| First Author | Vidal M | Year | 2012 |
| Journal | Cardiovasc Res | Volume | 96 |
| Issue | 2 | Pages | 255-64 |
| PubMed ID | 22843704 | Mgi Jnum | J:202653 |
| Mgi Id | MGI:5520157 | Doi | 10.1093/cvr/cvs249 |
| Citation | Vidal M, et al. (2012) beta-Adrenergic receptor stimulation causes cardiac hypertrophy via a Gbetagamma/Erk-dependent pathway. Cardiovasc Res 96(2):255-64 |
| abstractText | AIMS: Activation of the beta(1)-adrenergic receptor and its G protein, G(s), induces cardiac hypertrophy. However, activation of classic Galpha(s) effectors, adenylyl cyclases (AC) and protein kinase A, is not sufficient for induction of hypertrophy, which suggests the involvement of additional pathway(s) activated by G(s). Recently, we discovered that betagamma subunits of G(q) induce phosphorylation of the extracellular regulated kinases 1 and 2 (Erk1/2) at threonine188 and thereby induce hypertrophy. Here we investigated whether beta-adrenergic receptors might also induce cardiac hypertrophy via Erk(Thr188) phosphorylation. METHODS AND RESULTS: beta-Adrenergic receptor activation induced Erk(Thr188) phosphorylation in mouse hearts and in neonatal cardiomyocytes. Inhibition of Erk1/2 or overexpression of Erk(Thr188) phosphorylation-deficient mutants (Erk2(T188A) and Erk2(T188S)) significantly attenuated beta-adrenergic cardiomyocyte hypertrophy in vitro. Erk activity was stimulated by both isoproterenol and the direct AC activator forskolin, but only isoproterenol induced Erk(Thr188) phosphorylation. Erk(Thr188) phosphorylation required Gbetagamma released from G(s) and was prevented by Gbetagamma inhibition. Similarly, isoproterenol, but not forskolin, induced nuclear accumulation of Erk and cardiomyocyte hypertrophy. Long-term application of isoproterenol in mice caused left ventricular hypertrophy and cardiac remodelling, and this was reduced in Erk2(T188S) transgenic mice, supporting the physiological relevance of Erk(Thr188) phosphorylation. CONCLUSIONS: Activation of G(s) by beta-adrenergic receptors leads to (i) canonical Erk1/2 activation via AC, and (ii) release of Gbetagamma, which then associates with activated Erk1/2 and induces Erk(Thr188) phosphorylation, causing nuclear accumulation of Erk and ultimately cardiomyocyte hypertrophy. These findings reveal a new pathway critically involved in beta-adrenergically mediated cardiac hypertrophy and may yield new therapeutic strategies against hypertrophic remodelling. |
