Phospholipase D2 loss results in increased blood pressure via inhibition of the endothelial nitric oxide synthase pathway

Abstract

The Phospholipase D (PLD) superfamily is linked to neurological disease, cancer, and fertility, and a recent report correlated a potential loss-of-function PLD2 polymorphism with hypotension. Surprisingly, PLD2 −/− mice exhibit elevated blood pressure accompanied by associated changes in cardiac performance and molecular markers, but do not have findings consistent with the metabolic syndrome. Instead, expression of endothelial nitric oxide synthase (eNOS), which generates the potent vasodilator nitric oxide (NO), is decreased. An eNOS inhibitor phenocopied PLD2 loss and had no further effect on PLD2 −/− mice, confirming the functional relationship. Using a human endothelial cell line, PLD2 loss of function was shown to lower intracellular free cholesterol, causing upregulation of HMG Co-A reductase, the rate-limiting enzyme in cholesterol synthesis. HMG Co-A reductase negatively regulates eNOS, and the PLD2-deficiency phenotype of decreased eNOS expression and activity could be rescued by cholesterol supplementation and HMG Co-A reductase inhibition. Together, these findings identify a novel pathway through which the lipid signaling enzyme PLD2 regulates blood pressure, creating implications for on-going therapeutic development of PLD small molecule inhibitors. Finally, we show that the human PLD2 polymorphism does not trigger eNOS loss, but rather creates another effect, suggesting altered functioning for the allele.

Phospholipase D functional ablation has a protective effect in an Alzheimer’s disease Caenorhabditis elegans model

“…Concerning biometric and metabolic parameters, deletion of either of the PLD enzymes led to elevated body weight and increased adipose tissue content in aged animals 32 . However, while others did not observe elevated body weight in PLD2 knock-out animals 33 , PLD1 knock-out animals presented not only increased hepatic weight, but also increased triacylglycerol levels and increased cholesterol levels 27 . Here, in a C .…”

Enhanced Integrin Activation of PLD2-Deficient Platelets Accelerates Inflammation after Myocardial Infarction

“…Our results provide evidence for PLD2 as negative regulator of inflammation after MI. PLD2 was already shown to negatively regulate blood pressure via inhibition of the endothelial nitric oxide synthase (eNOS) signaling pathway [22]. In septic animals, loss of PLD2 is accompanied by increased bactericidal activity and recruitment of neutrophils into the lung [23].…”

Whole blood methylome-derived features to discriminate endocrine hypertension

“…2b). Gene set enrichment analysis of genes associated with the differentially methylated CpG sites in the four comparisons revealed enrichment in pathways related to blood pressure regulation mechanisms and hypertension, including MAPK, Rap1, phospholipase D and calcium signaling pathways [19][20][21][22][23] (FDR < 0.001 in all comparisons; Additional file 3: Table S2).…”

“…18 Service d'Endocrinologie, Center for Rare Adrenal Diseases, AP-HP, Hôpital Cochin, F-75014 Paris, France. 19 Institute of Health and Wellbeing, University of Glasgow, Glasgow G12 8RZ, UK.…”