Genetic Models Reveal That Brain Natriuretic Peptide Can Signal through Different Tissue-Specific Receptor-Mediated Pathways

• Published in: Endocrinology (Philadelphia) 2000-10, Vol.141 (10), p.3807-3813
• Main Authors: Chusho, Hideki, Ogawa, Yoshihiro, Tamura, Naohisa, Suda, Michio, Yasoda, Akihiro, Miyazawa, Takashi, Kishimoto, Ichiro, Komatsu, Yasato, Itoh, Hiroshi, Tanaka, Kiyoshi, Saito, Yoshihiko, Garbers, David L., Nakao, Kazuwa
• Format: Article
• Language: English
• Subjects: Amyloid P component; Animals; Atrial Natriuretic Factor - blood; Biological effects; Blood pressure; Bone and Bones - metabolism; Bone and Bones - physiology; Bones; Brain; Brain natriuretic peptide; Cardiac ventricles; Cardiovascular Physiological Phenomena; Cyclic GMP - blood; Cyclic GMP - metabolism; Cyclic GMP - urine; Endochondral bone; Guanylate cyclase; Guanylate Cyclase - deficiency; Guanylate Cyclase - genetics; Guanylate Cyclase - physiology; Heart; Heart Ventricles; Hypertrophy; Isoenzymes - genetics; Isoenzymes - physiology; Long bone; Mice; Mice, Knockout - genetics; Mice, Transgenic - genetics; Myocardium - metabolism; Natriuretic Peptide, Brain - blood; Natriuretic Peptide, Brain - genetics; Natriuretic Peptide, Brain - physiology; Osmolar Concentration; Ossification; Peptides; Phenotype; Phenotypes; Pressure effects; Receptors; Receptors, Cell Surface - physiology; Signal Transduction - physiology; Transgenic animals; Transgenic mice; Ventricles (cerebral); Vertebrae
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/endo.141.10.7692

Abstract Brain natriuretic peptide (BNP), a hormone produced primarily by the cardiac ventricle, is thought to be involved in a variety of homeostatic processes through its cognate receptor, guanylyl cyclase A (GC-A). We previously created transgenic mice overexpressing BNP under the control of the liver-specific human serum amyloid P component promoter (BNP-transgenic mice) and demonstrated that they exhibit reduced blood pressure and cardiac weight accompanied by an elevation of plasma cGMP concentrations and marked skeletal overgrowth through the activation of endochondral ossification. To address whether BNP exerts its biological effects solely through GC-A, we produced BNP-transgenic mice lacking GC-A (BNP-Tg/GC-A−/− mice) and examined their cardiovascular and skeletal phenotypes. The GC-A−/− mice are hypertensive with cardiac hypertrophy relative to wild-type littermates, which is not alleviated by overexpression of BNP in BNP-Tg/GC-A−/− mice. The BNP-Tg/GC-A−/− mice, however, continue to exhibit marked longitudinal growth of vertebrae and long bones comparably to BNP-Tg mice. This study provides genetic evidence that BNP reduces blood pressure and cardiac weight through GC-A, whereas it dramatically alters endochondral ossification in the absence of this receptor. Therefore, the BNP-Tg/GC-A−/− mice provide the first experimental model demonstrating that this natriuretic peptide can signal in a tissue-specific manner through a receptor other than GC-A.