Defective regulation of the ryanodine receptor induces hypertrophy in cardiomyocytes.
Recent studies on cardiac hypertrophy animal model suggest that inter-domain interactions within the ryanodine receptor (RyR2) become defective concomitant with the development of hypertrophy (e.g. de-stabilization of the interaction between N-terminal and central domains of RyR2; T. Oda, M. Yano, T. Yamamoto, T. Tokuhisa, S. Okuda, M. Doi, T. Ohkusa, Y. Ikeda, S. Kobayashi, N. Ikemoto, M. Matsuzaki, Defective regulation of inter-domain interactions within the ryanodine receptor plays a key role in the pathogenesis of heart failure, Circulation 111 (2005) 3400-3410). To determine if de-stabilization of the inter-domain interaction in fact causes hypertrophy, we introduced DPc10 (a peptide corresponding to the G(2460)-P(2495) region of RyR2, which is known to de-stabilize the N-terminal/central domain interaction) into rat neonatal cardiomyocytes by mediation of peptide carrier BioPORTER. After incubation for 24h the peptide induced hypertrophy, as evidenced by significant increase in cell size and [(3)H]leucine uptake. K201 or dantrolene, the reagents known to correct the de-stabilized inter-domain interaction to a normal mode, prevented the DPc10-induced hypertrophy. These results suggest that disruption of the normal N-terminal/central inter-domain interaction within the RyR2 is a causative mechanism of cardiomyocyte hypertrophy.
Hamada
Tomoyo
T
Boston Biomedical Research Institute, Cardiovascular Program, 64 Grove St., Watertown, MA 02472, USA.
Gangopadhyay
Jaya P
JP
Mandl
Adel
A
Erhardt
Peter
P
Ikemoto
Noriaki
N
D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
D019332:Endothelin-1; D010446:Peptide Fragments; D019837:Ryanodine Receptor Calcium Release Channel; C451408:ryanodine receptor calcium release channel (2460-2495), synthetic