Selective Activation of LOX-1 Mediates C-Reactive Protein Evoked Endothelial Vasodilator Dysfunction in Coronary Arterioles
Rationale: Studies in cultured endothelium implicate that lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) or Fcγ receptor II (CD32) contributes to the pro-atherogenic effects of C-reactive protein (CRP). However, identity of the receptors linking to deleterious actions of CRP in vasomotor regulation remains unknown.
Objective: We tested the hypothesis that LOX-1 contributes to adverse effects of CRP on endothelium-dependent vasomotor function in resistance arterioles.
Methods and Results: Porcine coronary arterioles were isolated for vasoreactivity study, dihydroethidium fluorescence staining of superoxide, immunohistochemical localization of receptors, immunoprecipitation of receptor/CRP interaction, and protein blot. Intraluminal treatment of pressurized arterioles with a pathophysiological level of CRP (7 µg/mL, 60 minutes) attenuated endothelium-dependent nitric oxide (NO)-mediated and prostacyclin (PGI2)-mediated dilations to serotonin and arachidonic acid, respectively. LOX-1 and CD32 were both detected in the endothelium of arterioles. Blockade of LOX-1 with either pharmacological antagonist κ-carrageenan or anti-LOX-1 antibody prevented the detrimental effect of CRP on vasodilator function, whereas anti-CD32 antibody treatment was ineffective. Denudation of endothelium and blockade of LOX-1 but not CD32 prevented CRP-induced elevation of superoxide in the vessel wall. CRP was co-immunoprecipitated with LOX-1 and CD32 from CRP-treated arterioles. Similarly, LOX-1 and CD32 blockade both prevented CRP-induced arteriolar expression of plasminogen activator inhibitor-1 (PAI-1), a thrombogenic protein.
Conclusions: CRP elicits endothelium-dependent oxidative stress and compromises NO- and PGI2-mediated vasomotor function via LOX-1 activation. By contrast, both LOX-1 and CD32 mediate PAI-1 upregulation in arterioles by CRP. Thus, activation of LOX-1 and CD32 may contribute to vasomotor dysfunction and pro-atherogenic actions of CRP, respectively.
- Received May 10, 2013.
- Revision received October 16, 2013.
- Accepted October 18, 2013.