Abstract 351: Mechano-sensitive Ppap2b Regulates Endothelial Responses to Athero-relevant Hemodynamic Forces

Rationale: PhosPhatidic-Acid-Phosphatase-type-2B (PPAP2B), an integral membrane protein that inactivates lysophosphatidic acid, was implicated in coronary artery disease (CAD) by genome-wide association studies (GWAS). However, it is unclear whether GWAS-identified CAD genes including PPAP2B participate in mechanotransduction mechanisms by which vascular endothelia respond to local athero-relevant blood flows that contribute to the regional nature of atherosclerosis. Approach and Results: Reduced endothelial PPAP2B was detected in vivo in swine aortic arch exposed to chronic disturbed flow and in mouse carotid artery subjected to surgically-induced acute disturbed flow. In culture, elevated PPAP2B was measured in human aortic endothelial cells (HAEC) under athero-protective flow mimicking hemodynamics of human distal carotid artery when compared with athero-susceptible waveform representing flow in carotid sinus. Disturbed flow-induced miR-92a was identified as a direct posttranscriptional inhibitor of mechano-sensitive PPAP2B. PPAP2B suppression abrogated athero-protection of unidirectional flow, shown by elevation of inflammatory genes. Inhibition of lysophosphatidic acid receptor 1 restored the flow-dependent, anti-inflammatory phenotype in PPAP2B-deficient cells. Moreover, PPAP2B inhibition resulted in myosin-light-chain phosphorylation and intercellular gaps, which were abolished by inhibition of lysophosphatidic acid receptors 1 and 2. Expression-quantitative-trait-locus-mapping demonstrated PPAP2B CAD risk allele is not linked to PPAP2B expression in various human tissues but significantly associated with reduced PPAP2B in HAEC. Conclusions: Athero-relevant flows dynamically modulate endothelial PPAP2B expression through miR-92a regulation. Mechano-sensitive PPAP2B plays an indispensable role in mediating cell alignment, promoting anti-inflammatory phenotype and maintaining vascular integrity of endothelial monolayer under athero-protective flow.