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Phosphoinositide 3-kinase (PI3K(p110alpha)) directly regulates key components of the Z-disc and cardiac structure.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2011 Sep 02; Vol. 286 (35), pp. 30837-30846. Date of Electronic Publication: 2011 Jul 11. - Publication Year :
- 2011
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Abstract
- Maintenance of cardiac structure and Z-disc signaling are key factors responsible for protecting the heart in a setting of stress, but how these processes are regulated is not well defined. We recently demonstrated that PI3K(p110α) protects the heart against myocardial infarction. The aim of this study was to determine whether PI3K(p110α) directly regulates components of the Z-disc and cardiac structure. To address this question, a unique three-dimensional virtual muscle model was applied to gene expression data from transgenic mice with increased or decreased PI3K(p110α) activity under basal conditions (sham) and in a setting of myocardial infarction to display the location of structural proteins. Key findings from this analysis were then validated experimentally. The three-dimensional virtual muscle model visually highlighted reciprocally regulated transcripts associated with PI3K activation that encoded key components of the Z-disc and costamere, including melusin. Studies were performed to assess whether PI3K and melusin interact in the heart. Here, we identify a novel melusin-PI3K interaction that generates lipid kinase activity. The direct impact of PI3K(p110α) on myocyte structure was assessed by treating neonatal rat ventricular myocytes with PI3K(p110α) inhibitors and examining the myofiber morphology of hearts from PI3K transgenic mice. Results demonstrate that PI3K is critical for myofiber maturation and Z-disc alignment. In summary, PI3K regulates the expression of genes essential for cardiac structure and Z-disc signaling, interacts with melusin, and is critical for Z-disc alignment.
- Subjects :
- Animals
Costameres metabolism
Cytoskeletal Proteins chemistry
Heart Failure metabolism
Immunoprecipitation
Insulin Receptor Substrate Proteins metabolism
Mice
Mice, Transgenic
Microscopy, Confocal methods
Muscle Cells cytology
Muscle Proteins chemistry
Oligonucleotide Array Sequence Analysis
Phosphatidylinositol 3-Kinases metabolism
Class Ia Phosphatidylinositol 3-Kinase metabolism
Gene Expression Regulation, Enzymologic
Myocardium metabolism
Myocytes, Cardiac metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 286
- Issue :
- 35
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 21757757
- Full Text :
- https://doi.org/10.1074/jbc.M111.271684