Lipoprotein-Associated Phospholipase A ₂ Protein Expression in the Natural Progression of Human Coronary Atherosclerosis

Abstract

Objective-Although lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) has received recent attention as a biomarker of inflammation and risk for acute coronary events, its relative expression in coronary plaque phenotypes, including unstable lesions, has not been established. Methods and Results-Coronary segments (nϭ30) were prospectively collected from 25 sudden coronary death patients for immunolocalization of Lp-PLA 2 . Lesion morphologies were classified as pathologic intimal thickening, fibroatheromas, thin-cap fibroatheromas (fibrous cap thicknesses Ͻ65 m), and rupture. The expression of Lp-PLA 2 was detected using a specific monoclonal antibody. Apoptosis was identified by DNA end-labeling using terminal deoxynucleotidyl transferase (TdT). Lp-PLA 2 staining in early plaques was absent or minimally detected. In contrast, thin-cap fibroatheromas and ruptured plaques showed intense Lp-PLA 2 expression within necrotic cores and surrounding macrophages including those in the fibrous cap. T he natural history of atherosclerosis in humans is a dynamic process involving the progression of early lesions to more complex plaques that are responsible for the majority of acute ischemic coronary and stroke events. Throughout lesion progression, there are transitional plaque phenotypes ranging from early lipid pools to those characterized by a dense fibrous cap of connective tissue and a strong collagen matrix overlying a core of lipids and necrotic debris, and ultimately, to plaques with large necrotic cores and thin fibrous caps invaded by macrophages, referred to as thin-cap fibroatheromas (TCFAs). 1 TCFAs are characterized by a thin fibrous cap (Ͻ65 m), a large necrotic core, an abundance of macrophages, and limited luminal narrowing. 2 It is widely held that the instability of the TCFA gives rise to the main clinical complications associated with rupture and thrombosis; however, there are important morphological differences between TCFA and ruptured plaques. 2 Ruptured plaques demonstrate even thinner fibrous caps (23Ϯ19 m), larger necrotic cores, and greater macrophage infiltrates compared with TCFAs. 2 In this context a better understanding of the biology of rupture-prone plaques has the potential to reduce the morbidity and mortality associated with atherothrombotic disease. See page 2417 and coverInflammation plays a primary role in the progression of human atheroma based on the local and systemic inflammatory responses observed throughout the spectrum of atherosclerotic disease-from initial lesion formation to plaque destabilization and rupture. 3 The key role of inflammation in atherosclerosis also is evidenced by numerous epidemiology studies indicating an association between inflammatory markers (eg, C-reactive protein [CRP], interleukin [IL]-6) and risk of future cardiovascular events. However, considerably less is known about whether the various inflammatory markers represent similar pathophysiologic processes or Original

Oxidatively modified phosphatidylserines on the surface of apoptotic cells are essential phagocytic ‘eat-me’ signals: cleavage and inhibition of phagocytosis by Lp-PLA2

“…For example, not only lyso-PS but also oxidatively modified species of lyso-PS (for example, formed by hydrolysis of multiply-oxygenated PSox species) as well as oxygenated FFAs can be generated from PSox by Lp-PLA 2 , which is highly expressed and secreted by activated monocyte-derived macrophages during instances of chronic inflammation. [40][41][42] These represent a wide diversity of potential signals. Strong anti-phagocytic effects of oxygenated FFAs, for example, have been reported.…”

Identification of a Domain That Mediates Association of Platelet-activating Factor Acetylhydrolase with High Density Lipoprotein

“…Elevated expression of PAF-AH activity and/or protein has been reported in patients with coronary artery disease by a number of groups, and is thought to be an independent predictor of disease severity in humans (24 -33). In addition, PAF-AH protein has been detected in atherosclerotic plaques of humans (34,35) and in experimental animals (36). These correlative findings led to the proposition that PAF-AH actively contributes to the pathogenesis of vascular disease and that inhibiting its enzymatic activity could be beneficial for the treatment of atherosclerosis and related disorders (37)(38)(39).…”

Darapladib for Preventing Ischemic Events in Stable Coronary Heart Disease

“…2, 3 In atherosclerotic plaques, lipoprotein-associated phospholipase A 2 increases the production of proinflammatory and proapoptotic mediators. [4][5][6][7][8] In a meta-analysis of individual records from 79,036 participants in 32 prospective studies, there was a continuous association between lipoprotein-associated phospholipase A 2 activity and the risk of coronary heart disease, with a relative increase in risk of 1.10 (95% confidence interval [CI], 1.05 to 1.16) for each 1-SD increase in lipoprotein-associated phospholipase A 2 activity, after adjustment for conventional risk factors.…”