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

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, ␣-myosin heavy chain promoter (␣-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 ␤-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.

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

“…MCIP1 may also be required to properly localize calcineurin to its cellular substrates. Overexpression of MCIP1 such as in the ␣MHC-MCIP1 transgenic model would be expected to shift the equilibrium toward the inactive, MCIP1-bound state (18). The constitutively active form of calcineurin expressed in the MCK-CnA* transgenic mouse may function independently of a permissive influence of MCIP1.…”

“…For example, cardiac overexpression of MCIP1 in transgenic mice can diminish hypertrophy in response to overexpression of a constitutively active form of calcineurin, as well as to chronic isoproterenol administration, pressure overload, and exercise (17,18). MCIP1 gene expression is also up-regulated in response to calcineurin signaling, suggesting that MCIP1 functions in a feedback inhibition loop to suppress calcineurin activity (19).…”

Key signalling factors and pathways in the molecular determination of skeletal muscle phenotype

“…AKAP79, cain/cabin 1, and CBHP are ubiquitous factors and were found to inhibit NFAT function or translocation to the nucleus (Crabtree, 2001). More recently, two additional endogenous calcineurin-specific inhibitors (DSCR1/MCIP1 and ZAKI-4/DSCR1L1/MCIP2), highly expressed in striated muscles and brain, were found (Yang et al, 2000;Rothermel et al, 2001). DSCR1 expression is induced by calcineurin and hence forms a negative feedback loop to limit calcineurin activation Signalling and pathways in molecular determination of skeletal muscle phenotype (Yang et al, 2000).…”

The SCF Cdc4 ubiquitin ligase regulates calcineurin signaling through degradation of phosphorylated Rcn1, an inhibitor of calcineurin

“…Precise regulation of calcineurin is important for a proper response to Ca 2ϩ signals. Aberrant calcineurin activity results in various disorders, such as osteoporosis (2), cardiac hypertrophy (3,4) and Down's syndrome (5,6). The mechanism responsible for activation of calcineurin in response to Ca 2ϩ signals appears to be conserved from human to yeast.…”

“…DSCR1 (Down's syndrome critical region 1) or MCIP (modulatory calcineurin-interacting protein), encoded in chromosome trisomy 21 in human, is highly expressed in the brain of Down's syndrome and is known to inhibit calcineurin through direct binding with the catalytic subunit of calcineurin (5,13). DSCR1/MCIP is also important in protection against cardiac hypertrophy (4,14), oxidative stress (15), and neurofibrillary tangle formation associated with Alzheimer's disease (16). Similarly, yeast Rcn1, a homolog of DSCR1/MCIP, inhibits calcineurin-dependent responses when overexpressed (11).…”