Multi-center research on molecular mechanism of cardiovascular remodeling using genetically-engineered animals

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We have been investigating the role of vasoactive substances produced within the heart and blood vessels (cardiovascular hormones) in cardiovascular remodeling and proposed the concept of "cardiovascular endocrinology and metabolism". We elucidated that ANP and BNP are secreted from the atrium and the ventricle of the heart, respectively, while CNP is secreted from the endothelial cell to act as an endothelium-derived vasorelaxing peptide. Our co-investigators also elucidated that the blood vessels produce potent vasoconstrictors, angiotensin II and endothelin. We also cloned the receptors for natriuretic peptides, angiotensin II and endothelin. In the present research, we developed genetically engineered animals, that is, knock-out mice (K/O) and transgenic mice (Tg) for these cardiovascular hormones and their receptors, and cross-bled them to see the interaction of these substances for cardiovascular remodeling in cooperation. We developed and possesses BNP Tg, BNP K/O, CNP Tg, CNP K … More /O, GC-A (the receptor for ANP and BNP) K/O, angiotensin receptor type 1 and type 2 K/O, endothelin receptor type A and type B K/O.BNP K/O elicited severe cardiac fibrosis with the up-regulation of the gene expression of angiotensin converting enzyme, TGF-β3 and collagen type I.Aortic banding of BNP K/O significantly enhanced the fibrosis. The results indicate the role of BNP as the anti-fibrotic cardiac local factor. BNP Tg exhibited long bone elongation and decreased blood pressure. When BNP Tg were cross-bled with GC-A K/O, which elicited cardiac hypertrophy and increase of blood pressure, obtained BNP Tg/GC-A K/O retained the phenotype of increased blood pressure and cardiac hypertrophy, but also exhibited long bone elongation. This result suggests the differential activation of BNP for natriuretic peptide receptor subtypes in different tissues. BNP Tg showed less significant renal damage, when the kidney was severely-injuried, suggesting the protective role of natriuretic peptides in the kidney. CNP K/O elicited dwarfism with impairment of enchondral ossification and exhibited early death. CNP Tg with collagen type II promotor, in which CNP is specifically over-expressed in the chondral growth plate, was developed. When CNP K/O were cross-bled with CNP Tg, the bone abnormality was abolished and the mice survived. Using this CNP K/O/CNP Tg, we are investigating the role of CNP in vascular remodeling. Less