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Coronary artery disease locus 1p32.2 and miR92a-PPAP2B signaling in endothelial mechanobiology

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Project Summary Atherosclerotic arterial disease remains the leading cause of morbidity and mortality among Americans. Atherosclerosis preferentially develops in arterial sites such as curvatures and bifurcations, where endothelial cells are activated by local disturbed flow. Recent studies have suggested new genes and previously unsus- pected biology that mechanistically contribute to atherosclerosis; however, the interplay between genetic pre- disposition of atherosclerosis and flow-mediated endothelial functions remains to be elucidated. Genome-wide association studies (GWAS) and subsequent investigations identified PhosPhatidic-Acid- Phosphatase-type-2B (PPAP2B, also known as LPP3 or PLPP3) as a gene at chr 1p32.2 that significantly influences risk of coronary artery disease (CAD). Moreover, reduced endothelial PPAP2B is associated with increased CAD susceptibility. We recently discovered a new mechanism that links disturbed flow to reduction in endothelial PPAP2B through a microRNA-mediated mechano-transduction pathway: disturbed flow activates endothelial miR-92a, which in turn suppresses PPAP2B directly and also indirectly by inhibiting the transcription factor KLF2 that activates PPAP2B; reduced endothelial PPAP2B then leads to increased endothelial inflammation and compromised monolayer integrity. Furthermore, previous studies showed that systemic delivery of miR-92a inhibitor suppressed miR-92a in a wide range of tissues and lessened atherosclerosis in mice. Although these results suggest that flow-sensitive miR92a-PPAP2B pathway contributes to the athero-susceptible endothelial phenotype, the potentially causal relationship between endothelial miR92a-PPAP2B pathway and atherogenesis in vivo remains uncertain. Moreover, the mechanism by which the CAD-associated causal variant in PPAP2B exerts its effect and its potential roles in endothelial mechano-transduction remains unexplored. We have gathered very strong evidence that PPAP2B genetic variation interacts with unidirectional flow in concert to promote endothelial PPAP2B. The overall goal is to elucidate the molecular convergence of CAD genetic predisposition and mechano-transduction mechanisms in the endothelial miR92a-PPAP2B path- way, dysregulation of which is hypothesized to causatively promote atherosclerosis. Our proposed studies ad- dress three questions of fundamental importance: 1) Does the endothelial miR92a-PPAP2B pathway causally regulate atherosclerosis in vivo? We test this in Aim 1 with new mouse models and innovative nanoparticles to selectively modulate endothelial miR92a-PPAP2B signaling. 2) How does the CAD protective allele at rs17114036 influence PPAP2B expression? In Aim 2, we functionally characterize the rs17114036-depedent enhancer in PPAP2B employing complementary in vivo and in vitro genetic approaches. 3) What is the addi- tional role of KLF2 in regulating allele-specific PPAP2B expression? We address the dynamic regulation of this rs17114036-containing enhancer by mechanical and pharmacological stimuli via KLF2 in Aim 3.
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