© 1999 American Heart Association, Inc.
Editorials |
LOX-1, a Possible Clue to the Missing Link Between Hypertension and Atherogenesis
From the Department of Geriatric Medicine, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
Correspondence to Toru Kita, MD, Department of Geriatric Medicine, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan. E-mail tkita{at}kuhp.kyoto-u.ac.jp
Key Words: angiotensin II • oxidized LDL • LOX-1 • endothelial cell • atherosclerosis
Our understanding of the molecular mechanism of atherosclerosis has changed during the past 20 years. A large variety of different risk factors such as smoking, shear stress, hypertension, hypercholesterolemia, diabetes mellitus, and obesity lead to endothelial activation and/or dysfunction, which can elicit a series of cellular interactions that culminate in the lesions of atherosclerosis. To date, there have been many studies investigating how hypercholesterolemia, particularly hyperLDL-cholesterolemia, affects endothelial cells and forms atherosclerotic lesions.1 2 3 Although hypertension is an established risk factor for the development of atherosclerosis, the underlying molecular mechanisms have not been clearly elucidated. There is a great deal of experimental, epidemiological, and clinical evidence suggesting that the renin-angiotensin system plays an important role in the pathogenesis of atherosclerotic formation. It has been suggested that hypertensive patients with high renin profiles, who are likely to be associated with increased plasma angiotensin II (Ang II) levels, have a higher risk of myocardial infarction than those with low renin profiles.4 5 Several experimental studies on hyperlipidemic animal models have suggested that interaction of the renin-angiotensin system and hyperLDL-cholesterolemia could play an important role in atherogenesis. In addition, it has been shown that angiotensin-converting enzyme (ACE) inhibitors reduce atherosclerotic formation in several experimental animal models, such as Watanabe heritable hyperlipidemic (WHHL) rabbits, cholesterol-fed mice, and monkeys.6 7 8 9
The study in this issue of Circulation Research presented by Li et al10 demonstrated that Ang II increases uptake of oxidized LDL (ox-LDL) by human coronary artery endothelial cells (HCAECs) via an induced LOX-1 expression and enhanced ox-LDL–mediated cell injury. For the first time, Li et al have indicated the presence of AT1 in HCAECs. Furthermore, they have demonstrated that Ang II induced the expression of LOX-1 via AT1. Therefore, taken together with the findings of Nickenig et al,11 who showed that LDL upregulates AT1 expression in HCAECs, and others, who have demonstrated that Ang II enhances the uptake and oxidation of LDL by monocytes and macrophages,12 it is strongly suggested that the cross talk between Ang II and ox-LDL plays an important role in atherosclerotic formation in the body. Although the Li et al10 study is limited to in vitro findings, these results may provide a long-sought molecular link between hypertension, hyperlipidemia, the principal risk factors for coronary artery disease, and the development of atherosclerosis.
Oxidized LDL and Its Receptor (LOX-1)
The earliest events in atherosclerosis have
suggested that monocyte recruitment into lesions might involve the
activation and/or dysfunction of vascular endothelial
cells or, in other words, endothelial adhesiveness for
circulating monocytes and T lymphocytes into the
subendothelial spaces. This endothelial
activation and/or dysfunction has been implicated in the pathogenesis
of atherosclerosis, characterized by intimal thickening
and lipid deposition in the arterial wall, ie, "fatty
streak."2 Oxidative modification appeared to be a
biologically plausible modification of LDL. The importance of ox-LDL in
atherosclerosis was first established through the use
of the antioxidant probucol, in studies of genetic
hyperlipidemic rabbits (WHHL rabbits).3 13
Furthermore, accumulating evidence suggests that ox-LDL is a key
component in the formation of
atherosclerosis3 13 14 , and ox-LDL is a
chemoattractant for monocytes15 and is cytotoxic for
endothelial cells in the culture system.16
Also, ox-LDL is a mitogenic activator for
macrophages and smooth muscle cells.17 Ox-LDL is
recognized by the scavenger receptors on the surface of
macrophage membranes, and the macrophage becomes foam
cells. Incorporation of ox-LDL into macrophages is mediated by
at least six membrane proteins, including the class A and class B
scavenger receptors, such as CD36, SRBI, and so on.18 19
Sakai et al20 demonstrated that lysophosphatidylcholine
from endocytosed ox-LDL, through a class A scavenger receptor, plays an
essential role in ox-LDL–induced macrophage proliferation.
Nagy et al21 and Tontonoz et al22 showed that
ox-LDL activates CD36-mediated ox-LDL uptake through a
peroxisome proliferator-activated receptor gamma
(PPAR
)–dependent transcriptional signaling pathway. They identified
two of the major oxidized lipid components of ox-LDL, 9-HODE
(9-hydroxyoctadecadlenoic acid) and 13-HODE (13-hydroxyoctadecadlenoic
acid), as endogenous activators and ligands of
PPAR.
With regard to the biological effect on endothelial
cells, ox-LDL and its lipid constituents (such as
lysophosphatidylcholine) impair endothelial
production of nitric oxide (NO)23 and induce the
endothelial expression of leukocyte adhesion molecules
and smooth muscle growth factors, which may be involved in
atherosclerosis.24 25 26 It has been
suggested that vascular endothelial cells in culture
and in vivo internalize and degrade ox-LDL through a receptor-mediated
pathway that does not involve the macrophage scavenger
receptors.27 Sawamura, Kume et al28 first
identified LOX-1 as a critical molecule that is responsible for ox-LDL
uptake by endothelial cells.28 29 The
expression of endothelial LOX-1 is induced by tumor
necrosis factor-
(TNF-) and shear stress.30 31
Moreover, in animal models such as WHHL rabbits and spontaneously
hypertensive rats (SHR), LOX-1 is expressed in the
endothelial cells.32 33 34 35 Because foam cell
formation of endothelial cells has not been identified
either in vitro or in vivo, ox-LDL uptake by LOX-1 in vascular
endothelial cells in vivo may not result in massive
lipid accumulation. However, ox-LDL uptake via LOX-1 in vascular
endothelium may cause endothelial
activation and/or dysfunction, given that a variety of biological
effects of ox-LDL and its lipid constituents on
endothelial cells have been reported.
Physiological levels of laminar fluid flow shear
stress transcriptionally induced LOX-1 expression in bovine aortic
endothelial cells by a mechanism dependent upon
[Ca2+] mobilization.31
Endothelial expression of LOX-1 may also be dynamically
modulated, in vivo, in response to changes in blood
flow.31 An in vivo study by Nagase et al33
suggested this possibility. Although
pathophysiological consequences of ox-LDL uptake by
vascular endothelial cells through LOX-1 still need to
be fully clarified, modulated expression of this novel ox-LDL receptor
by inflammatory stimuli and fluid mechanical stimuli may play an
important role in the selective localization of atherosclerotic lesions
in vascular tissues. Recently, it was demonstrated that LOX-1 is
expressed in human and murine macrophages,36 37 38
which are induced by TNF-38 ; however, we do not know
how the mechanism is regulated. We do know that the macrophages
incorporate ox-LDL through the scavenger receptors, such as class A and
CD36, and then get converted into foam cells, but the role of LOX-1 in
macrophages is not clear.
Hypertension and Atherosclerosis
Endothelial cells play numerous physiological roles in the maintenance of vascular tonus. The molecules involved in these events, prostacyclin (PGI2), endothelin (ET), Ang II, and NO, have all attracted an increasing amount of attention from researchers. Vasomotor tone of the artery appears to be controlled by the constant action of NO.2 Inhibition of the formation of NO and PGI2 permits opposing forces of vasodilation, which results from vasoconstrictors such as ET, Ang II, or thromboxane A2, to determine the capacity of the artery to maintain its lumen in the presence of the changing forces caused by the formation and progression of the lesions of atherosclerosis. Several studies have already proved that LDL from hypertensive patients is more susceptible to oxidation than LDL from normotensive controls. In addition, hypertensive patients with elevated plasma Ang II levels show a 5-fold increased incidence of myocardial infarction compared with normal or decreased levels of Ang II.5 39 Treatment of patients with left ventricular dysfunction using ACE inhibitors reduces the incidence of recurrent myocardial infarction and its mortality.40 In addition to its vasoactive role, Ang II directly induces oxidative stress in the vasculature by generating superoxide anions through the activation of NADH/NADPH oxidase in cultured rat aortic smooth muscle cells and in aortas of rats made hypertensive by infusion of Ang II.41 42 Capers et al43 showed a marked inflammatory response characterized by the infiltration of monocytes/macrophages in the aortas made hypertensive by infusion of Ang II. Chen et al44 demonstrated that Ang II directly stimulates MCP-1 gene expression in the vasculature via AT1. Keider et al12 demonstrated that Ang II stimulates macrophage-mediated oxidation of LDL, and they also showed that Ang II enhanced the uptake and oxidation of monocytes and macrophages. The study by Li et al10 described the presence of AT1 in HCAECs and showed that Ang II increases the uptake of ox-LDL by HCAECs in a concentration-dependent manner. This increased uptake is due to the upregulation of LOX-1 by Ang II, which causes a concentration-dependent increase in ox-LDL uptake by HCAECs and enhanced ox-LDL–mediated cell injury. This study helps to explain the previous report that LOX-1 expression was found to be upregulated in SHR, which increases Ang II expression.33
We still do not know whether endothelial cells are injured in SHR or other animal models. However, a recent study by Rueckschloss et al45 demonstrated that LOX-1 is downregulated in arteries of patients undergoing therapy with ACE inhibitors. In the near future, we should know the molecular mechanism for which Ang II upregulates LOX-1 and how incorporated ox-LDL injures endothelial cells. Furthermore, in general, we still do not know the physiological or even the pathophysiological implications of how LOX-1 molecules act in the body. We should continue to seek further evidence of how LOX-1 is regulated both in vitro and in vivo and how LOX-1 recognizes ox-LDL particles.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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