Abstract
The pleiotropic functions of circulating high density lipoprotein (HDL) on peripheral vascular health are well established. HDL plays a pivotal role in reverse cholesterol transport and is also known to suppress inflammation, endothelial activation and apoptosis in peripheral vessels. Although not expressed in the central nervous system, HDL has nevertheless emerged as a potential resilience factor for dementia in multiple epidemiological studies. Animal model data specifically support a role for HDL in attenuating the accumulation of β-amyloid within cerebral vessels concomitant with reduced neuroinflammation and improved cognitive performance. As the vascular contributions to dementia are increasingly appreciated, this review seeks to summarize recent literature focused on the vasoprotective properties of HDL that may extend to cerebral vessels, discuss potential roles of HDL in dementia relative to brain-derived lipoproteins, identify gaps in current knowledge, and highlight new opportunities for research and discovery.
Highlights
A key protein found in most high density lipoprotein (HDL) particles is apolipoprotein A-I, which makes up 70% of its protein content[2]
Several mechanisms by which HDL exerts antiinflammatory effects on endothelial cells have been described. These include pathways dependent on the HDL receptor SR-B1[31–33] as well as through vascular sphingosine 1 phosphate (S1P) receptor 1 and 3[34], which trigger a signaling cascade through the PI3K/Akt pathway leading to phosphorylation of endothelial nitric oxide synthase
The vasoprotective effects of nitric oxide produced by endothelial nitric oxide synthase (eNOS) phosphorylation are well-established, and include vasodilation, reduced endothelial cell permeability, and inhibition of vascular cell adhesion molecule-1 (VCAM-1) expression via downregulation of the pro-inflammatory NFkB signaling pathway[35]
Summary
The cholesterol efflux capacity (CEC) of HDL is modified in CVD[22–26], metabolic syndrome[27], and during acute inflammation[28]. Several mechanisms by which HDL exerts antiinflammatory effects on endothelial cells have been described These include pathways dependent on the HDL receptor SR-B1[31–33] as well as through vascular sphingosine 1 phosphate (S1P) receptor 1 and 3[34], which trigger a signaling cascade through the PI3K/Akt pathway leading to phosphorylation of endothelial nitric oxide synthase (eNOS). The vasoprotective effects of nitric oxide produced by eNOS phosphorylation are well-established, and include vasodilation, reduced endothelial cell permeability, and inhibition of vascular cell adhesion molecule-1 (VCAM-1) expression via downregulation of the pro-inflammatory NFkB signaling pathway[35]. HDL isolated from children with chronic kidney disease exhibits reduced ability to protect from endothelial cell activation [42-43]. Exercise training improves the ability of HDL to protect endothelial cells from tumor necrosis factor-α induced injury, monocyte adhesion, and VCAM-1 expression in metabolic syndrome while elevating eNOS activation[47].
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