Brief reviews
HDL Stimulation of Endothelial Nitric Oxide Synthase: A Novel Mechanism of HDL Action

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Abstract

High-density lipoprotein (HDL), apolipoprotein A-I (apoA-I), and the principal high-affinity HDL receptor, scavenger receptor class B type I (SR-BI), are antiatherogenic and beneficial to the response to vascular injury. However, the fundamental mechanisms underlying these properties remain complex and not well understood. Recent work in both cell culture and in mice indicates that HDL causes robust activation of endothelial nitric oxide synthase (eNOS), and that this effect is mediated in endothelial cell caveolae by SR-BI through a process that requires apoA-I binding. Further studies have revealed that HDL stimulates eNOS through src- and PI3 kinase-mediated signaling, which leads to parallel activation of Akt and mitogen-activated protein kinases and their resultant independent modulation of the enzyme. As such, signaling initiated by HDL increases the production of the potent atheroprotective molecule nitric oxide, and this novel mechanism of action may be critically involved in the impact of the lipoprotein on vascular health and disease.

Section snippets

HDL-Induced Activation of eNOS

Potential novel actions of HDL in the vascular wall were approached first in cultured endothelial cells. In studies of the effects of HDL on eNOS (Yuhanna et al. 2001), exposure to the lipoprotein (10 μg/mL) for 15 min caused a 5-fold increase in enzymatic activity, which was similar to the maximal stimulation obtained with the calcium ionophore A23187 (Figure 1A). HDL stimulation of eNOS was concentration dependent, with maximal activation occurring at 10 μg/mL and above. eNOS stimulation was

Role of apoA-I and SR-BI

The principal apolipoproteins in HDL are apoA-I and apoA-II. The circulating level of apoA-I, as well as HDL, is a major negative predictor of atherosclerosis and coronary artery disease risk. In contrast, apoA-II levels do not correlate with atheroprotection (Fidge et al. 1999, Gordon and Rifkind 1989, Zambon and Hokanson 1998). Consistent with the epidemiologic data in humans, transgenic mice overexpressing apoA-I have decreased aortic fatty streak development upon placement on an atherogenic

Proximal Signaling by HDL

The mechanisms by which HDL activates eNOS have been elucidated recently (Mineo et al. 2003). A variety of eNOS stimuli, including shear stress and estrogen, modulate eNOS activity by phosphorylating the enzyme on serine, threonine, or tyrosine residues Corson et al. 1996, Garcia-Cardena et al. 1996a, Michel et al. 1993. The kinases involved include Akt (also known as protein kinase B [PKB]), PKA, PKC, and calmodulin-dependent kinase II Boo et al. 2002, Butt et al. 2000, Chen et al. 1999a,

Summary and Future Direction

In addition to serving classic functions in cholesterol homeostasis and reverse cholesterol transport, recent work Yuhanna et al. 2001, Mineo et al. 2003 has shown that HDL has novel actions in endothelium to promote the production of the atheroprotective signaling molecule NO. We also now know that the high-affinity HDL receptor SR-BI is required, and that this process is mediated by kinase cascades that converge to regulate the activity of eNOS. The basis on which SR-BI initiates signaling is

Acknowledgements

This work was supported by Scientist Development Program (0235107N) from the American Heart Association (to C.M.) and NIH (Grants HL58888, HL53546, and HD30276 (to P.W.S.).

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