Heart Care Info - Heart Disease Prevention & Treatment

PON-dering differences in HDL function in coronary artery disease

C Mineo... - The Journal of clinical investigation, 2011 - Am Soc Clin Investig HDL cholesterol activates endothelial cell production of the atheroprotective signaling molecule NO, and it promotes endothelial repair. In this issue of the JCI, Besler et al. provide new data indicating that HDL from stable coronary artery disease (CAD) or acute coronary ...

Besler and colleagues now report that whereas HDL from healthy individuals (HDL Healthy) causes an increase in bioavailable endothelium-derived NO, HDL from patients with stable CAD or acute coronary syndrome (HDLCAD) causes no increase or an actual decrease in NO (10). This is related to decreased activating e NOS Ser1177 phosphorylation and increased inactivating e NOS Thr495 phosphorylation by HDLCAD (Figure 1B). They also show that in an e NOS-dependent manner, HDL Healthy promotes endothelial repair and blunts NF-κB activation and VCAM-1 expression, thereby preventing endothelial cell–monocyte adhesion, whereas HDLCAD lacks these properties. They interrogated the basis for the adverse effects of HDLCAD on endothelial function, finding that total binding of HDLCAD to endothelium is decreased, but relative SR-BI–dependent binding is not altered. However, the researchers did not use endothelial cells to evaluate the effect of HDLCAD on cholesterol efflux, which is critically involved in endothelial HDL SR-BI–mediated signaling to e NOS. When the efflux capacity of HDL is specifically altered, the relative activation of e NOS changes in parallel (17). If HDLCAD has a blunted capacity to promote cholesterol efflux from endothelial cells, this might help to explain the observed impairment in NO generation. This could be experimentally tested by the ex vivo addition of phosphatidylcholine (18) to enhance the endothelial cell cholesterol efflux capacity of HDLCAD and determination of whether doing so restores the ability to generate NO.

Besler and colleagues additionally demonstrated that through a process involving the endothelial multiligand receptor known as lectin-type oxidized LDL receptor 1 (LOX-1), HDLCAD activates endothelial PKCβII, which in turn inhibits Akt-activating phosphorylation (Akt-Ser473) and e NOS-activating phosphorylation (e NOS-Ser1177) events and NO production (Figure 1B). Recognizing that endothelial LOX-1 is activated by oxidized lipids, they then evaluated the potential role of malondialdehyde (MDA) and found that MDA content is increased in HDLCAD compared with HDL Healthy. They also show that the addition of MDA to HDL Healthy blunts endothelial NO production and activates endothelial PKCβII in a LOX-1–dependent fashion. Since HDL-associated paraoxonase 1 (PON1) diminishes MDA formation, they then evaluated PON1 and found that although its abundance is nearly doubled in HDLCAD versus HDL Healthy, its enzyme activity is markedly decreased in HDLCAD. The researchers further found that PON1 inactivation in HDL Healthy leads to greater PKCβII activation, decreased activating e NOS-Ser1177 phosphorylation and increased inactivating e NOS-Thr495 phosphorylation, blunted NO production, increased monocyte–endothelial cell adhesion, and impaired endothelial repair. These findings suggest a potential mechanistic link between decreased PON1 activity in HDLCAD and exaggerated PKCβII activation and impaired e NOS and endothelial function. Furthermore, they showed that HDL from Pon1–/– mice fails to stimulate NO production or to antagonize endothelial inflammatory activation, and that supplementation of Pon1–/– HDL with purified PON1 restores these functions (10). Since cholesterol-free lipoprotein particles consisting solely of apo A-I and phosphatidylcholine are sufficient to cause e NOS activation (17), similar to HDLCAD, the Pon1–/– HDL must contain component(s) that blunt e NOS activation such as MDA, which decreases efflux capacity via the modification of apo A-I (19). Although the available evidence implicates MDA, the modified component of HDLCAD and Pon1–/– HDL that is directly responsible for LOX-1– and PKCβII-mediated e NOS inactivation requires further clarification. It is also unclear what causes the downregulation of PON1 activity in HDLCAD, even though its abundance is increased. In any case, the findings by Besler et al. importantly indicate that HDL-associated PON1 has a major impact on endothelial function, which is consistent with the reported inverse relationship between PON1 activity and cardiovascular disease development (20).

The work by Besler and colleagues has provided valuable evidence that HDL from CAD patients differs from HDL from healthy individuals in its capacity to invoke signaling in endothelial cells that induces e NOS activation and subsequent antiatherogenic and antiinflammatory processes. It also supports the concept that the cardiovascular impact of HDL is not simply related to its abundance. Furthermore, the findings suggest that assays of HDL action on endothelium may increase our ability to assign cardiovascular disease risk, and they may enhance our understanding of the outcomes of future trials testing HDL-targeted therapies. However, there are a number of remaining questions. Do the differences in endothelial intracellular signaling observed in cell culture in response to HDL Healthy versus HDLCAD reflect disparities in HDL-induced signaling in vivo? Are there differences in other critical endothelial cell phenotypes in vivo besides repair, such as leukocyte adhesion? The authors also appropriately point out that it remains unknown whether their findings represent a cause or a consequence of CAD. In this regard, the homogeneity of the functional defect in HDLCAD observed in this study is surprising, and additional cross-sectional studies with a wider spectrum of cardiovascular disease incidence and severity as well as prospective studies are now warranted. Combined with the recent study of atherosclerotic vascular disease and HDL macrophage cholesterol efflux (12), the work by Besler et al. indicates that we no longer need to ponder, but instead can conclude that measures of HDL function are clinically relevant. If we are earnest in our desire to harness the cardiovascular protective potential of HDL, we must go well beyond the quantification and even successful modification of HDL abundance, and reliably quantify and ultimately take therapeutic advantage of the bases for differences in HDL function.