LOX-1, a possible clue to the missing link between hypertension and atherogenesis.

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.1–3 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 reninangiotensin 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.6–9 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.