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

Autor(es):Mostrar menos -

Zaglia, Tania ^{[1, 2]} ; Milan, Giulia ^[1] ; Franzoso, Mauro ^{[1, 2]} ; 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]}

Afiliação do(s) autor(es)

^[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

• Tipo de documento: Artigo Científico
• Fonte: Cardiovascular Research; v. 97, n. 2, p. 240-250, FEB 2013.
• Citações Web of Science: 33

Resumo

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)

• Processo FAPESP: 10/50048-1 - Bases celulares e funcionais do exercício físico na doença cardiovascular
• Beneficiário: Carlos Eduardo Negrão
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 08/56483-1 - Papel dos receptores B2-adrenérgicos nas alterações músculo-esqueléticas desencadeadas pela insuficiência cardíaca
• Beneficiário: Vanessa Azevedo Voltarelli
• Modalidade de apoio: Bolsas no Brasil - Mestrado