Myocyte-enriched calcineurin-interacting protein, MCIP1, inhibits cardiac hypertrophy in vivo

Beverly A. Rothermel, Timothy A. McKinsey, Rick B. Vega, Rebekka L. Nicol, Pradeep Mammen, John Yang, Christopher L. Antos, John M. Shelton, Rhonda Bassel-Duby, Eric N. Olson, R. Sanders Williams

Research output: Contribution to journalArticle

254 Citations (Scopus)

Abstract

Signaling events controlled by calcineurin promote cardiac hypertrophy, but the degree to which such pathways are required to transduce the effects of various hypertrophic stimuli remains uncertain. In particular, the administration of immunosuppressive drugs that inhibit calcineurin has inconsistent effects in blocking cardiac hypertrophy in various animal models. As an alternative approach to inhibiting calcineurin in the hearts of intact animals, transgenic mice were engineered to overexpress a human cDNA encoding the calcineurin-binding protein, myocyte-enriched calcineurin-interacting protein-1 (hMCIP1) under control of the cardiac-specific, α-myosin heavy chain promoter (α-MHC). In unstressed mice, forced expression of hMCIP1 resulted in a 5-10% decline in cardiac mass relative to wild-type littermates, but otherwise produced no apparent structural or functional abnormalities. However, cardiac-specific expression of hMCIP1 inhibited cardiac hypertrophy, reinduction of fetal gene expression, and progression to dilated cardiomyopathy that otherwise result from expression of a constitutively active form of calcineurin. Expression of the hMCIP1 transgene also inhibited hypertrophic responses to β-adrenergic receptor stimulation or exercise training. These results demonstrate that levels of hMCIP1 producing no apparent deleterious effects in cells of the normal heart are sufficient to inhibit several forms of cardiac hypertrophy, and suggest an important role for calcineurin signaling in diverse forms of cardiac hypertrophy. The future development of measures to increase expression or activity of MCIP proteins selectively within the heart may have clinical value for prevention of heart failure.

Original languageEnglish (US)
Pages (from-to)3328-3333
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume98
Issue number6
DOIs
StatePublished - Mar 13 2001

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Calcineurin
Cardiomegaly
Muscle Cells
Proteins
Cardiac Myosins
Myosin Heavy Chains
Dilated Cardiomyopathy
Immunosuppressive Agents
Transgenes
Adrenergic Receptors
Transgenic Mice
Carrier Proteins
Animal Models
Heart Failure
Complementary DNA
Exercise
Gene Expression
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Myocyte-enriched calcineurin-interacting protein, MCIP1, inhibits cardiac hypertrophy in vivo. / Rothermel, Beverly A.; McKinsey, Timothy A.; Vega, Rick B.; Nicol, Rebekka L.; Mammen, Pradeep; Yang, John; Antos, Christopher L.; Shelton, John M.; Bassel-Duby, Rhonda; Olson, Eric N.; Williams, R. Sanders.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 98, No. 6, 13.03.2001, p. 3328-3333.

Research output: Contribution to journalArticle

Rothermel, Beverly A. ; McKinsey, Timothy A. ; Vega, Rick B. ; Nicol, Rebekka L. ; Mammen, Pradeep ; Yang, John ; Antos, Christopher L. ; Shelton, John M. ; Bassel-Duby, Rhonda ; Olson, Eric N. ; Williams, R. Sanders. / Myocyte-enriched calcineurin-interacting protein, MCIP1, inhibits cardiac hypertrophy in vivo. In: Proceedings of the National Academy of Sciences of the United States of America. 2001 ; Vol. 98, No. 6. pp. 3328-3333.
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