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Prof. Dobromir Dobrev
Chronic beta-adrenergic stimulation promotes the progression to heart failure and a better understanding of the underlying signal transduction abnormalities is expected to lead to the development of novel drugs with a better efficacy and safety profiles. This session provided novel insights into the signal transduction of the beta-adrenergic receptor system and discussed potential new targets for the treatment of hypertrophy and heart failure.
Jean-Luc Balligand (Brussels, BE) showed a specific pathway of how compartmentalized nitric oxide (NO) signalling may tune the cardiac inotropic responses to isoproterenol. Endothelial NOS-derived NO activates guanylate cyclase, increasing the formation of intracellular cGMP. This results in enhanced myocyte relaxation through protein kinase G/cGMP-dependent desensitisation of cardiac myofilaments, favoring the stretch-dependent increase in contractility. At the same time, activation of NO signalling reduced the positive inotropic and chronotropic responses to isoproterenol. This dual action of NO obviously mimics the effects of a “small beta-adrenergic blockade” without the known adverse effects of classical beta-blockers. The unique NO signalling required selective activation of beta3-adrenoceptors, which may offer the opportunity of specific targeting of this pathway. Barbara Casadei (Oxford, UK) further elaborated on NO signalling by focusing on the effects of NO derived by the neuronal type of NOS. Deletion of nNOS in mice reduced the negative inotropic effect to a selective beta3-adrenoceptor agonist, consistent with the known negative inotropic actions of NO in the heart. nNOS co-localises with SERCA-inhibitory phospholamban and knock-out of nNOS in mice resulted in enhanced basal cardiomyocyte contractility, likely because of increased calcium uptake into the sarcoplasmic reticulum through SERCA. Conversely, nNOS deletion in mice exacerbated LV adverse remodelling after myocardial infarction that could not solely be explained by lack of NO, because the abundance of xanthine oxireductase was increased and was associated with eNOS “uncoupling” and enhanced production of reactive oxygen species. Thus, the consequences of increased nNOS abundance in patients with heart failure are difficult to predict and much more work is needed to define clearly the specific roles of eNOS- and nNOS-derived NO in the heart. The role of different subtypes of G-protein coupled receptor kinases (GRKs) in the heart is still incompletely understood. Besides their role in regulating beta-adrenoceptor desensitisation, some GRKs may exert G-protein coupled receptor independent actions, as described by Guido Iaccarino (Napoli, IT). He showed that GRK2 and GRK5 may modulate the evolution of cardiac hypertrophy and presented compelling evidence that GRK5 localises in the nucleus where it specifically inhibits nuclear factor kappa-B transcriptional activity, reducing cardiomyocyte hypertrophy. Since nuclear factor kappa-B is a key contributor to a variety of disease conditions, future targeting of GRK5 may have broad therapeutic implications. The role of Signal Transducer and Activator of Signal Transduction 3 (STAT3) in the remodelling process during hypertrophy and heart failure was reviewed by Denise Hilfiker-Kleiner (Hannover, DE). She demonstrated that STAT3 knock-out mice responded to chronic isoproterenol application with impaired diastolic function and increased fibrosis, inflammation and necrosis. Although increased oxidative stress, altered energy balance and impaired cardiomyocyte calcium handling may well contribute, the specific signalling pathways that underlie the deleterious phenotype in STAT3 knock-out mice are still largely unknown.
In conclusion, activation of the cardiac beta-adrenergic system causes complex alterations of cardiac function that induce adaptive and maladaptive cardiac responses in disease states. The dissection of the adaptive and maladaptive signal transduction components is a clear challenge for the future with the hope to identify novel innovative therapeutics.
News and views on beta-adrenergic receptors
This congress report accompanies a presentation given at the ESC Congress 2009. Written by the author himself/herself, this report does not necessarily reflect the opinion of the European Society of Cardiology.
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