Selective Activation of Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 Mediates C-Reactive Protein–Evoked Endothelial Vasodilator Dysfunction in Coronary Arterioles

Abstract

I nflammation-related cardiovascular disturbance is regarded as a pivotal event in the development of atherosclerosis. 1 C-reactive protein (CRP), a biomarker of inflammation and cardiovascular deterioration, is becoming an emerging risk factor for cardiovascular disease. The landmark Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) study recently showed that statin therapy significantly reduced the CRP levels, along with the incidence of major cardiovascular events, in apparently healthy individuals with elevated CRP (≥2 µg/mL). 2,3Despite the lack of direct evidence for a causal link of CRP, accumulating findings suggest that CRP is actively involved in promoting adverse cardiovascular outcomes because of its proatherogenic effects on vascular cells. 4 In cell culture models, CRP, at relatively high pharmacological concentrations (25-100 µg/mL), has been shown to elevate reactive oxygen species generation from vascular cells 5,6 and impair nitric oxide (NO) synthase (NOS) activity and NO production, 7,8 as well as prostacyclin (PGI 2 ) release, 5 from endothelial cells. Extending the studies from a homogeneous cell type in culture, we recently demonstrated in intact coronary arterioles that CRP, at a clinically relevant concentration (7 µg/mL), impairs endothelium-dependent NO-mediated and PGI 2 -mediated dilations by reducing NO bioavailability 9 and inhibiting PGI 2 synthase activation, respectively.10 The detrimental effect of CRP on vasodilator function depended on endothelial production of reduced form of nicotinamide dinucleotide phosphate (NAD[P]H) oxidase-derived superoxide

The Gene Polymorphism of LOX1 Predicts the Incidence of LVH in Patients with Essential Hypertension

“…The sLOX-1 level, however, may be a better parameter than hs-CRP to differentiate the LVH+ patients from the LVH- patients based on the ROC curves. These experimental results correlate to close functional partnership of LOX1 and CRP that has been well studied in their pro-atherogenic effects on vascular cells [16,38,39,40,41]. Among all, a recent study suggested that L5, a subfraction of plasma LDL, CRP and the LOX-1 may constitute a positive feedback loop that contributes to endothelial dysfunction [39].…”

“…LOX-1 along with Fcγ receptors functions as a receptor for CRP [42]. CRP elicits oxidative stress and compromises vasomotor function on porcine coronary arterioles via LOX-1 activation [38]. In addition, CRP promotes the release of soluble LOX-1 from macrophages by activating tumor necrosis factor alpha (TNF-α) converting enzyme [39] and increases vascular permeability through direct binding to LOX-1[42].…”

“…In addition, CRP promotes the release of soluble LOX-1 from macrophages by activating tumor necrosis factor alpha (TNF-α) converting enzyme [39] and increases vascular permeability through direct binding to LOX-1[42]. On the other hand, LOX-1 mediated upregulation of a thrombogenic protein, plasminogen activator inhitor-1 (PAI-1) in arterioles by CRP [38]. LOX-1 may be also involved in CRP-induced complement activation, and thus may serve to locate the site of CRP-induced complement activation and inflammation [42].…”

Interplay between CRP, Atherogenic LDL, and LOX-1 and Its Potential Role in the Pathogenesis of Atherosclerosis

“…It has been shown that CRP increases vascular permeability through a direct interaction with LOX-1 dependent on calcium that can be outcompeted with phosphorylcholine (3 ). In addition, CRP induces monocyte-endothelial cell adhesion through LOX-1 (8 ) and impairs endotheliumdependent vasodilator function through LOX-1 (30 ). Furthermore, Fujita and colleagues (31 ) have shown in hypertensive rats that LOX-1 is also involved in CRPinduced complement activation, whereby LOX-1 may have a role in tethering CRP to the cell membrane to induce complement activation.…”

“…2). Although Fc␥Rs were initially postulated to mediate the effects of CRP outside of complement activation, evidence has indicated that both LOX-1 and Fc␥Rs mediate some effects of CRP (30 ). Importantly, OxLDL and plasma L5 isolated from hypercholesterolemic patients have been shown to induce the release of CRP from human aortic endothelial cells in a LOX-1-dependent manner, whereas native LDL has no effect (32,33 ).…”