دانلود رایگان مقاله تراکم بینش به نقش فسفولیپاز D2 در بیماری های انسان

Abstract

Phospholipase D2 (PLD2) is a lipid-signaling enzyme that produces the signaling molecule phosphatidic acid (PA) by catalyzing the hydrolysis of phosphatidylcholine (PC). The molecular characteristics of PLD2, the mechanisms of regulation of its activity, its functions in the signaling pathway involving PA and binding partners, and its role in cellular physiology have been extensively studied over the past decades. Although several potential roles of PLD2 have been proposed based on the results of molecular and cell-based studies, the pathophysiological functions of PLD2 in vivo have not yet been fully investigated at the organismal level. Here, we address accumulated evidences that provide insight into the role of PLD2 in human disease. We summarize recent studies using animal models that provide direct evidence of the function of PLD2 in several pathological conditions such as vascular disease, immunological disease, and neurological disease. In light of the use of recently developed PLD2-specific inhibitors showing potential in alleviating pathological conditions, improving our understanding of the role of PLD2 in human disease would be necessary to target the regulation of PLD2 activity as a therapeutic strategy.

3. Conclusions and perspectives

Because of the absence of research tools for in vivo evaluation, studies on PLD2 function have been conducted primarily at the molecular and cellular level. Recently, genetically engineered mouse models have been developed, and they have given researchers the opportunity to validate proposed functions and identify novel roles of PLD2 at the organismal level. In contrast to previous expectations, however, PLD2 KO mice have not shown an evident phenotype under normal conditions. Molecular compensation by either other isoform(s) or PA-generating enzymes, or systemic compensation at the organismal level, could be possible explanation for this phenomenon. Much effort has gone into unveiling PLD2 functions in particular conditions such as diseases, allowing better prediction of its functions than normal conditions. Recent reports have suggested specific contributions of PLD2 to pathological conditions, such as pathological angiogenesis, sepsis, and Alzheimer's disease. However, many pathophysiological conditions, including cancer development, remain to be tested. In addition, because PLD2 is expressed ubiquitously in most cell types, more intricate studies using conditional KO (tissue-specific and inducible) animal models are required to clearly reveal the cell-, tissue-, and organ-specific functions of PLD2. Recent studies have shown ameliorating effects of isotype-specific inhibitors of PLD on some diseases. The new inhibitors overcame limitations of previously used pan-PLD inhibitors. Furthermore, the use of an effective PLD2 inhibitor will provide opportunities to better understand PLD2 functions in various disease conditions and suggest potential therapeutic strategy for these diseases.