Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology · 2015
Identification of Amino Acid Residues in Angiotensin II Type 1 Receptor Sensing Mechanical Stretch and Function in Cardiomyocyte Hypertrophy.
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Jiang Guoliang, Gong Hui, Niu Yuhong, Yang Chunjie, Wang Shijun, Chen Zhidan, Ye Yong, Zhou Ning, Zhang Guoping, Ge Junbo, Zou Yunzeng
Аннотация
BACKGROUND/AIMS: Angiotensin II (AngII) type 1 receptor (AT1R) could be activated by mechanical stress without the involvement of AngII during the development of cardiac hypertrophy. We aimed to identify sensing sites of AT1R for activation by mechanical stretch.
METHODS: We constructed several site-directed mutations of AT1R (AT1R(K199Q), AT1R(L212F), AT1R(Q257A) and AT1R(C289A)), transfected them respectively into COS7 cells or angiotensinogen knockout cardiomyocytes (ATG(−/−)-CMs), and observed cellular events after mechanical stretch.
RESULTS: AngII-induced phosphorylation of ERKs and Jak2, and redistribution of Gαq11 in AT1R(WT)- COS7 or -ATG(−/−)-CMs were dramatically decreased in AT1R(K199Q)- or AT1R(Q257A)- COS7 cells or -ATG(−/−)- CMs, while those effects induced by mechanical stretch were greatly suppressed in COS7 cells or ATG(−/−)-CMs expressing AT1R(L212F), AT1R(Q257A) or AT1R(C289A) compared with these cells expressing AT1R(WT). AngII-induced hypertrophic responses (the increase in hypertrophic genes expression and cross-sectional area) in AT1R(WT)- ATG(−/−)-CMs were partly abolished in AT1R(K199Q)-ATG(−/−)- CMs or AT1R(Q257A) -ATG(−/−)-CMs, while these responses induced by mechanical stretch were greatly inhibited in ATG(−/−)-CMs overexpressing AT1R(L212F), AT1R(Q257A )or AT1R(C289A).
CONCLUSION: These results indicated that Leu212, Gln257 and Cys289 in AT1R are not only sensing sites for mechanical stretch but also functional amino residues for activation of the receptor and cardiomyocytes hypertrophy induced by mechanical stretch.
METHODS: We constructed several site-directed mutations of AT1R (AT1R(K199Q), AT1R(L212F), AT1R(Q257A) and AT1R(C289A)), transfected them respectively into COS7 cells or angiotensinogen knockout cardiomyocytes (ATG(−/−)-CMs), and observed cellular events after mechanical stretch.
RESULTS: AngII-induced phosphorylation of ERKs and Jak2, and redistribution of Gαq11 in AT1R(WT)- COS7 or -ATG(−/−)-CMs were dramatically decreased in AT1R(K199Q)- or AT1R(Q257A)- COS7 cells or -ATG(−/−)- CMs, while those effects induced by mechanical stretch were greatly suppressed in COS7 cells or ATG(−/−)-CMs expressing AT1R(L212F), AT1R(Q257A) or AT1R(C289A) compared with these cells expressing AT1R(WT). AngII-induced hypertrophic responses (the increase in hypertrophic genes expression and cross-sectional area) in AT1R(WT)- ATG(−/−)-CMs were partly abolished in AT1R(K199Q)-ATG(−/−)- CMs or AT1R(Q257A) -ATG(−/−)-CMs, while these responses induced by mechanical stretch were greatly inhibited in ATG(−/−)-CMs overexpressing AT1R(L212F), AT1R(Q257A )or AT1R(C289A).
CONCLUSION: These results indicated that Leu212, Gln257 and Cys289 in AT1R are not only sensing sites for mechanical stretch but also functional amino residues for activation of the receptor and cardiomyocytes hypertrophy induced by mechanical stretch.