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Theses

Role of Phospholipase D in Vascular Calcification

Abstract : Vascular calcification is the accumulation of calcium phosphate crystals in blood vessels via a pathological process that resembles physiological bone or cartilage formation. Calcification in the medial layer is mainly seen in diabetic and chronic kidney disease patients. Its main consequence is the loss of elasticity which is indispensable for the function of large arteries. Accordingly, vascular medial calcification was significantly associated with mortality in hemodialysis patients. Vascular calcification treatments are limited to those that correct its causative health problems, but no efficient, specific and targeted interventions are available. Therefore, a deep understanding of its molecular mechanisms is needed to find novel therapeutic targets. Phospholipase D catalyses the hydrolysis of phospholipids into phosphatidic acid and a head group. It is implicated in different cellular functions and diseases. It was found to be activated by factors involved in osteogenesis and others involved in vascular calcification. Thus, we investigated its role in vascular calcification in 3 models: an in-vitro model of murine smooth muscle cell line MOVAS cultured with ascorbic acid and β-glycerophosphate, an ex-vivo model of rat aortas cultured in high phosphate medium, and an in-vivo model of adenine-induced kidney disease in rats in which vascular calcification is induced by further administration of high phosphorus/calcium diet and active vitamin D injections. Calcification was detected in these models using different approaches including alkaline phosphatase activity, calcium dosage, and/or evaluation of osteo-chondrocytic markers expression. Pld1 expression was seen upregulated in all the three models, especially during early stages of calcification, and was accompanied with increased phospholipase D activity in the in-vitro and ex-vivo model. The inhibition of total phospholipase D activity in these two models, or that of phospholipase D1 in case of MOVAS model, abolished calcification. Phospholipase D2-specific inhibition did not induce significant effects. Two pathways by which phospholipase D can be activated were tested, protein kinase C and sphingosine 1-phosphate pathways, but they were found to be involved in calcification but not necessary for phospholipase D activation during this process. Alternatively, the preliminary results showed that PLD may be acting by activation of sphingosine kinase 2 whose activity was found necessary for calcification in the MOVAS model. Further investigations are needed to understand the mechanisms by which phospholipase D is activated and by which it is acting. Phospholipase D could be a novel target for vascular calcification especially that its inhibition in patients did not induce adverse health effects
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Submitted on : Thursday, April 19, 2018 - 3:30:06 PM
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Najwa Skafi. Role of Phospholipase D in Vascular Calcification. Cellular Biology. Université de Lyon; Université libanaise, 2017. English. ⟨NNT : 2017LYSE1339⟩. ⟨tel-01771501⟩

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