Lipoprotein-associated phospholipase A2: The story continues.

Fubao Huang,Jianhua Shen,Kai Wang

doi:10.1002/med.21597

Abstract

Inflammation is thought to play an important role in the pathogenesis of vascular diseases. Lipoprotein‐associated phospholipase A2 (Lp‐PLA2) mediates vascular inflammation through the regulation of lipid metabolism in blood, thus, it has been extensively investigated to identify its role in vascular inflammation‐related diseases, mainly atherosclerosis. Although darapladib, the most advanced Lp‐PLA2 inhibitor, failed to meet the primary endpoints of two large phase III trials in atherosclerosis patients cotreated with standard medical care, the research on Lp‐PLA2 has not been terminated. Novel pathogenic, epidemiologic, genetic, and crystallographic studies regarding Lp‐PLA2 have been reported recently, while novel inhibitors were identified through a fragment‐based lead discovery strategy. More strikingly, recent clinical and preclinical studies revealed that Lp‐PLA2 inhibition showed promising therapeutic effects in diabetic macular edema and Alzheimer's disease. In this review, we not only summarized the knowledge of Lp‐PLA2 established in the past decades but also emphasized new findings in recent years. We hope this review could be valuable for helping researchers acquire a much deeper insight into the nature of Lp‐PLA2, identify more potent and selective Lp‐PLA2 inhibitors, and discover the potential indications of Lp‐PLA2 inhibitors.

Highlights

An increasing number of patients are currently suffering from a variety of vascular diseases, which is a general term for a large class of diseases, including atherosclerosis, peripheral arterial diseases, cerebrovascular diseases (CVDs), aneurysms, and retinopathy.[1]
In addition to the decreased binding affinity of the substrate and high flexibility, nitration of Tyr[307] and Tyr[335] led to the disorientation of the catalytic triad and a reduction in the molecular interactions of NT‐Tyr[307] and NT‐Tyr[335] with other residues of the protein.[47]. Even though these findings offered some plausible mechanism for the reduction in enzymatic activity of Lp‐PLA2 under oxidative stress, further insights into the molecular mechanisms are anticipated through studies using other biophysical techniques such as nuclear magnetic resonance, cryoelectron microscopy and X‐ray crystallography
40 years ago, Farr et al reported the presence of an acid‐labile factor that rapidly inactivated platelet‐activating factor (PAF) in human serum, later referred to as pPAF‐AH.[269,270]

Summary

Introduction

An increasing number of patients are currently suffering from a variety of vascular diseases, which is a general term for a large class of diseases, including atherosclerosis, peripheral arterial diseases, cerebrovascular diseases (CVDs), aneurysms, and retinopathy.[1].

Results

Conclusion