Beta 3 adrenoreceptors protect from hypertrophic remodelling through AMP‐activated protein kinase and autophagy
Abstract Aims The abundance of beta 3‐adrenergic receptors (β3‐ARs) is upregulated in diseased human myocardium. We previously showed that cardiac‐specific expression of β3‐AR inhibits the hypertrophic response to neurohormonal stimulation. Here, we further analysed signalling pathways involved in t...
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Wiley
2020-06-01
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| Series: | ESC Heart Failure |
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| Online Access: | https://doi.org/10.1002/ehf2.12648 |
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| author | Emilie Dubois‐Deruy Roselle Gelinas Christophe Beauloye Hrag Esfahani Lauriane Y.M. Michel Chantal Dessy Luc Bertrand Jean‐Luc Balligand |
| author_facet | Emilie Dubois‐Deruy Roselle Gelinas Christophe Beauloye Hrag Esfahani Lauriane Y.M. Michel Chantal Dessy Luc Bertrand Jean‐Luc Balligand |
| author_sort | Emilie Dubois‐Deruy |
| collection | DOAJ |
| description | Abstract Aims The abundance of beta 3‐adrenergic receptors (β3‐ARs) is upregulated in diseased human myocardium. We previously showed that cardiac‐specific expression of β3‐AR inhibits the hypertrophic response to neurohormonal stimulation. Here, we further analysed signalling pathways involved in the anti‐hypertrophic effect of β3‐AR. Methods and results In vitro hypertrophic responses to phenylephrine (PE) were analysed in neonatal rat ventricular myocytes (NRVM) infected with a recombinant adenovirus expressing the human β3‐AR (AdVhβ3). We confirmed results in mice with cardiomyocyte‐specific moderate expression of human β3‐AR (β3‐TG) and wild‐type (WT) littermates submitted to thoracic transverse aortic constriction (TAC) for 9 weeks. We observed a colocalization of β3‐AR with the AMP‐activated protein kinase (AMPK) both in neonatal rat and in adult mouse cardiomyocytes. Treatment of NRVM with PE induced hypertrophy and a decrease in phosphorylation of Thr172‐AMPK (/2, P = 0.0487) and phosphorylation of Ser79‐acetyl‐CoA carboxylase (ACC) (/2.6, P = 0.0317), inducing an increase in phosphorylated Ser235/236 S6 protein (×2.5, P = 0.0367) known to be involved in protein synthesis. These effects were reproduced by TAC in WT mice but restored to basal levels in β3‐AR expressing cells/mice. siRNA targeting of AMPK partly abrogated the anti‐hypertrophic effect of β3‐AR in response to PE in NRVM. Concomitant with hypertrophy, autophagy was decreased by PE, as measured by microtubule‐associated protein 1 light chain 3 (LC3)‐II/LC3‐I ratio (/2.6, P = 0.0010) and p62 abundance (×3, P = 0.0016) in NRVM or by TAC in WT mice (LC3‐II/LC3‐I ratio: /5.4, P = 0.0159), but preserved in human β3‐AR expressing cells and mice, together with reduced hypertrophy. Conclusions Cardiac‐specific moderate expression of β3‐AR inhibits the hypertrophic response in part through AMPK activation followed by inhibition of protein synthesis and preservation of autophagy. Activation of the cardiac β3‐AR pathway may provide future therapeutic avenues for the modulation of hypertrophic remodelling. |
| format | Article |
| id | doaj-art-e857d977b4014689b2a3e9935f6fcd2f |
| institution | Kabale University |
| issn | 2055-5822 |
| language | English |
| publishDate | 2020-06-01 |
| publisher | Wiley |
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| series | ESC Heart Failure |
| spelling | doaj-art-e857d977b4014689b2a3e9935f6fcd2f2025-02-03T10:25:46ZengWileyESC Heart Failure2055-58222020-06-017392093210.1002/ehf2.12648Beta 3 adrenoreceptors protect from hypertrophic remodelling through AMP‐activated protein kinase and autophagyEmilie Dubois‐Deruy0Roselle Gelinas1Christophe Beauloye2Hrag Esfahani3Lauriane Y.M. Michel4Chantal Dessy5Luc Bertrand6Jean‐Luc Balligand7Institut de Recherche Expérimentale et Clinique (IREC), Pole of Pharmacology and Therapeutics (FATH) Université Catholique de Louvain (UCLouvain) and Cliniques Universitaires Saint‐Luc B1.57.04, 57 Avenue Hippocrate Brussels 1200 BelgiumInstitut de Recherche Expérimentale et Clinique (IREC), Pole of Cardiovascular Pathology (CARD) Université Catholique de Louvain (UCLouvain) and Cliniques Universitaires Saint‐Luc Brussels BelgiumInstitut de Recherche Expérimentale et Clinique (IREC), Pole of Cardiovascular Pathology (CARD) Université Catholique de Louvain (UCLouvain) and Cliniques Universitaires Saint‐Luc Brussels BelgiumInstitut de Recherche Expérimentale et Clinique (IREC), Pole of Pharmacology and Therapeutics (FATH) Université Catholique de Louvain (UCLouvain) and Cliniques Universitaires Saint‐Luc B1.57.04, 57 Avenue Hippocrate Brussels 1200 BelgiumInstitut de Recherche Expérimentale et Clinique (IREC), Pole of Pharmacology and Therapeutics (FATH) Université Catholique de Louvain (UCLouvain) and Cliniques Universitaires Saint‐Luc B1.57.04, 57 Avenue Hippocrate Brussels 1200 BelgiumInstitut de Recherche Expérimentale et Clinique (IREC), Pole of Pharmacology and Therapeutics (FATH) Université Catholique de Louvain (UCLouvain) and Cliniques Universitaires Saint‐Luc B1.57.04, 57 Avenue Hippocrate Brussels 1200 BelgiumInstitut de Recherche Expérimentale et Clinique (IREC), Pole of Cardiovascular Pathology (CARD) Université Catholique de Louvain (UCLouvain) and Cliniques Universitaires Saint‐Luc Brussels BelgiumInstitut de Recherche Expérimentale et Clinique (IREC), Pole of Pharmacology and Therapeutics (FATH) Université Catholique de Louvain (UCLouvain) and Cliniques Universitaires Saint‐Luc B1.57.04, 57 Avenue Hippocrate Brussels 1200 BelgiumAbstract Aims The abundance of beta 3‐adrenergic receptors (β3‐ARs) is upregulated in diseased human myocardium. We previously showed that cardiac‐specific expression of β3‐AR inhibits the hypertrophic response to neurohormonal stimulation. Here, we further analysed signalling pathways involved in the anti‐hypertrophic effect of β3‐AR. Methods and results In vitro hypertrophic responses to phenylephrine (PE) were analysed in neonatal rat ventricular myocytes (NRVM) infected with a recombinant adenovirus expressing the human β3‐AR (AdVhβ3). We confirmed results in mice with cardiomyocyte‐specific moderate expression of human β3‐AR (β3‐TG) and wild‐type (WT) littermates submitted to thoracic transverse aortic constriction (TAC) for 9 weeks. We observed a colocalization of β3‐AR with the AMP‐activated protein kinase (AMPK) both in neonatal rat and in adult mouse cardiomyocytes. Treatment of NRVM with PE induced hypertrophy and a decrease in phosphorylation of Thr172‐AMPK (/2, P = 0.0487) and phosphorylation of Ser79‐acetyl‐CoA carboxylase (ACC) (/2.6, P = 0.0317), inducing an increase in phosphorylated Ser235/236 S6 protein (×2.5, P = 0.0367) known to be involved in protein synthesis. These effects were reproduced by TAC in WT mice but restored to basal levels in β3‐AR expressing cells/mice. siRNA targeting of AMPK partly abrogated the anti‐hypertrophic effect of β3‐AR in response to PE in NRVM. Concomitant with hypertrophy, autophagy was decreased by PE, as measured by microtubule‐associated protein 1 light chain 3 (LC3)‐II/LC3‐I ratio (/2.6, P = 0.0010) and p62 abundance (×3, P = 0.0016) in NRVM or by TAC in WT mice (LC3‐II/LC3‐I ratio: /5.4, P = 0.0159), but preserved in human β3‐AR expressing cells and mice, together with reduced hypertrophy. Conclusions Cardiac‐specific moderate expression of β3‐AR inhibits the hypertrophic response in part through AMPK activation followed by inhibition of protein synthesis and preservation of autophagy. Activation of the cardiac β3‐AR pathway may provide future therapeutic avenues for the modulation of hypertrophic remodelling.https://doi.org/10.1002/ehf2.12648Adrenergic receptorAMP‐activated kinase (AMPK)AutophagyHeart failureCardiac hypertrophy |
| spellingShingle | Emilie Dubois‐Deruy Roselle Gelinas Christophe Beauloye Hrag Esfahani Lauriane Y.M. Michel Chantal Dessy Luc Bertrand Jean‐Luc Balligand Beta 3 adrenoreceptors protect from hypertrophic remodelling through AMP‐activated protein kinase and autophagy ESC Heart Failure Adrenergic receptor AMP‐activated kinase (AMPK) Autophagy Heart failure Cardiac hypertrophy |
| title | Beta 3 adrenoreceptors protect from hypertrophic remodelling through AMP‐activated protein kinase and autophagy |
| title_full | Beta 3 adrenoreceptors protect from hypertrophic remodelling through AMP‐activated protein kinase and autophagy |
| title_fullStr | Beta 3 adrenoreceptors protect from hypertrophic remodelling through AMP‐activated protein kinase and autophagy |
| title_full_unstemmed | Beta 3 adrenoreceptors protect from hypertrophic remodelling through AMP‐activated protein kinase and autophagy |
| title_short | Beta 3 adrenoreceptors protect from hypertrophic remodelling through AMP‐activated protein kinase and autophagy |
| title_sort | beta 3 adrenoreceptors protect from hypertrophic remodelling through amp activated protein kinase and autophagy |
| topic | Adrenergic receptor AMP‐activated kinase (AMPK) Autophagy Heart failure Cardiac hypertrophy |
| url | https://doi.org/10.1002/ehf2.12648 |
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