2024-03-28T13:58:38Zhttp://repisalud.isciii.es/oai/requestoai:repisalud.isciii.es:20.500.12105/79732023-10-05T07:58:33Zcom_20.500.12105_2145com_20.500.12105_2051com_20.500.12105_2144col_20.500.12105_2146
00925njm 22002777a 4500
dc
Felkin, Leanne E
author
Narita, Takuya
author
Germack, Renée
author
Shintani, Yasunori
author
Takahashi, Kunihiko
author
Sarathchandra, Padmini
author
Lopez-Olaneta, Marina
author
Gomez-Salinero, Jesus M.
author
Suzuki, Ken
author
Barton, Paul J R
author
Rosenthal, Nadia
author
Lara-Pezzi, Enrique
author
2011-06
BACKGROUND: Calcineurin is a calcium-regulated phosphatase that plays a major role in cardiac hypertrophy. We previously described that alternative splicing of the calcineurin Aβ (CnAβ) gene generates the CnAβ1 isoform, with a unique C-terminal region that is different from the autoinhibitory domain present in all other CnA isoforms. In skeletal muscle, CnAβ1 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 RESULTS: We generated transgenic mice overexpressing CnAβ1 in postnatal cardiomyocytes under the control of the α-myosin heavy chain promoter. In contrast to previous studies using an artificially truncated calcineurin, CnAβ1 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 CnAβ1 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 CnAβ1 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. CONCLUSIONS: Calcineurin Aβ1 shows a unique mode of action that improves cardiac function after myocardial infarction, activating different cardioprotective pathways without inducing maladaptive hypertrophy. These features make CnAβ1 an attractive candidate for the development of future therapeutic approaches.
Circulation. 2011; 123(24):2838-47
0009-7322
http://hdl.handle.net/20.500.12105/7973
21632490
10.1161/CIRCULATIONAHA.110.012211
1524-4539
Circulation
Calcineurin splicing variant calcineurin Aβ1 improves cardiac function after myocardial infarction without inducing hypertrophy