Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypercholesterolemia, the driving force of atherosclerosis, accelerates the expansion and mobilization of hematopoietic stem and progenitor cells (HSPCs). The molecular determinants connecting hypercholesterolemia with hematopoiesis are unclear. Here, we report that a somite-derived prohematopoietic cue, AIBP, orchestrates HSPC emergence from the hemogenic endothelium, a type of specialized endothelium manifesting hematopoietic potential. Mechanistically, AIBP-mediated cholesterol efflux activates endothelial Srebp2, the master transcription factor for cholesterol biosynthesis, which in turn transactivates Notch and promotes HSPC emergence. Srebp2 inhibition impairs hypercholesterolemia-induced HSPC expansion. Srebp2 activation and Notch up-regulation are associated with HSPC expansion in hypercholesterolemic human subjects. Genome-wide chromatin immunoprecipitation followed by sequencing (ChIP-seq), RNA sequencing (RNA-seq), and assay for transposase-accessible chromatin using sequencing (ATAC-seq) indicate that Srebp2 transregulates Notch pathway genes required for hematopoiesis. Our studies outline an AIBP-regulated Srebp2-dependent paradigm for HSPC emergence in development and HPSC expansion in atherosclerotic cardiovascular disease.
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PMID:AIBP-mediated cholesterol efflux instructs hematopoietic stem and progenitor cell fate. 3106 80

Atherosclerosis is a vascular disease responsible for acute heart attacks and stroke, which are leading causes of death not only in industrialized countries but also worldwide, and the number of patients afflicted by this disease has been increasing in Japan. High-density lipoprotein (HDL) is the plasma lipoprotein that carries what is often called your "good cholesterol" through the blood. This good cholesterol moniker is associated with HDL because higher circulating levels of this lipoprotein are associated with a well-known reduction in the risk of arteriosclerosis. Moreover, many protective mechanisms by which HDL could reduce atherosclerosis are described, including reverse cholesterol transport, along with anti-oxidant, anti-inflammatory and anti-thrombosis activities. However, HDL-modulating therapies to lower cardiovascular risk are not yet available. It has recently been proposed that apolipoprotein A-I (apoA-I) binding protein (AIBP) enhances HDL function by accelerating lipid release from cells and reducing associated inflammatory processes. In this context, our research is focused on the function of HDL-related proteins, such as proteins that regulate HDL production (ATP-binding cassette transporters), and HDL-binding proteins. We expect that these studies could eventually help in the development of HDL-related prognostic and therapeutic strategies to reduce the burden of cardiovascular disease in the future.
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PMID:[Challenges in Drug Development Targeting Anti-atherosclerotic Proteins]. 3200 37