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Adenosine regulation of microtubule dynamics in cardiac hypertrophy.
- Source :
-
American journal of physiology. Heart and circulatory physiology [Am J Physiol Heart Circ Physiol] 2009 Aug; Vol. 297 (2), pp. H523-32. Date of Electronic Publication: 2009 Jun 12. - Publication Year :
- 2009
-
Abstract
- There is evidence that endogenous extracellular adenosine reduces cardiac hypertrophy and heart failure in mice subjected to chronic pressure overload, but the mechanism by which adenosine exerts these protective effects is unknown. Here, we identified a novel role for adenosine in regulation of the cardiac microtubule cytoskeleton that may contribute to its beneficial effects in the overloaded heart. In neonatal cardiomyocytes, phenylephrine promoted hypertrophy and reorganization of the cytoskeleton, which included accumulation of sarcomeric proteins, microtubules, and desmin. Treatment with adenosine or the stable adenosine analog 2-chloroadenosine, which decreased hypertrophy, specifically reduced accumulation of microtubules. In hypertrophied cardiomyocytes, 2-chloroadenosine or adenosine treatment preferentially targeted stabilized microtubules (containing detyrosinated alpha-tubulin). Consistent with a role for endogenous adenosine in reducing microtubule stability, levels of detyrosinated microtubules were elevated in hearts of CD73 knockout mice (deficient in extracellular adenosine production) compared with wild-type mice (195%, P < 0.05). In response to aortic banding, microtubules increased in hearts of wild-type mice; this increase was exaggerated in CD73 knockout mice, with significantly greater amounts of tubulin partitioning into the cold-stable Triton-insoluble fractions. The levels of this stable cytoskeletal fraction of tubulin correlated strongly with the degree of heart failure. In agreement with a role for microtubule stabilization in promoting cardiac dysfunction, colchicine treatment of aortic-banded mice reduced hypertrophy and improved cardiac function compared with saline-treated controls. These results indicate that microtubules contribute to cardiac dysfunction and identify, for the first time, a role for adenosine in regulating cardiomyocyte microtubule dynamics.
- Subjects :
- 2-Chloroadenosine metabolism
2-Chloroadenosine pharmacology
5'-Nucleotidase genetics
Adenosine pharmacology
Animals
Cardiomegaly pathology
Cells, Cultured
Disease Models, Animal
Mice
Mice, Inbred BALB C
Mice, Knockout
Microtubules drug effects
Myocardial Contraction drug effects
Myocardial Contraction physiology
Myocytes, Cardiac cytology
Myocytes, Cardiac drug effects
Myocytes, Cardiac metabolism
Rats
Rats, Sprague-Dawley
Tubulin metabolism
Adenosine metabolism
Cardiomegaly drug therapy
Cardiomegaly metabolism
Colchicine pharmacology
Microtubules metabolism
Tubulin Modulators pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1522-1539
- Volume :
- 297
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- American journal of physiology. Heart and circulatory physiology
- Publication Type :
- Academic Journal
- Accession number :
- 19525375
- Full Text :
- https://doi.org/10.1152/ajpheart.00462.2009