Genetic models reveal that brain natriuretic peptide can signal through different tissue-specific receptor-mediated pathways

被引:31
作者
Chusho, H
Ogawa, Y
Tamura, N
Suda, M
Yasoda, A
Miyazawa, T
Kiskimoto, I
Komatsu, Y
Itoh, H
Tanaka, K
Saito, Y
Garbers, DL
Nakao, K
机构
[1] Kyoto Univ, Grad Sch Med, Dept Med & Clin Sci, Sakyo Ku, Kyoto 6068507, Japan
[2] Univ Texas, SW Med Ctr, Howard Hughes Med Inst, Dallas, TX 75235 USA
[3] Univ Texas, SW Med Ctr, Dept Pharmacol, Dallas, TX 75235 USA
关键词
D O I
10.1210/en.141.10.3807
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
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页码:3807 / 3813
页数:7
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