Expression of Neutrophil Gelatinase–Associated Lipocalin in Atherosclerosis and Myocardial Infarction

Abstract

Objective-Neutrophil gelatinase-associated lipocalin (NGAL) modulates the activity of matrix metalloproteinase (MMP) 9, an important mediator of vascular remodeling and plaque instability in atherosclerosis. This study aimed to analyze the expression of NGAL in atherosclerotic plaques and myocardial infarction (MI). Methods and Results-Atherosclerotic apolipoprotein E (apoE)Ϫ/Ϫ ϫ low-density lipoprotein receptor (LDLR) Ϫ/Ϫ and C57BL/6J control mice were exposed to brief hypoxic stress (10 minutes of 10% oxygen). Expression of the mouse NGAL homolog (24p3) and MMP-9 was analyzed 48 hours later by quantitative RT-PCR, immunohistochemistry, and zymography. Hypoxic stress increased NGAL/24p3 mRNA in the cardiac vasculature. NGAL/24p3 was also increased in atherosclerotic plaques of apolipoprotein E Ϫ/Ϫ ϫ LDLR Ϫ/Ϫ mice compared with C57BL/6J mice. Mice developing MI exhibited the highest plaque mRNA expression of NGAL/24p3 and MMP-9. Zymography revealed strong proteolytic activity in areas rich in 24p3 and MMP-9 protein. Immunohistochemistry performed on human carotid endarterectomy specimens and control tissue from the internal mammary artery showed colocalization of MMP-9 and NGAL with macrophages in the atherosclerotic plaques. Conclusions-NGAL/24p3 is increased in atherosclerotic plaques and MI. Colocalization with MMP-9 in areas with high-proteolytic activity suggests a role for NGAL/24p3 in modulating the MMP-9-mediated remodeling of plaques and infarcted hearts. Key Words: atherosclerosis Ⅲ myocardial infarction Ⅲ hypoxia Ⅲ matrix metalloproteinase Ⅲ remodeling C omplications to coronary atherosclerosis leading to myocardial infarction were previously believed to be because of the physical obstruction of the vessel lumen; however, 60% to 70% of myocardial infarctions (MIs) result from nonocclusive plaques. 1-4 Current evidence instead suggest that physical disruption of atherosclerotic plaques triggers thrombus formation, which may lead to MI. 5-7 The 2 major precipitating factors of thrombus formation are disruption of the plaque cap and erosion of its endothelial lining. Inflammation within the atherosclerotic plaque has been suggested to promote the progression toward plaque disruption by causing plaque instability. 8 Inflammatory mediators found in the atheroma have been shown to inhibit smooth muscle growth and collagen production and to augment matrix metalloproteinase (MMP) activity. 9 -12 This can result in decreased collagen content and weakening of plaque structure, leaving the fibrous cap prone to rupture.MMPs are a family of endopeptidases capable of degrading the molecular components of the extracellular matrix. They play important roles in a variety of pathological processes, such as atherosclerosis and tumor cell invasion. In particular, gelatinase B (MMP-9) is thought to be associated with diseases such as abdominal aortic aneurysm, atherosclerosis, and plaque rupture. 13 In cancer patients, urinary highmolecular weight MMPs have been shown to be independent predictors of metastatic cancers,...

Neutrophil Gelatinase-Associated Lipocalin induces the expression of heme oxygenase-1 and superoxide dismutase 1, 2

“…It has been reported that hypoxic stress and acute infraction increase Lcn2 expression in mouse macrophages (Hemdahl et al 2006, Jiang et al 2008). This supports the idea that expression of lipocalin-2 is a response that these cells show against hypoxic stress.…”

Lipocalin-2 Induces Cardiomyocyte Apoptosis by Increasing Intracellular Iron Accumulation

“…Work to date has focused principally on the proinflammatory and metabolic effects of Lcn2 (11,13,(51)(52)(53)), yet less is known regarding cardiovascular effects. Several studies have now shown that Lcn2 was elevated during ischemia-reperfusion processes and in coronary heart disease and myocardial infarction (12,20,21,23). Here, we analyzed the effect of Lcn2 on cardiomyocyte apoptosis, an important component of cardiac remodeling leading to heart failure (24,25).…”

“…It was suggested that Lcn2 may mediate the innate immune responses in the pathogenesis of heart failure (17)(18)(19)(20). Lcn2 expression is significantly augmented in patients with coronary heart disease and myocardial infarction (12,21). Plasma Lcn2 was increased after carotid artery injury in rats (22) and in a heterotopic mouse transplanted heart after ischemia/ reperfusion (23).…”

Serum concentrations of atherogenic proteins neutrophil gelatinase-associated lipocalin and its complex with matrix metalloproteinase-9 are significantly lower in women with polycystic ovary syndrome: hint of a protective mechanism?

“…The formation of a complex with NGAL and MMP-9 is crucial for atherotic plaque erosion and thrombus formation (12)(13)(14). Hemdahl et al have shown increased expression of NGAL and co-localization with MMP-9 in atherosclerotic plaques and myocardial infarction lesions (15).…”