Back to Search
Start Over
Calcineurin splicing variant calcineurin Aβ1 improves cardiac function after myocardial infarction without inducing hypertrophy.
- Source :
-
Circulation [Circulation] 2011 Jun 21; Vol. 123 (24), pp. 2838-47. Date of Electronic Publication: 2011 May 31. - Publication Year :
- 2011
-
Abstract
- 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.<br />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.<br />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.
- Subjects :
- Activating Transcription Factor 4 genetics
Activating Transcription Factor 4 metabolism
Animals
Calcineurin metabolism
Cardiomegaly genetics
Cardiomegaly physiopathology
Fibrosis
Gene Expression Profiling
Mice
Mice, Transgenic
Myocardial Infarction metabolism
Myocarditis genetics
Myocarditis metabolism
Myocarditis physiopathology
Myocardium metabolism
Myocardium pathology
Myosin Heavy Chains genetics
Myosin Heavy Chains metabolism
Protein Isoforms genetics
Signal Transduction physiology
Calcineurin genetics
Heart physiology
Myocardial Contraction physiology
Myocardial Infarction genetics
Myocardial Infarction physiopathology
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4539
- Volume :
- 123
- Issue :
- 24
- Database :
- MEDLINE
- Journal :
- Circulation
- Publication Type :
- Academic Journal
- Accession number :
- 21632490
- Full Text :
- https://doi.org/10.1161/CIRCULATIONAHA.110.012211