Table 1.

Overview of investigations on HDL and endothelial cell dysfunction.

Disease Studied.	Experimental/Clinical Investigation	HDL-Endothelial Property in Focus	HDL Main Alteration	Cellular Mechanisms	Ref.
Coronary Artery Disease	clinical, in vitro ECs, rabbit	Anti-inflammatory	HDL in acute phase reaction: ↑ SAA and ceruloplasmin on HDL, ↓ HDL PON-1 activity, ↓ apo A-I levels	ECs: ↑ expression of monocyte chemotactic protein 1	[100]
	clinical, in vitro ECs	clinical, in vitro Ecs	CAD patients: ↑ malondialdehyde (MDA), ↓ HDL PON-1 activity	CAD-HDL activates LOX-1-> ↑ PK CβII activation and ↓ endothelial NO production	[94]
	clinical, in vitro ECs	Nitric oxide (NO) production	CAD patients: ↓ HDL-S1P	CAD-HDL loaded with S1P-> ↑ phosphorylation of ERK1/2, Akt and eNOSser1177 ↑ vasodilation of mesenteric arteries	[104]
	clinical, in vitro ECs, mice	Anti-thrombotic, NO production	CAD patients	↑ tissue factor and plasminogen activator inhibitor type 1, and ↓ tissue factor pathway inhibitor and tissue plasminogen activator. ↑ laser-injured carotid artery arterial thrombus formation in mice	[105]
	clinical, in vitro ECs	Anti-oxidant	CAD patients: ↑ myeloperoxidase (MPO), ↓ HDL PON-1 activity	↑ chlorotyrosine content, site-specific PON1 methionine oxidation, and↓PON1 activity	[106]
	clinical, in vitro ECs	Anti-apoptotic	HDL ↓ clusterin, ↑ apolipoprotein C-III	Lack of HDL- clusterin-> ↓ PI3K/Akt and ↓ endothelial Bcl-xL. High HDL-apoC-III -> ↑ phosphorylation of p38-MAPK and ↑ Bcl-2 protein tBid.	[93]
	clinical, in vitro ECs	Anti-inflammatory	CAD patients	CAD-HDL:↓ inhibition of TNFα-induced endothelial VCAM-1 mRNA expression	[107]
Diabetes mellitus type 2/Obesity	clinical, rats, in vitro ECs	NO production	Obese and post bariatric patients	Glucagon-like-1 treatment in obese rats->HDL-induced endothelial NO production, ↑ vasodilation of aortas	[108]
	clinical, mice, in vitro ECs	NO production, anti-oxidant	T2DM patients:↑MDA and MPO	niacin-treated patients: ↑ vasodilation of mice aortas, ↑ endothelial Repair Capacity of Early EPCs. ↓ Lipid peroxidation->masking positively charged lysine residues	[109]
	clinical, in vitro ECs	Anti-apoptotic, anti-oxidant	T2DM patients: ↓ apoD, ↓ apoM. HDL-S1P controversial	↓ Anti-apoptotic->↓HDL-GPLD1 and sphingadienine-based sphingomyelins. HAECs with glycated-ox-HDL-> ↑ H2O2 and ↓ catalase and Cu(2+), Zn(2+)-superoxide dismutase. Glycation of PON1 induces endothelial ER stress	[2,110,111]
Chronic kidney disease	clinical, in vitro ECs	NO production, anti-oxidant, anti-inflammatory	CKD patients: ↑ symmetric dimethylarginine (SDMA)	CKD-HDL impairs Akt-eNOS-NO production via Toll-like receptor-2 (TLR-2) and induces JNK-NADPH oxidase-dependent ↑ superoxide production	[112,113]
	clinical, in vitro ECs	NO production, anti-oxidant, anti-inflammatory	CAD and CKD patients: ↑ SAA	↓ endothelial NO production, ↓ inhibition of TNFα-induced endothelial VCAM-1 expression, ↑ superoxide production	[114]
	clinical, mice, in vitro ECs	endothelial glycocalyx protection	hemodialysis CKD patients: ↑ SDMA	↓endothelial glycocalyx by activation of matrix metalloproteinases-9 upon induction of TLR-2-signaling	[38]
	clinical, in vitro ECs	Endothelial regeneration, anti-apoptotic, anti-oxidant	End-stage CKD patients: ↑ Carbamylation, ↓ HDL PON-1 activity	↓ proliferation and migration of HAECs->↓VEGFR2 and SR-BI signaling pathways	[115]
Chronic inflammatory disease	clinical, in vitro ECs	Nitric oxide production, anti-oxidant, anti-inflammatory	systemic lupus erythematosus and rheumatoid arthritis HDL: ↓ HDL PON-1 activity	↓ endothelial NO production, blunted TNFα-induced endothelial VCAM-1 expression, ↑ superoxide production	[116,117]
	clinical, in vitro ECs	Anti-inflammatory, anti-apoptotic, anti-oxidant	Psoriasis HDL: ↑MDA, ↓ HDL PON-1 activity	↓ inhibition of TNFα-induced monocyte adherence to ECs and endothelial apoptosis	[118]
	clinical, in vitro ECs	Nitric oxide production, anti-oxidant, anti-inflammatory	periodontitis patients HDL: ↓ HDL PON-1 activity, ↑ SAA and ↑complement factor C3.	↓ endothelial NO production, blunted TNFα-induced endothelial VCAM-1 expression, ↑ superoxide production	[119]
Infection sepsis COVID-19	clinical, rodents models, in vitro Ecs	Anti-inflammatory, anti-apoptotic, anti-oxidant	septic patients: ↓ HDL PON-1 activity and apoA-I levels, ↓ HDL-S1P, ↑ SAA, apoC-III and apoE.	↑ endothelial leakage, ↑ expressions of adhesion proteins and pro-inflammatory cytokines via ↑ NF-κB signaling and ↓ junction protein expression, ↓ proliferation and migration abilities of endothelial cells	[120,121]
	clinical, in vitro ECs	Anti-apoptotic	severely ill COVID-19 patients: ↑ SAA and alpha-1 antitrypsin, ↓ HDL PON-1 activity, ↓ apoA-I levels	↓ inhibition of TNFα-induced endothelial permeability, VE-cadherin disorganization and apoptosis	[122]

Additional abbreviations: EC: endothelial cell, TNFα: tumor necrosis factor alfa, GPLD1: glycosylphosphatidyl-inositol specific phospholipase D1, LOX-1: lectin-like oxidized LDL receptor 1, VEGFR2: vascular endothelial growth factor receptor 2, PKC BII: protein kinase CβII, H2O2: hydrogen peroxide.