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Crosstalk between Src and β-arrestin2 orchestrates cardiac hypertrophic responses under mechanical stresses

Research paper by Shijun Wang, Jian Wu, Zhen Wang, Yunzeng Zou

Indexed on: 24 Nov '17Published on: 03 Jan '15Published in: Cardiovascular regenerative medicine



Abstract

The activity of Src, one of the non-receptor tyrosine kinase family proteins, is increased during mechanical stretch-evoked cardiac hypertrophy. Angiotensin II (AngII) type 1 receptor (AT1-R) plays a pivotal role in hypertrophic responses under mechanical stresses independently of Ang II. However, whether Src is critically involved in AngII-independent AT1-R signaling transduction and cardiac hypertrophy is not yet clear. Here we have reported that Src tyrosine kinase is activated and recruited by β-arrestin2, both bind to membrane AT1-R and trigger the intracellular ERK1/2 signaling pathway, leading to the development of cardiac hypertrophy. Our findings highlight that mechanical stretch-induced, β-arrestin2-dependent Src-ERK hypertrophic pathway, might be partly different from the Ang-II-induced one, which is dependent on G protein coupling. In the former, neither Gαq-mediated protein kinase C (PKC) nor IP3 are activated by mechanical stretch in cardiomyocytes, however, inhibition of Src kinase causes attenuation of ERK1/2 signaling and improves pressure overload-induced cardiac hypertrophy and dysfunction in mice lacking AngII. Our work suggests that Src might be one of the potential therapeutic targets for pressure overload-induced myocardial remodeling.The activity of Src, one of the non-receptor tyrosine kinase family proteins, is increased during mechanical stretch-evoked cardiac hypertrophy. Angiotensin II (AngII) type 1 receptor (AT1-R) plays a pivotal role in hypertrophic responses under mechanical stresses independently of Ang II. However, whether Src is critically involved in AngII-independent AT1-R signaling transduction and cardiac hypertrophy is not yet clear. Here we have reported that Src tyrosine kinase is activated and recruited by β-arrestin2, both bind to membrane AT1-R and trigger the intracellular ERK1/2 signaling pathway, leading to the development of cardiac hypertrophy. Our findings highlight that mechanical stretch-induced, β-arrestin2-dependent Src-ERK hypertrophic pathway, might be partly different from the Ang-II-induced one, which is dependent on G protein coupling. In the former, neither Gαq-mediated protein kinase C (PKC) nor IP3 are activated by mechanical stretch in cardiomyocytes, however, inhibition of Src kinase causes attenuation of ERK1/2 signaling and improves pressure overload-induced cardiac hypertrophy and dysfunction in mice lacking AngII. Our work suggests that Src might be one of the potential therapeutic targets for pressure overload-induced myocardial remodeling.3