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

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 adminis tration of immunosuppressive drugs that inhibit calcineurin has inconsisten t effects in blocking cardiac hypertrophy in various animal models. As an a lternative approach to inhibiting calcineurin in the hearts of intact anima ls, transgenic mice were engineered to overexpress a human cDNA encoding th e calcineurin-binding protein, myocyte-enriched calcineurin-interacting pro tein-1 (hMCIP1) under control of the cardiac-specific, alpha -myosin heavy chain promoter (alpha -MHC). In unstressed mice, forced expression of hMCIP 1 resulted in a 5-10% decline in cardiac mass relative to wild-type litterm ates, but otherwise produced no apparent structural or functional abnormali ties. However, cardiac-specific expression of hMCIP1 inhibited cardiac hype rtrophy, reinduction of fetal gene expression, and progression to dilated c ardiomyopathy that otherwise result from expression of a constitutively act ive form of calcineurin. Expression of the hMCIP1 transgene also inhibited hypertrophic responses to beta -adrenergic receptor stimulation or exercise training. These results demonstrate that levels of hMCIP1 producing no app arent deleterious effects in cells of the normal heart are sufficient to in hibit several forms of cardiac hypertrophy, and suggest an important role f or calcineurin signaling in diverse forms of cardiac hypertrophy. The futur e development of measures to increase expression or activity of MCIP protei ns selectively within the heart may have clinical value for prevention of h eart failure.