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The IP3 receptor regulates cardiac hypertrophy in response to select stimuli.

RATIONALE: 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. METHODS AND 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. CONCLUSION: 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.

Pubmed ID: 20616315

Authors

  • Nakayama H
  • Bodi I
  • Maillet M
  • DeSantiago J
  • Domeier TL
  • Mikoshiba K
  • Lorenz JN
  • Blatter LA
  • Bers DM
  • Molkentin JD

Journal

Circulation research

Publication Data

September 3, 2010

Associated Grants

  • Agency: NHLBI NIH HHS, Id: F32 HL090211
  • Agency: NHLBI NIH HHS, Id: R01 HL062231
  • Agency: NHLBI NIH HHS, Id: R01 HL062927
  • Agency: NHLBI NIH HHS, Id: R01 HL062927-12
  • Agency: NHLBI NIH HHS, Id: R37 HL030077
  • Agency: Howard Hughes Medical Institute, Id:
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Age Factors
  • Angiotensin II
  • Animals
  • Arrhythmias, Cardiac
  • Calcineurin
  • Calcium Signaling
  • Cardiomegaly
  • Disease Models, Animal
  • Endothelin-1
  • GTP-Binding Protein alpha Subunits, Gq-G11
  • Inositol 1,4,5-Trisphosphate
  • Inositol 1,4,5-Trisphosphate Receptors
  • Isoproterenol
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Myocytes, Cardiac
  • Phenotype
  • Physical Exertion