The IP3 receptor regulates cardiac hypertrophy in response to select stimuli.
BACKGROUND
Inositol 1,4,5-trisphosphate (IP(3)) is a second messenger that regulates intracellular Ca(2+) release through IP(3) receptors located in the sarco(endo)plasmic reticulum of cardiac myocytes. Many prohypertrophic G protein-coupled receptor (GPCR) signaling events lead to IP(3) liberation, although its importance in transducing the hypertrophic response has not been established in vivo.


OBJECTIVE
Here, we generated conditional, heart-specific transgenic mice with both gain- and loss-of-function for IP(3) receptor signaling to examine its hypertrophic growth effects following pathological and physiological stimulation.


RESULTS
Overexpression of the mouse type-2 IP(3) receptor (IP(3)R2) in the heart generated mild baseline cardiac hypertrophy at 3 months of age. Isolated myocytes from overexpressing lines showed increased Ca(2+) transients and arrhythmias in response to endothelin-1 stimulation. Although low levels of IP(3)R2 overexpression failed to augment/synergize cardiac hypertrophy following 2 weeks of pressure-overload stimulation, such levels did enhance hypertrophy following 2 weeks of isoproterenol infusion, in response to Galphaq overexpression, and/or in response to exercise stimulation. To inhibit IP(3) signaling in vivo, we generated transgenic mice expressing an IP(3) chelating protein (IP(3)-sponge). IP(3)-sponge transgenic mice abrogated cardiac hypertrophy in response to isoproterenol and angiotensin II infusion but not pressure-overload stimulation. Mechanistically, IP(3)R2-enhanced cardiac hypertrophy following isoproterenol infusion was significantly reduced in the calcineurin-Abeta-null background.


CONCLUSIONS
These results indicate that IP(3)-mediated Ca(2+) release plays a central role in regulating cardiac hypertrophy downstream of GPCR signaling, in part, through a calcineurin-dependent mechanism.
Nakayama
Hiroyuki
H
Howard Hughes Medical Institute, Cincinnati Children's Hospital Medical Center, 240 Albert Sabin Way, Cincinnati, OH 45229-3039, USA.
Bodi
Ilona
I
Maillet
Marjorie
M
DeSantiago
Jaime
J
Domeier
Timothy L
TL
Mikoshiba
Katsuhiko
K
Lorenz
John N
JN
Blatter
Lothar A
LA
Bers
Donald M
DM
Molkentin
Jeffery D
JD
D000367:Age Factors; D000804:Angiotensin II; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D019703:Calcineurin / Q000172:deficiency / Q000235:genetics; D020013:Calcium Signaling; D006332:Cardiomegaly / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D004195:Disease Models, Animal; D019332:Endothelin-1; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics / Q000378:metabolism; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007545:Isoproterenol; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D005082:Physical Exertion
D019332:Endothelin-1; D053496:Inositol 1,4,5-Trisphosphate Receptors; D000804:Angiotensin II; D015544:Inositol 1,4,5-Trisphosphate; D019703:Calcineurin; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D007545:Isoproterenol