What is the clinical evidence from this study?

Study design: Other. Population: Cardiac hypertrophy. Intervention: MCIP1 knockout vs. Wild-type/baseline. Primary outcome: Cardiac hypertrophic response to stress stimuli.

January 6, 2003Proceedings of the National Academy of Sciences220 citationsOpen Access

Dual roles of modulatory calcineurin-interacting protein 1 in cardiac hypertrophy

RVRick B. VegaAstraZeneca (Poland)BRBeverly A. RothermelThe University of Texas Southwestern Medical Center CWCarla J. WeinheimerUniversity of Washington

Key Result

MCIP1 knockout exacerbated the hypertrophic response to activated calcineurin but blunted cardiac hypertrophy in response to pressure overload or chronic adrenergic stimulation.

Structured PICO

Does genetic deletion of MCIP1 alter the cardiac hypertrophic response to stress stimuli in mice?

Population

MCIP1 null mice subjected to various stress stimuli to investigate the in vivo role of MCIP1 in cardiac hypertrophy.

Intervention

Genetic deletion of MCIP1 subjected to stress stimuli (activated calcineurin transgene, pressure overload, or chronic adrenergic stimulation)

Comparator

Wild-type mice (implied)

Outcome

Cardiac hypertrophic responsesurrogate

MCIP1 has dual roles in cardiac hypertrophy, acting to either facilitate or suppress calcineurin signaling depending on the specific hypertrophic stimulus.

Abstract

The calcium/calmodulin-dependent protein phosphatase calcineurin stimulates cardiac hypertrophy in response to numerous stimuli. Calcineurin activity is suppressed by association with modulatory calcineurin-interacting protein (MCIP)1DSCR1, which is up-regulated by calcineurin signaling and has been proposed to function in a negative feedback loop to modulate calcineurin activity. To investigate the involvement of MCIP1 in cardiac hypertrophy in vivo, we generated MCIP1 null mice and subjected them to a variety of stress stimuli that induce cardiac hypertrophy. In the absence of stress, MCIP1(-/-) animals exhibited no overt phenotype. However, the lack of MCIP1 exacerbated the hypertrophic response to activated calcineurin expressed from a muscle-specific transgene, consistent with a role of MCIP1 as a negative regulator of calcineurin signaling. Paradoxically, however, cardiac hypertrophy in response to pressure overload or chronic adrenergic stimulation was blunted in MCIP1(-/-) mice. These findings suggest that MCIP1 can facilitate or suppress cardiac calcineurin signaling depending on the nature of the hypertrophic stimulus. These opposing roles of MCIP have important implications for therapeutic strategies to regulate cardiac hypertrophy through modulation of calcineurin-MCIP activity.

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