The IP3 receptor regulates cardiac hypertrophy in response to select stimuli

Hiroyuki Nakayama, Ilona Bodi, Marjorie Maillet, Jaime Desantiago, Timothy L. Domeier, Katsuhiko Mikoshiba, John N. Lorenz, Lothar A. Blatter, Donald M Bers, Jeffery D. Molkentin

Research output: Contribution to journalArticle

111 Citations (Scopus)

Abstract

Rationale: Inositol 1,4,5-trisphosphate (IP3) is a second messenger that regulates intracellular Ca2+ 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 IP3 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 IP3 receptor signaling to examine its hypertrophic growth effects following pathologiCa2+ and Physiological stimulation. Methods and Results: Overexpression of the mouse type-2 IP 3 receptor (IP3R2) in the heart generated mild baseline cardiac hypertrophy at 3 months of age. Isolated myocytes from overexpressing lines showed increased Ca2+ transients and arrhythmias in response to endothelin-1 stimulation. Although low levels of IP3R2 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 Gαq overexpression, and/or in response to exercise stimulation. To inhibit IP3 signaling in vivo, we generated transgenic mice expressing an IP3 chelating protein (IP3-sponge). IP3-sponge transgenic mice abrogated cardiac hypertrophy in response to isoproterenol and angiotensin II infusion but not pressure-overload stimulation. Mechanistically, IP3R2-enhanced cardiac hypertrophy following isoproterenol infusion was significantly reduced in the calcineurin-Aβ-null background. Conclusion: These results indicate that IP3-mediated Ca2+ release plays a central role in regulating cardiac hypertrophy downstream of GPCR signaling, in part, through a calcineurin-dependent mechanism.

Original languageEnglish (US)
Pages (from-to)659-666
Number of pages8
JournalCirculation Research
Volume107
Issue number5
DOIs
StatePublished - Sep 3 2010

Fingerprint

Inositol 1,4,5-Trisphosphate Receptors
Cardiomegaly
Isoproterenol
Transgenic Mice
Calcineurin
Porifera
G-Protein-Coupled Receptors
Pressure
Reticulum
Inositol 1,4,5-Trisphosphate
Second Messenger Systems
Endothelin-1
Cardiac Myocytes
Angiotensin II
Muscle Cells
Hypertrophy
Cardiac Arrhythmias
Growth
Proteins

Keywords

  • calcineurin
  • calcium
  • hypertrophy
  • signaling

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Nakayama, H., Bodi, I., Maillet, M., Desantiago, J., Domeier, T. L., Mikoshiba, K., ... Molkentin, J. D. (2010). The IP3 receptor regulates cardiac hypertrophy in response to select stimuli. Circulation Research, 107(5), 659-666. https://doi.org/10.1161/CIRCRESAHA.110.220038

The IP3 receptor regulates cardiac hypertrophy in response to select stimuli. / Nakayama, Hiroyuki; Bodi, Ilona; Maillet, Marjorie; Desantiago, Jaime; Domeier, Timothy L.; Mikoshiba, Katsuhiko; Lorenz, John N.; Blatter, Lothar A.; Bers, Donald M; Molkentin, Jeffery D.

In: Circulation Research, Vol. 107, No. 5, 03.09.2010, p. 659-666.

Research output: Contribution to journalArticle

Nakayama, H, Bodi, I, Maillet, M, Desantiago, J, Domeier, TL, Mikoshiba, K, Lorenz, JN, Blatter, LA, Bers, DM & Molkentin, JD 2010, 'The IP3 receptor regulates cardiac hypertrophy in response to select stimuli', Circulation Research, vol. 107, no. 5, pp. 659-666. https://doi.org/10.1161/CIRCRESAHA.110.220038
Nakayama H, Bodi I, Maillet M, Desantiago J, Domeier TL, Mikoshiba K et al. The IP3 receptor regulates cardiac hypertrophy in response to select stimuli. Circulation Research. 2010 Sep 3;107(5):659-666. https://doi.org/10.1161/CIRCRESAHA.110.220038
Nakayama, Hiroyuki ; Bodi, Ilona ; Maillet, Marjorie ; Desantiago, Jaime ; Domeier, Timothy L. ; Mikoshiba, Katsuhiko ; Lorenz, John N. ; Blatter, Lothar A. ; Bers, Donald M ; Molkentin, Jeffery D. / The IP3 receptor regulates cardiac hypertrophy in response to select stimuli. In: Circulation Research. 2010 ; Vol. 107, No. 5. pp. 659-666.
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