Fig. 2

Schematic representation of the possible mechanisms underlying the association of eNOS Glu298Asp polymorphism and low levels of HDL with inducible myocardial ischemia and obstructive CAD. The endothelial cells produce a multitude of different molecules, including nitric oxide (NO) which is mainly generated by endothelial nitric oxide synthase (eNOS) starting from L-arginine. The eNOS Glu298Asp polymorphism has been shown to modify the primary structure of the enzyme leading to a decreased NO synthesis causing reduced macrovascular and microvascular vasodilation (Tesauro M et al. Proc Natl Acad Sci U S A. 2000; Persu A et al. Hum Mol Genet 2002) which may trigger inducible myocardial ischemia. Reduced NO availability also limits its antiatherogenic properties, i.e., its capability to counteract conditions such as oxidative stress, and inflammation. On the other hand, an alteration of either the abundance and/or composition of HDL, is able to decrease the anti-atherosclerotic properties of these particles involving not only their contribution to the reverse cholesterol transport (RCT) but also their anti-inflammatory actions. HDL is involved in RCT by scavenging cholesterol from foam cells in atherosclerotic plaque. Briefly, ApoA-I initiates cholesterol efflux by binding to adenosine triphosphate-binding cassette transporter A1 (ABCA1), with further uptake through the ATP-binding cassette transporter G1 (ABCG1) and scavenger receptor class B type I (SR-BI). Cholesterol, esterified by lecithin-cholesterol acyl transferase (LCAT), is included into the lipid core of mature HDL, and then transported to the liver for excretion. HDL also promotes endothelial function by stimulating eNOS via shingosine-1-phosphate (S1P), and ApoA-I (Vecoli C et el. J Cell Biochem 2011). Moreover, HDL inhibits the expression of recruitment factors for inflammatory cells such as intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule (VCAM-1), stimulated by tumor necrosis factor-α (TNF-α) which is released by foam cells. Dotted Arrows denote reduced effects while dotted T bars denote reduced inhibitory effects