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Dysfunctional ryanodine receptor and cardiac hypertrophy: role of signaling molecules.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Yamaguchi, Naohiro Chakraborty, Asima Pasek, Daniel A. Molkentin, Jeffery D. Meissner, Gerhard |
| Copyright Year | 2011 |
| Abstract | Mice with three amino acid mutations in the calmodulin binding domain of type-2 ryanodine receptor ion channel (Ryr2(ADA/ADA) mice) have impaired intracellular Ca(2+) handling and cardiac hypertrophy with death at an early age. In this report, the role of signaling molecules implicated in cardiac hypertrophy of Ryr2(ADA/ADA) mice was investigated. Calcineurin A-β (CNA-β) and nuclear factor of activated T cell (NFAT) signaling were monitored in mice carrying either luciferase transgene driven by NFAT-dependent promoter or knockout of CNA-β. NFAT transcriptional activity in Ryr2(ADA/ADA) hearts was not markedly upregulated at embryonic day 16.5 compared with wild-type but significantly increased at postnatal days 1 and 10. Ablation of CNA-β extended the life span of Ryr2(ADA/ADA) mice and enhanced cardiac function without improving sarcoplasmic reticulum Ca(2+) handling or suppressing the expression of genes implicated in cardiac hypertrophy. Embryonic day 16.5 Ryr2(ADA/ADA) mice had normal heart weights with no major changes in Akt1 and class II histone deacetylase phosphorylation and myocyte enhancer factor-2 activity. In contrast, phosphorylation levels of Erk1/2, p90 ribosomal S6 kinases (p90RSKs), and GSK-3β were increased in hearts of embryonic day 16.5 homozygous mutant mice. The results indicate that an impaired calmodulin regulation of RyR2 was neither associated with an altered CNA-β/NFAT, class II histone deacetylase (HDAC)/MEF2, nor Akt signaling in embryonic day 16.5 hearts; rather increased Erk1/2 and p90RSK phosphorylation levels likely leading to reduced GSK-3β activity were found to precede development of cardiac hypertrophy in mice expressing dysfunctional ryanodine receptor ion channel. |
| Starting Page | 870 |
| Ending Page | 876 |
| Page Count | 7 |
| File Format | PDF HTM / HTML |
| DOI | 10.1152/ajpheart.00719.2010 |
| PubMed reference number | 21421818 |
| Journal | Medline |
| Volume Number | 300 |
| Issue Number | 6 |
| Alternate Webpage(s) | http://ajpheart.physiology.org/content/ajpheart/300/6/h2187.full.pdf |
| Journal | American journal of physiology. Heart and circulatory physiology |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
