Oxidized LDL Autoantibodies, Endothelial Dysfunction, and Transplant-Associated Arteriosclerosis
One of the major limitations of cardiac transplantation is the development of transplant coronary arteriopathy or transplant-associated arteriosclerosis that can be associated with progressive coronary artery occlusion.1 The condition is thought to be immune-mediated and may be related to the expression by the endothelium of the transplanted coronary artery of HLA-DR, which is recognized as foreign by CD4+ T-lymphocytes.2 The resulting interaction is associated with a chronic, localized inflammatory response.
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One manifestation of transplant-associated arteriosclerosis is reflected in abnormality of the vasodilator function of the endothelium (endothelial dysfunction).3 Endothelium-dependent vasodilation is mediated by several factors generated by endothelial cells, most prominently NO.4,5⇓ One of the important mechanisms by which endothelial vasodilator function becomes impaired is by the excessive production of reactive oxygen species (ROS) and especially oxygen free radicals (O2−).4 At appropriate stoichiometry, O2− reacts with NO to degrade it, causing the loss of its dilator effect on vascular smooth muscle. This chemistry is particularly relevant to the article in this issue of Arteriosclerosis, Thrombosis, and Vascular Biology by Fang and colleagues6 in which they show that in heart transplant patients the extent of acetylcholine-induced, endothelial-dependent coronary artery dilation at one year is inversely related to the blood levels of autoantibodies to oxidized low density lipoprotein (OxLDL). In contrast, there was no correlation between endothelial dysfunction in these patients and levels of either circulating OxLDL or LDL.
Oxidized LDL has been thought to play an important role in the pathogenesis of atherosclerosis since the original observations of Steinberg and colleagues7,8⇓ in the early 1980s that LDL must be oxidatively modified for it to be taken up by macrophages and resulting in the formation of foam cells, one of the characteristic features of the atherosclerotic lesion. OxLDL is a very biologically active molecule and is a potent proinflammatory agent in the arterial wall as well as very immunogenic as reflected in the presence of anti-OxLDL antibodies both in the circulation as well as in atherosclerotic lesions.9 OxLDL has come to be viewed as a core, central element in the pathogenesis of atherosclerosis.10 In more recent years, the original oxidation hypothesis of the pathogenesis of atherosclerosis of Steinberg et al7,8⇓ and Witzum10 has been expanded to incorporate concepts that the fundamental metabolic abnormality in many vasculopathies including atherosclerosis and hypertensive and diabetic vascular disease involves the stimulation of oxidation-sensitive signaling pathways in vascular cells that are mediated by intracellular ROS.11–13⇓⇓ These ROS are generated by oxidases coupled to hormone and cytokine receptors as well as to receptors for advanced glycation end products (RAGE) in diabetes. In this broader context, the generation of OxLDL may be one important consequence of a generalized shift in the metabolism of vascular cells and, in particular, the endothelium to an oxidized state that represents an adaptation, or frequently, a maladaptation as part of a stress response that depends on reduction-oxidation (redox)-mediated signaling to modulate kinases and transcriptional control pathways. Whether vascular injury is metabolically mediated as in hyperlipidemia or immune-mediated as in transplant-associated arteriosclerosis, it is likely to be associated with redox stress and the generation of excessive ROS. As inferred above, excessive vascular oxidative stress would be expected to be manifested by endothelial vasodilator dysfunction.
Evidence of high oxidative stress has been demonstrated for at least a year after lung transplantation in humans,14 and early endothelial dysfunction correlates with the development of transplant coronary artery disease at one year after transplant.3 Vasomotor dysfunction resulting from excess endothelial production of ROS and degradation of NO is hemodynamically important in regulating coronary blood flow in both atherosclerosis15 and in transplant-related coronary artery disease.16 As suggested, this vasomotor abnormality is a marker of a more general metabolic derangement of redox state that is also associated with a proinflammatory phenotype. Thus, redox-sensitive signaling pathways are associated with stimulation of endothelial expression of adhesion molecules and chemokines that attract monocytes and T-cells into the arterial wall.11–13⇓⇓ These inflammatory cells are the essential elements of cardiac transplant coronary arteriopathy.
The role of OxLDL autoantibodies in the pathogenesis of transplant-associated atherosclerosis is not fully understood.9 T-lymphocytes from human atherosclerotic plaques recognize OxLDL,17 and the presence of anti-OxLDL antibodies is associated with progression of carotid artery disease18 and early onset peripheral vascular disease.19 In the report by Fang and colleagues, 6 anti-OxLDL correlated, as noted, better with endothelial dysfunction than did plasma LDL or OxLDL levels. OxLDL is cleared relatively rapidly from plasma by the reticular endothelial system9 whereas the plasma antibodies would be expected to be more long lived and to represent an integrated measure of the formation of OxLDL in the arterial wall. Thus, the data of Fang et al6 are consistent with the notion that anti-OxLDL antibodies may represent a suitable measure of the oxidative state of the coronary vasculature in transplant associated arteriosclerosis. The findings are provocative and it will be interesting to see additional studies on the subject.
The development of reliable markers of the metabolic (redox) state of the vasculature is a major goal for many research groups investigating vascular diseases generally. Such markers would be important both as diagnostic reagents as well as providing therapeutic endpoints. The article by Fang et al6 could represent an important step is this journey.
- ↵Uretsky BF, Murali S, Reddy PS, Rabin B, Lee A, Griffith BP, Hardesty RL, Trento A, Bahnson HT. Development of coronary artery disease in cardiac transplant patients receiving immunosuppressive therapy with cyclosporine and prednisone. Circulation. 1987; 76: 827–834.
- ↵Davis SF, Yeung AC, Meredith IT, Charbonneau F, Ganz P, Selwyn AP, Anderson TJ. Early endothelial dysfunction predicts the development of transplant coronary artery disease at 1 year posttransplant. Circulation. 1996; 93: 457–462.
- ↵Furchgott RF, Vanhoutte PM. Endothelium-derived relaxing and contracting factors. FASEB J. 1989; 3: 2007–2018.
- ↵Fang JC, Kinlay S, Behrendt D, Hikita H, Witztum JL, Selwyn AP, Ganz P. Circulating autoantibodies to oxidized LDL correlate with impaired coronary endothelial function after cardiac transplantation. Arterioscler Thromb Vasc Biol. 2002; 22: 2044–2048.
- ↵Steinberg D. Low density lipoprotein oxidation and its pathobiological significance. J Biol Chem. 1997; 272: 20963–20966.
- ↵Marui N, Offermann M, Swerlick R, Kunsch C, Rosen CA, Ahmad M, Alexander RW, Medford RM. Vascular cell-adhesion molecule-1 (VCAM-1) gene transcription and expression are regulated through an antioxidant sensitive mechanism in human vascular endothelial cells. J Clin Invest. 1993; 92: 1866–1874.
- ↵Alexander RW. Hypertension and the pathogenesis of atherosclerosis: oxidative stress and the mediation of arterial inflammatory response—a new perspective. Hypertension. 1995; 25: 155–161.
- ↵Kunsch C, Medford RM. Oxidative stress as a regulator of gene expression in the vasculature. Circ Res. 1999; 85: 753–766.
- ↵Stemme S, Fraber B, Holm J, Wiklund O, Witztum JL, Hansson GK. T lymphocytes from human atherosclerotic plaques recognize oxidized low density lipoprotein. Proc Natl Acad Sci U S A. 1995; 92: 3893–3897.
- ↵Bergmark C, Wu R, de Faire U, Lefvert AK, Swedenborg J. Patients with early-onset peripheral vascular disease have increased levels of autoantibodies against oxidized LDL. Arterioscler Thromb Vasc Biol. 1995; 15: 441–445.