Chronic kidney disease (CKD) is an independent risk factor for coronary artery disease (CAD). Coronary artery disease is the leading cause of morbidity and mortality in patients with CKD. The outcomes of CAD are poorer in patients with CKD. In addition to traditional risk factors, several uremia-related risk factors such as inflammation, oxidative stress, endothelial dysfunction, coronary artery calcification, hyperhomocysteinemia, and immunosuppressants have been associated with accelerated atherosclerosis. A number of uremia-related biomarkers are identified as predictors of cardiac outcomes in CKD patients. The symptoms of CAD may not be typical in patients with CKD. Both dobutamine stress echocardiography and radionuclide myocardial perfusion imaging have moderate sensitivity and specificity in detecting obstructive CAD in CKD patients. Invasive coronary angiography carries a risk of contrast nephropathy in patients with advanced CKD. It should be reserved for those patients with a high risk for CAD and those who would benefit from revascularization. Guideline-recommended therapies are, in general, underutilized in renal patients. Medical therapy should be considered the initial strategy for clinically stable CAD. The effects of statins in patients with advanced CKD have been neutral despite a lipid-lowering effect. Compared to non-CKD population, percutaneous coronary intervention (PCI) is associated with higher procedure complications, restenosis, and future cardiac events even in the drug-eluting stent era in patients with CKD. Compared with PCI, coronary artery bypass grafting (CABG) reduces repeat revascularizations but is associated with significant perioperative morbidity and mortality. Screening for CAD is an important part of preoperative evaluation for kidney transplant candidates.

Diabetes is associated with enhanced inflammatory responses and cardiovascular complications such as atherosclerosis. However, it is unclear whether similar responses are present in cells derived from experimental animal models of diabetes. We examined our hypothesis that macrophages and short-term cultured vascular smooth muscle cells (VSMCs) derived from obese, insulin-resistant, and diabetic db/db mice would exhibit increased proatherogenic responses relative to those from control db/؉ mice. We observed that macrophages from db/db mice exhibit significantly increased expression of key inflammatory cytokines and chemokines as well as arachidonic acid-metabolizing enzymes cyclooxygenase-2 and 12/15-lipoxygenase that generate inflammatory lipids. Furthermore, VSMCs derived from db/db mice also showed similar enhanced expression of inflammatory genes. Expression of inflammatory genes was also significantly increased in aortas derived from db/db mice. Both macrophages and VSMCs from db/db mice demonstrated significantly increased oxidant stress, activation of key signaling kinases, and transcription factors cAMP response element-binding protein and nuclear factor-B, involved in the regulation of atherogenic and inflammatory genes. Interestingly, VSMCs from db/db mice displayed enhanced migration as well as adhesion to WEHI mouse monocytes relative to db/؉. Thus, the diabetic milieu and a potential hyperglycemic memory can induce aberrant behavior of vascular cells. These new results demonstrate that monocyte/macrophages and VSMCs derived from db/db mice display a "preactivated" and proinflammatory phenotype associated with the pathogenesis of diabetic vascular dysfunction and atherosclerosis. Diabetes

Objective-Vascular smooth muscle cells (VSMCs) may regulate monocyte functions within atherosclerotic lesions. We investigated the impact of VSMC/monocyte interactions on monocyte apoptosis and scavenger receptor CD36 expression, key events related to monocyte survival and differentiation. Methods and Results-Serum deprivation significantly increased THP-1 and human peripheral blood monocyte apoptosis.However, this was significantly reversed by physical binding to human VSMCs (HVSMCs). On binding to HVSMCs, antiapoptotic kinase Akt and its downstream targets were phosphorylated, and Bcl-2 expression was enhanced.Binding-mediated suppression of apoptosis and Akt phosphorylation were attenuated by a phosphoinositide 3-kinase inhibitor and also by an antibody to vascular cell adhesion molecule-1. CD36 expression was also significantly increased in THP-1 cells and in human peripheral blood monocytes after binding to HVSMCs, and this was mediated by both direct contact and soluble factors. Extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinase phosphorylation was increased in THP-1 cells after HVSMC coculture. Furthermore, an ERK1/2 inhibitor blocked monocyte CD36 upregulation. Contact-dependent CD36 induction and ERK1/2 phosphorylation in monocytes were inhibited by blocking vascular cell adhesion molecule-1 on HVSMC, whereas soluble factor-induced CD36 expression was attenuated by a monocyte chemoattractant protein-1 neutralizing antibody. I n response to atherogenic stimuli, monocytes in circulation adhere and migrate across the endothelium to the intimal space where they differentiate, take up lipid, and form foam cells. The role of vascular endothelial cells in the recruitment of monocytes during early steps of atherosclerosis has been well studied. [1][2][3] However, these initial processes may be reversible and do not cause clinical consequences. 1,2 It is the subsequent prolonged intimal retention of monocyte/macrophage and foam cell formation that are central features of atherogenesis. 1,2 However, the mechanisms by which monocytes/macrophages are retained within the vessel wall, survive, and differentiate to foam cells are not well documented. Once they transmigrate into the subendothelial intimal space, these monocyte functions are regulated mainly by the influence of local factors that are not well characterized. Furthermore, very little is known about the role of intimal vascular smooth muscle cells (VSMCs) in regulating subendothelial monocyte functions. Conclusions-TheseVSMC migration and proliferation are also welldocumented hallmarks of early atherosclerotic lesions. 1,4 Accumulating evidence suggests that interactions between transmigrated monocytes and VSMCs may contribute to monocyte retention and function within the vasculature. First, the potential of VSMCs to interact with monocytes is suggested by the fact that VSMCs express adhesion molecules within atherosclerotic lesions but not in the normal vascular wall. 5 A highly significant association was found between V...

Cai, Qiangjun, Linda Lanting, and Rama Natarajan. Growth factors induce monocyte binding to vascular smooth muscle cells: implications for monocyte retention in atherosclerosis. Am J Physiol Cell Physiol 287: C707-C714, 2004. First published May 12, 2004 10.1152/ajpcell.00170.2004.-Adhesive interactions between monocytes and vascular smooth muscle cells (VSMC) may contribute to subendothelial monocyte-macrophage retention in atherosclerosis. We investigated the effects of angiotensin II (ANG II) and plateletderived growth factor (PDGF)-BB on VSMC-monocyte interactions. Treatment of human aortic VSMC (HVSMC) with ANG II or PDGF-BB significantly increased binding to human monocytic THP-1 cells and to peripheral blood monocytes. This was inhibited by antibodies to monocyte ␤1-and ␤2-integrins. The binding was also attenuated by blocking VSMC arachidonic acid (AA) metabolism by inhibitors of 12/15-lipoxygenase (12/15-LO) or cyclooxygenase-2 (COX-2). Conversely, binding was enhanced by overexpression of 12/15-LO or COX-2. Direct treatment of HVSMC with AA or its metabolites also increased binding. Furthermore, VSMC derived from 12/15-LO knockout mice displayed reduced binding to mouse monocytic cells relative to genetic control mice. Using specific signal transduction inhibitors, we demonstrated the involvement of Src, phosphoinositide 3-kinase, and MAPKs in ANG II-or PDGF-BBinduced binding. Interestingly, after coculture with HVSMC, THP-1 cell surface expression of the scavenger receptor CD36 was increased. These results show for the first time that growth factors may play additional roles in atherosclerosis by increasing monocyte binding to VSMC via AA metabolism and key signaling pathways. This can lead to monocyte subendothelial retention, CD36 expression, and foam cell formation.angiotensin II; platelet-derived growth factor-BB; cell interaction; CD36 MONOCYTES-MACROPHAGES play a key role in all stages of atherosclerosis (28). In response to atherogenic stimuli, monocytes in circulation adhere and migrate across the endothelium. These initial processes may be reversible, whereas the subsequent prolonged intimal retention of monocytes-macrophages is a central pathogenic process in atherogenesis (20). However, the mechanisms by which subendothelial retention of monocytes occurs and the role of vascular smooth muscle cells (VSMC) in this process are unclear.Migration and proliferation of VSMC are also well-documented events in atherosclerosis (30). Increasing evidence suggests that adhesive interactions between migrated monocytes and VSMC may contribute to monocyte-macrophage retention within the vasculature. The potential of VSMC to interact with monocytes is suggested by the fact that VSMC express adhesion molecules within atherosclerotic lesions but not in normal vessels (2). In addition, a highly significant association was found between VSMC vascular cell adhesion molecule (VCAM)-1 expression and intimal macrophage content (17, 25). Furthermore, a strong focal expression of intercellular adhesion molecule (IC...

Diabetes is associated with significantly accelerated rates of atherosclerosis, key features of which include the presence of excessive macrophage-derived foam cells in the subendothelial space. We examined the hypothesis that enhanced monocyte-vascular smooth muscle cell (VSMC) interactions leading to subendothelial monocyte retention and differentiation to macrophages under diabetic conditions may be underlying mechanisms. Human aortic VSMCs (HVSMCs) treated with diabetic stimuli high glucose (HG) or S100B, a ligand of the receptor for advanced glycation end products, exhibited significantly increased binding of THP-1 monocytic cells. Diabetic stimuli increased the expression of the adhesive chemokine fractalkine (FKN) in HVSMCs. Pretreatment of HVSMCs with FKN or monocyte chemoattractant protein-1 (MCP-1) neutralizing antibodies significantly inhibited monocyte-VSMC binding, whereas monocytes treated with FKN showed enhanced binding to VSMC. Mouse aortic VSMCs (MVSMCs) derived from type 2 diabetic db/db mice exhibited significantly increased FKN levels and binding to mouse WEHI78/24 monocytic cells relative to nondiabetic control db/+ cells. The enhanced monocyte binding in db/db cells was abolished by both FKN and MCP-1 antibodies. Endothelium-denuded aortas from db/db mice and streptozotocin-induced diabetic mice also exhibited enhanced FKN expression and monocyte binding, relative to respective controls. Coculture with HVSMCs increased CD36 expression in THP-1 cells, and this was significantly augmented by treatment of HVSMCs with S100B or HG. CD36 mRNA and protein levels were also significantly increased in WEHI78/24 cells after coincubation with db/db MVSMCs relative to control MVSMCs. These results demonstrate that diabetic conditions may accelerate atherosclerosis by inducing key chemokines in the vasculature that promote VSMC-monocyte interactions, subendothelial monocyte retention, and differentiation.