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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Cardiac sympathetic neurons provide trophic signal to the heart via 2-adrenoceptor-dependent regulation of proteolysis

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Author(s):
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Zaglia, Tania [1, 2] ; Milan, Giulia [1] ; Franzoso, Mauro [2, 1] ; Bertaggia, Enrico [1] ; Pianca, Nicola [1] ; Piasentini, Eleonora [1] ; Voltarelli, Vanessa A. [3] ; Chiavegato, David [1] ; Brum, Patricia C. [3] ; Glass, David J. [4] ; Schiaffino, Stefano [1, 5] ; Sandri, Marco [1, 5, 2] ; Mongillo, Marco [1, 5, 2]
Total Authors: 13
Affiliation:
[1] Univ Padua, VIMM, I-35129 Padua - Italy
[2] Univ Padua, Dept Biomed Sci, I-35121 Padua - Italy
[3] Univ Sao Paulo, Affiliat Sch Phys Educ & Sport, BR-05508900 Sao Paulo - Brazil
[4] Novartis Inst Biomed Res, Cambridge, MA 02139 - USA
[5] CNR, Inst Neurosci, I-35121 Padua - Italy
Total Affiliations: 5
Document type: Journal article
Source: Cardiovascular Research; v. 97, n. 2, p. 240-250, FEB 2013.
Web of Science Citations: 34
Abstract

Increased cardiac sympathetic neuron (SN) activity has been associated with pathologies such as heart failure and hypertrophy, suggesting that cardiac innervation regulates cardiomyocyte trophism. Whether continuous input from the SNs is required for the maintenance of the cardiomyocyte size has not been determined thus far. To address the role of cardiac innervation in cardiomyocyte size regulation, we monitored the effect of pharmacological sympathetic denervation in mice on cardiac structure, function, and signalling from 24 h to 30 days in the absence of other pathological stimuli. SN ablation caused an immediate reduction in the cardiomyocyte size with minimal consequences on the resting contractile function. Atrophic remodelling was mediated by the ubiquitinproteasome system through FOXO-dependent early induction of the muscle-specific E3 ubiquitin ligases Atrogin-1/MAFbx and MuRF1, which was followed by activation of the autophagylysosome system. MuRF1 was found to be determinant in denervation atrophy as remodelling did not develop in denervated MuRF1 knock-out (KO) hearts. These effects were caused by decreased basal stimulation of cardiomyocyte 2-adrenoceptor (AR), as atrophy was prevented by treatment of denervated mice with the 2-AR agonist clenbuterol. Consistent with these data, we also observed that 2-AR KO mice showed cardiac atrophy at rest. Cardiac SNs are strong regulators of the cardiomyocyte size via 2-AR-dependent repression of proteolysis, demonstrating that the neuro-cardiac axis operates constitutively for the determination of the physiological cardiomyocyte size. These results are of great clinical relevance given the role of -AR in cardiovascular diseases and their modulation in therapy. (AU)

FAPESP's process: 08/56483-1 - Role of B2-adrenergic receptors in skeletal muscle disorders triggered by heart failure
Grantee:Vanessa Azevedo Voltarelli
Support type: Scholarships in Brazil - Master
FAPESP's process: 10/50048-1 - Cellular and functional bases of exercise in cardiovascular diseases
Grantee:Carlos Eduardo Negrão
Support type: Research Projects - Thematic Grants