Abstract 18189: Direct Binding of LOX-1 With AT1 Receptors Mediates Ox-LDL-Induced Cardiomyocyte Hypertrophy
Introduction: Lectin-like oxidized low-density lipoprotein (ox-LDL) and its receptor LOX-1 as well as angiotensin II (AngII) and its type 1 receptor (AT1-R) have been implicated in the development of cardiomyocye hypertrophy, however, the relationship between them remains unknown.
Hypothesis: We here demonstrate that ox-LDL induces hypertrophic responses by stimulating direct association and interaction of LOX-1 with AT1-R.
Methods: Ox-LDL (250 ng/kg/min), AngII (200 ng/kg/min),Losartan (3 mg/kg/day), LOX-1 neutralizing antibody (0.6 mg/kg/day) and Enalapril (10 mg/kg/day) were continuously administered by Alzet osmotic minipumps implanted subcutaneously into the mice. Transthoratic echocardiography was performed.
Results: Ox-LDL induced hypertrophic responses both in vivo and in vitro, which could be abolished following inhibition of either LOX-1 or AT1-R by both pharmacologic and RNA silence methods but not by attenuation of AngII, suggesting that LOX-1 and AT1-R rather than AngII are critically involved in the effect of ox-LDL. This observation was supported by similar results obtained from the mice and cultured cardiomyocytes lacking endogenous AngII. We therefore examined how LOX-1 and AT1-R are involved in ox-LDL-induced hypertrophic responses by using the mice and cells lacking AngII. Stimulation with ox-LDL simultaneously induced upregulation as well as the association of LOX-1 and AT1-R, and the upregulation and association of the two receptors were abolished by either LOX-1 or AT1-R inhibition. Overexpression of both AT1-R and LOX-1 enhanced ox-LDL-stimulated protein kinase phosphorylation. Furthermore, by using a bimolecular fluorescence complementation assay, we observed the direct binding of the N-terminal of LOX-1 with C-terminal of AT1-R following stimulation with ox-LDL but not with AngII.
Conclusions: Our data suggest that direct binding of LOX-1 with AT1-R is an important mechanism for ox-LDL to induce cardiomyocyte hypertrophy, no matter whether AngII exists or does not.
Author Disclosures: H. Gong: None. L. Lin: None. N. Zhou: None. J. Wu: None. Y. Ye: None. C. Yang: None. G. Zhang: None. J. Ge: None. Y. Zou: None.
- © 2016 by American Heart Association, Inc.