Submitted on March 13, 2007
Accepted on September 11, 2007
Interaction of BMP10 with Tcap may modulate the course of hypertensive cardiac hypertrophy
Noritsugu Nakano1, Hisae Hori1, Mibako Abe2, Hiroki Shibata1, Takuro Arimura1, Taishi Sasaoka3, Motoji Sawabe4, Kouji Chida4, Tomio Arai4, Ken-ichi Nakahara5, Toru Kubo6, Ken Sugimoto7, Tomohiro Katsuya7, Toshio Ogihara8, Yoshinori Doi6, Tohru Izumi3, and Akinori Kimura9*
1 Molecular Pathogenesis, Med Res Inst, Tokyo Med Dent Univ, Tokyo, Japan
2 Genome Diversity, School of Biomedical Science, Tokyo Medical and Dental University, Japan
3 Internal Medicine and Cardiology, Kitasato University School of Medicine,, Tokyo, Japan
4 Pathology, Tokyo Metropolitan Geriatric Hospital, Japan
5 Cardiology, Nagasaki Medical Center, Tokyo, Japan
6 Medicine and Geriatrics, Kochi University School of Medicine, Japan
7 Geriatric Medicine, Osaka University Graduate School of Medicine, Japan
8 Department of Geriatric Medicine, Osaka University Medical School, Suita 565, United States
9 Molecular Pathogenesis, Med Res Inst, Tokyo Med Dent Univ, Tokyo, Japan; Genome Diversity, School of Biomedical Science, TokMed Dent yo Univ, Tokyo, Japan
* To whom correspondence should be addressed. E-mail: akitis{at}mri.tmd.ac.jp.
Elevated wall stress by hypertension induces an adaptive myocardial hypertrophy via releasing pro-hypertrophic hormones such as angiotensin-II. In this study, we investigated the involvement of bone morphogenetic protein 10 (BMP10) in the hypertension-induced cardiac hypertrophy. Expression of BMP10 was increased in the hypertrophied ventricles from hypertensive rats. BMP10 localized on cell surface and at stretch-sensing Z-disc of cardiomyocytes, where BMP10 interacted with Tcap. A rare variant of human BMP10 gene, Thr326Ile, was found to be associated with hypertensive dilated cardiomyopathy. The variant BMP10 demonstrated decreased binding to Tcap and increased extracellular secretion. Conditioned medium from cells transfected with wild type or variant BMP10 induced hypertrophy in rat neonatal cardiomyocytes, except that medium from variant BMP10 carrying cells showed enhanced effect reflecting the increased secretion. These observations suggested that hypertension induced expression of pro-hypertrophic BMP10 and the hypertrophic effect of BMP10 was modulated, at least in part, by its binding to Tcap at the Z-disc.
