Lcn2 expression is closely related to metabolism and inflammation, both of which contribute to the pathogenic process of atherosclerosis. In addition, serum LCN2 levels are positively associated with the subsequent development of CAD in patients with coronary artery atherosclerosis. Furthermore, this relationship has been described in CAD patients of Caucasian and Asian (Korean) ethnic origin, with the former showing the positive association between CAD severity in patients with myocardial infarction (vs. those with stable angina) [16–18]. Increased serum LCN2 levels were also shown to be gender- (in men vs. women) and weight- (in obese vs. normal weight) related . In the present study, obvious gender-related differences were observed as well (in agreement with the previous studies) which led to the study design including gender stratification analysis (with a men focus in the regression analysis). Ultimately, the Chinese men in our study who had CAD also had significantly higher serum LCN2 levels than either the women or their non-CAD men counterparts.
Studies to elucidate the pathogenic molecular mechanism of Lcn2 in atherosclerosis and CAD have shown that the Lcn2/MMP-9 complex acts to destabilize the artery plaque . This complex has been detected in clinical specimens of plaques on the side facing the lumen area and in lipid centers, suggesting an involvement in vascular inflammation and reconstruction in myocardial ischemia . MMP-9 alone, however, has been suggested to promote atherosclerosis by degrading the vascular basement membrane, thereby increasing endothelial permeability and allowing more white blood cells and inflammatory cytokines to infiltrate the intima. Indeed, the conditions of plaque bleeding and hypoxia are accompanied by increased levels of the Lcn2/MMP-9 complex; since the complexed form also acts to protect the MMP-9 protein from degradation, it is more capable of exerting a further effect (both in its beneficial and detrimental manners) on the surrounding tissue. The differential effects of MMP-9 have been seen in different stages of CAD. It is believed that the uncomplexed protein’s degradation might be initially beneficial to vascular repair. However, the constant inflammatory stimulation and up-regulated Lcn2 may lead to increased levels of the more stable Lcn2/MMP-9 complex, thereby destabilizing the plaques and prompting the acute cardiovascular event .
The current study included a cohort of patients at high risk of metabolic diseases, especially MS. The results suggested that serum LCN2 levels were 1.25-times higher in the patients with MS than those without MS; furthermore, the levels of LCN2 increased along with increases in the number of MS components in the men patients. Patients with metabolic disorders have been previously shown to have a higher rate of cardiovascular diseases . MS, in particular, and its components (which are characterized as conventional risk factors of cardiovascular diseases) is known to cause endothelial damage leading to formation of the atherosclerotic plaque and facilitating lipid infiltration that contributes to atherosclerosis progression [29, 30]. In agreement with this pathogenic process, serum HDL-c has been previously demonstrated as negatively correlated with serum LCN2 levels ; likewise, in the current study serum TG was identified as a positive influencing factor of serum LCN2 levels, indicating that the related pathogenic mechanism of atherosclerosis may involve disruption of lipid metabolism.
Chronic inflammation is another well-recognized feature of CAD development. Previous studies have shown that patients with acute coronary syndrome also have increased levels of serum CRP [31, 32], which are positively associated with serum LCN2 levels even after adjusting for several confounders . In this study, the number of neutrophils, generally known to be an index of inflammation status, was found to be positively correlated with serum LCN2 levels. Similar results were obtained in the current study of Chinese cohort, suggesting that LCN2 might prompt the inflammatory process that induces atherosclerosis.
When interpreting the results from the current study, three inherent limitations to the study design must be remembered. Firstly, the sample size was relatively small. Secondly, the cross-sectional nature of the study precluded the ability to confirm whether LCN2 itself was a predictor of CAD. Finally, additional factors that may influence in the outcome of our population were not measured, including MMP-9 , retinol binding protein 4 and resistin . Subsequent investigations should consider each of these features to provide further insights into this pathogenesis topic.