Role of gp130-mediated signalling pathways in the heart and its impact on potential therapeutic aspects

IL-6-type cytokines bind to plasma membrane receptor complexes containing the common signal transducing receptor chain gp130 that is ubiquitously expressed in most tissues including the heart. The two major signalling cascades activated by the gp130 receptor, SHP2/ERK and STAT pathways, have been demonstrated to play important roles in cardiac development, hypertrophy, protection and remodelling in response to physiological and pathophysiological stimuli. Experimental data, both in vivo and in vitro, imply beneficial effects of gp130 signalling on cardiomyocytes in terms of growth and survival. In contrast, it has been reported that elevated serum levels of IL-6 cytokines and gp130 proteins are strong prognostic markers for morbidity and mortality in patients with heart failure or after myocardial infarction. Moreover, it has been shown that the local gp130 receptor system is altered in failing human hearts. In the present review, we summarize the basic principles of gp130 signalling, which requires simultaneous activation of STAT and ERK pathways under the tight control of positive and negative intracellular signalling modulators to provide a balanced biological outcome. Furthermore, we highlight the key role of the gp130 receptor and its major downstream effectors in the heart in terms of development and regeneration and in response to various physiological and pathophysiological stress situations. Finally, we comment on tissue-specific diversity and challenges in targeted pharmacological interference with components of the gp130 receptor system.