TY - JOUR
T1 - Calcineurin splicing variant calcineurin A{beta}1 improves cardiac function after myocardial infarction without inducing hypertrophy
AU - Felkin, Leanne
AU - Narita, Takuya
AU - Germack, Renee
AU - Shintani, Yasunori
AU - Takahashi, Kunihiko
AU - Sarathchandra, Padmini
AU - Lopez-Olaneta, Marina
AU - Gomez-Salinero, Jesus
AU - Suzuki, Ken
AU - Barton, Paul J R
AU - Rosenthal, Nadia Alicia
AU - Lara-Pezzi, Enrique
PY - 2011
Y1 - 2011
N2 - Backgrounda??Calcineurin is a calcium-regulated phosphatase that plays a major role in cardiac hypertrophy. We previously described that alternative splicing of the calcineurin AI? (CnAI?) gene generates the CnAI?1 isoform, with a unique C-terminal region that is different from the autoinhibitory domain present in all other CnA isoforms. In skeletal muscle, CnAI?1 is necessary for myoblast proliferation and stimulates regeneration, reducing fibrosis and accelerating the resolution of inflammation. Its role in the heart is currently unknown. Methods and Resultsa??We generated transgenic mice overexpressing CnAI?1 in postnatal cardiomyocytes under the control of the I?-myosin heavy chain promoter. In contrast to previous studies using an artificially truncated calcineurin, CnAI?1 overexpression did not induce cardiac hypertrophy. Moreover, transgenic mice showed improved cardiac function and reduced scar formation after myocardial infarction, with reduced neutrophil and macrophage infiltration and decreased expression of proinflammatory cytokines. Immunoprecipitation and Western blot analysis showed interaction of CnAI?1 with the mTOR complex 2 and activation of the Akt/SGK cardioprotective pathway in a PI3K-independent manner. In addition, gene expression profiling revealed that CnAI?1 activated the transcription factor ATF4 downstream of the Akt/mTOR pathway to promote the amino acid biosynthesis program, to reduce protein catabolism, and to induce the antifibrotic and antiinflammatory factor growth differentiation factor 15, which protects the heart through Akt activation. Conclusionsa??Calcineurin AI?1 shows a unique mode of action that improves cardiac function after myocardial infarction, activating different cardioprotective pathways without inducing maladaptive hypertrophy. These features make CnAI?1 an attractive candidate for the development of future therapeutic approaches.
AB - Backgrounda??Calcineurin is a calcium-regulated phosphatase that plays a major role in cardiac hypertrophy. We previously described that alternative splicing of the calcineurin AI? (CnAI?) gene generates the CnAI?1 isoform, with a unique C-terminal region that is different from the autoinhibitory domain present in all other CnA isoforms. In skeletal muscle, CnAI?1 is necessary for myoblast proliferation and stimulates regeneration, reducing fibrosis and accelerating the resolution of inflammation. Its role in the heart is currently unknown. Methods and Resultsa??We generated transgenic mice overexpressing CnAI?1 in postnatal cardiomyocytes under the control of the I?-myosin heavy chain promoter. In contrast to previous studies using an artificially truncated calcineurin, CnAI?1 overexpression did not induce cardiac hypertrophy. Moreover, transgenic mice showed improved cardiac function and reduced scar formation after myocardial infarction, with reduced neutrophil and macrophage infiltration and decreased expression of proinflammatory cytokines. Immunoprecipitation and Western blot analysis showed interaction of CnAI?1 with the mTOR complex 2 and activation of the Akt/SGK cardioprotective pathway in a PI3K-independent manner. In addition, gene expression profiling revealed that CnAI?1 activated the transcription factor ATF4 downstream of the Akt/mTOR pathway to promote the amino acid biosynthesis program, to reduce protein catabolism, and to induce the antifibrotic and antiinflammatory factor growth differentiation factor 15, which protects the heart through Akt activation. Conclusionsa??Calcineurin AI?1 shows a unique mode of action that improves cardiac function after myocardial infarction, activating different cardioprotective pathways without inducing maladaptive hypertrophy. These features make CnAI?1 an attractive candidate for the development of future therapeutic approaches.
UR - http://circ.ahajournals.org/content/123/24/2838.full.pdf+html
U2 - 10.1161/CIRCULATIONAHA.110.012211
DO - 10.1161/CIRCULATIONAHA.110.012211
M3 - Article
VL - 123
SP - 2838
EP - 2847
JO - Circulation
JF - Circulation
SN - 0009-7322
IS - 24
ER -