Oxidized LDL but not angiotensin II induces cardiomyocyte hypertrophic responses through the interaction between LOX-1 and AT1 receptors.

Abstract

It is well known that lectin-like oxidized low-density lipoprotein (ox-LDL) and its receptor LOX-1, angiotensin II (AngII) and its type 1 receptor (AT1-R) play an important role in the development of cardiac hypertrophy. However, the molecular mechanism is not clear. In this study, we found that ox-LDL-induced cardiac hypertrophy was suppressed by inhibition of LOX-1 or AT1-R but not by AngII inhibition. These results suggest that the receptors LOX-1 and AT1-R, rather than AngII, play a key role in the role of ox-LDL. The same results were obtained in mice lacking endogenous AngII and their isolated cardiomyocytes. Ox-LDL but not AngII could induce the binding of LOX-1 and AT1-R; inhibition of LOX-1 or AT1-R but not AngII could abolish the binding of these two receptors. Overexpression of wild type LOX-1 with AT1-R enhanced ox-LDL-induced binding of two receptors and phosphorylation of ERKs, however, transfection of LOX-1 dominant negative mutant (lys266ala / lys267ala) or an AT1-R mutant (glu257ala) not only reduced the binding of two receptors but also inhibited the ERKs phosphorylation. Phosphorylation of ERKs induced by ox-LDL in LOX-1 and AT1-R-overexpression cells was abrogated by an inhibitor of Gq protein rather than Jak2, Rac1 or RhoA. Genetically, an AT1-R mutant lacking Gq protein coupling ability inhibited ox-LDL induced ERKs phosphorylation. Furthermore, through bimolecular fluorescence complementation analysis, we confirmed that ox-LDL rather than AngII stimulation induced the direct binding of LOX-1 and AT1-R. We conclude that direct binding of LOX-1 and AT1-R and the activation of downstream Gq protein are important mechanisms of ox-LDL-induced cardiomyocyte hypertrophy.

• Authors: Li Lin, Ning Zhou, Le Kang, Qi Wang, Jian Wu, Xiaoyan Wang, Chunjie Yang, Guoping Zhang, Yunqin Chen, Hong Jiang, Ruizhen Chen, Xiangdong Yang, Aijun Sun, Hui Gong, Jun Ren, Hiroshi Akazawa, Komuro Issei, Junbo Ge, Cheng Yang, Yunzeng Zou
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 162 Pg. 110-118 (01 2022) ISSN: 1095-8584 [Electronic] England
• PMID: 34555408 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021. Published by Elsevier Ltd.

Chemical References

• Lipoproteins, LDL
• Receptors, LDL
• Receptors, Oxidized LDL
• Scavenger Receptors, Class E
• oxidized low density lipoprotein
• Angiotensin II

Topics

• Angiotensin II (metabolism, pharmacology)
• Animals
• Cells, Cultured
• Lipoproteins, LDL (metabolism)
• Mice
• Myocytes, Cardiac (metabolism)
• Receptors, LDL (metabolism)
• Receptors, Oxidized LDL (metabolism)
• Scavenger Receptors, Class E (genetics, metabolism)