(A) HDL_Healthy stimulates eNOS through multiple mechanisms. HDL binding to SR-BI via apoA-I causes cholesterol efflux (orange circles) that is sensed by SR-BI, leading to PDZK1-dependent activation of Src family kinase(s), PI3K, and Akt, which phosphorylates eNOS Ser1177 and thereby increases enzyme activity. SR-BI–, Src-, and PI3K-dependent Erk MAPK activation is also required for eNOS activation by HDL. HDL-associated S1P and related molecules may activate the lysophospholipid receptor S1P₃ to stimulate eNOS. HDL_Healthy contains active PON1, which suppresses the formation of oxidized lipids and lipoproteins such as MDA. The net effect of eNOS activation by HDL_Healthy is to blunt endothelial cell–monocyte adhesion and promote endothelial repair. (B) HDL_CAD activates inhibitory signaling that suppresses eNOS activation. HDL_CAD has reduced PON1 activity that potentially leads to greater formation of MDA, which activates LOX-1 and thereby stimulates PKCβ. PKCβ inhibits stimulatory Akt and eNOS phosphorylation events, and it enhances the inhibitory phosphorylation of eNOS at Thr495. As a result, HDL_CAD has an impaired capacity to favorably influence endothelial cell–monocyte adhesion or endothelial repair. It is unknown whether the loss in PON1 activity leads to alterations in other HDL constituents besides MDA that activate LOX-1. Whether HDL_CAD has decreased capacity to evoke cholesterol efflux from endothelial cells — possibly via MDA-related modification of apoA-I, resulting in attenuated SR-BI–dependent signaling — is also unknown. In addition, it is unknown whether endothelial cell signaling activated by cargo molecules such as S1P is altered in HDL_CAD.