Summary of Research Project Results under JSPS FY2002
"Research for the Future Program"

1.Research Institution Kyoto University
2.Research Area Life Sciences
3.Research Field Genetic and Environmental Factors in Diseases Prevalent in Adults and the Elderly
4.Term of Project FY 1998 - FY 2002
5.Project Number 98L00801
6.Title of Project Molecular Elucidation of Significance of Cardiovascular Hormones in Vascular Protection and Regeneration

7.Project Leader
Name Institution,Department Title of Position
Kazuwa, Nakao Kyoto University, Graduate School of Medicine Professor

8.Core Members

Name Institution,Department Title of Position
Hiroshi, Itoh Kyoto University, Graduate School of Medicine Associate Professor
Yoshihiro, Ogawa Kyoto University, Graduate School of Medicine Associate Professor

9.Summary of Research Results

  Cardiovascular homeostasis is maintained through complex interactions among a variety of cardiovascular hormones, such as natriuretic peptides; atrial, brain and C-type natriuretic peptides (ANP, BNP and CNP).
  To explore the physiologic roles of these peptides in vivo, we produced mice with targeted disruption of BNP and demonstrated that they exhibit cardiac fibrosis with no sign of systemic hypertension. These observations establish BNP as a cardiocyte-derived antifibrotic factor that is involved in the regulation of ventricular remodeling. We also created CNP-deficient mice and found that they show severe dwarfism as a result of impaired endochondral ossification, with early death. The animals obtained in this study will serve as the useful models to examine the role of natriuretic peptides in vascular protection and regeneration in vivo.
  Using the adenovirus expressing CNP gene, we elucidated that overexpression of CNP in the blood vessel wall induces inhibition of proliferation and migration of vascular smooth muscle cells with re-differentiation and also promoted endothelial regeneration with suppression of thrombogeniety. We also demonstrated using BNP-transgenic mice and the transgenic mice and knock-out mice of cGMP-dependent protein kinase (cGK), the signal-transduction molecule of natriuretic peptides, that natriuretic peptides/cGMP/cGK cascade possess the capability to regenerate blood vessel itself. Gene transfer of CNP into ischemic mouse model, blood flow was significantly augmented with enhanced vascular regeneration.

10.Key Words
(1)knock-out mice   (2)transgenic mice   (3)hormone
(4)natriuretic peptides   (5)cGMP   (6)endothelial cells
(7)vascular smooth muscle cells   (8)adenovirus   (9)vascular regeneration