolism; Proline - pharmacokinetics; Radioimmunoassay; RNA, Messenger - metabolism; Signal Transduction - drug effects; Signal Transduction - physiology; Vertebrates: cardiovascular system; Heart; Cell culture; remodeling; cardiac fibroblasts; Metalloendopeptidases; cGMP; Biosynthesis; Enzymatic activity; Extracellular matrix; protein kinase G; Dog; Fissipedia; Brain natriuretic peptide; Carnivora; Enzyme; Transferases; 3',5'-GMP; Gene expression; In vitro; Peptidases; Vertebrata; Mammalia; Protein kinase; Animal; Hydrolases; Circulatory system; Fibroblast
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.0000046234.73401.70

ABSTRACT—Cardiac fibroblasts (CFs) produce extracellular matrix proteins and participate in the remodeling of the heart. It is unknown if brain natriuretic peptide (BNP) is synthesized by CFs and if BNP participates in the regulation of extracellular matrix turnover. In this study, we examined the production of BNP in adult canine CFs and the role of BNP and its signaling system on collagen synthesis and on the activation of matrix metalloproteinases (MMPs). BNP mRNA was detected in CFs, and a specific radioimmunoassay demonstrated that BNP1-32 was secreted into the media at a rate of 11.2±1.0 pg/10 cells per 48 hours (mean±SEM). The amount of BNP secretion was significantly (P <0.01) augmented by 10 mol/L tumor necrosis factor-α in a time-dependent manner. BNP significantly (P <0.01) inhibited de novo collagen synthesis as assessed by [H]proline incorporation, whereas zymographic MMP-2 (gelatinase) abundance was significantly (P <0.05) stimulated by BNP between 10 and 10 mol/L. In addition, protein expression of MMP-1, -2, and -3 and membranous type-1 MMP was significantly increased by 10 mol/L BNP. The cGMP analogue 8-bromo-cGMP (10 mol/L) mimicked the BNP effect, whereas inhibition of protein kinase G by KT5823 (10 mol/L) significantly (P <0.05) attenuated BNP-induced zymographic MMP-2 abundance. In summary, this study reports that BNP is present in cultured CFs and that BNP decreases collagen synthesis and increases MMPs via cGMP–protein kinase G signaling. These in vitro findings support a role for BNP as a regulator of myocardial structure via control of cardiac fibroblast function.