Adipose tissue depots originate from distinct precursor cells, are functionally diverse, and modulate disease processes in a depot-specific manner. However, the functional properties of perivascular adipocytes, and their influence on disease of the blood vessel wall, remain to be determined. We show that human coronary perivascular adipocytes exhibit a reduced state of adipocytic differentiation as compared with adipocytes derived from subcutaneous and visceral (perirenal) adipose depots. Secretion of antiinflammatory adiponectin is markedly reduced, whereas that of proinflammatory cytokines interleukin-6, interleukin-8, and monocyte chemoattractant protein-1, is markedly increased in perivascular adipocytes. These depot-specific differences in adipocyte function are demonstrable in both freshly isolated adipose tissues and in vitro–differentiated adipocytes. Murine aortic arch perivascular adipose tissues likewise express lower levels of adipocyte-associated genes as compared with subcutaneous and visceral adipose tissues. Moreover, 2 weeks of high-fat feeding caused further reductions in adipocyte-associated gene expression, while upregulating proinflammatory gene expression, in perivascular adipose tissues. These changes were observed in the absence of macrophage recruitment to the perivascular adipose depot. We conclude that perivascular adipocytes exhibit reduced differentiation and a heightened proinflammatory state, properties that are intrinsic to the adipocytes residing in this depot. Dysfunction of perivascular adipose tissue induced by fat feeding suggests that this unique adipose depot is capable of linking metabolic signals to inflammation in the blood vessel wall.

Background— Ghrelin is a novel growth hormone-releasing peptide that has been shown to improve cachexia in heart failure and cancer and to ameliorate the hemodynamic and metabolic disturbances in septic shock. Because cytokine-induced inflammation is critical in these pathological states and because the growth hormone secretagogue receptor has been identified in blood vessels, we examined whether ghrelin inhibits proinflammatory responses in human endothelial cells in vitro and after administration of endotoxin to rats in vivo. Methods and Results— Human umbilical vein endothelial cells (HUVECs) were treated with or without tumor necrosis factor-α (TNF-α), and induction of proinflammatory cytokines and mononuclear cell adhesion were determined. Ghrelin (0.1 to 1000 ng/mL) inhibited both basal and TNF-α-induced cytokine release and mononuclear cell binding. Intravenous administration of ghrelin also inhibited endotoxin-induced proinflammatory cytokine production in rats in vivo. Ghrelin inhibited H ₂ O ₂ -induced cytokine release in HUVECs, suggesting that the peptide blocks redox-mediated cellular signaling. Moreover, ghrelin inhibited basal and TNF-α-induced activation of nuclear factor-κB. Des-acyl ghrelin had no effect on TNF-α-induced cytokine production in HUVECs, suggesting that the antiinflammatory effects of ghrelin require interaction with endothelial growth hormone secretagogue receptors. Conclusions— Ghrelin inhibits proinflammatory cytokine production, mononuclear cell binding, and nuclear factor-κB activation in human endothelial cells in vitro and endotoxin-induced cytokine production in vivo. These novel antiinflammatory actions of ghrelin suggest that the peptide could play a modulatory role in atherosclerosis, especially in obese patients, in whom ghrelin levels are reduced.

The role of inflammation in the pathogenesis of abdominal aortic aneurysms (AAA) is well established. The inflammatory process leads to protease-mediated degradation of the extracellular matrix and apoptosis of smooth muscle cells (SMC), which are the predominant matrix synthesizing cells of the vascular wall. These processes act in concert to progressively weaken the aortic wall, resulting in dilatation and aneurysm formation. Oxidative stress is invariably increased in, and contributes importantly to, the pathophysiology of inflammation. Moreover, reactive oxygen species (ROS) play a key role in regulation of matrix metalloproteinases and induction of SMC apoptosis. ROS may also contribute to the pathogenesis of hypertension, a risk factor for AAA. Emerging evidence suggests that ROS and reactive nitrogen species (RNS) are associated with AAA formation in animal models and in humans. Although experimental data are limited, several studies suggest that modulation of ROS production or activity may suppress AAA formation and improve experimental outcome in rodent models. Although a number of enzymes can produce injurious ROS in the vasculature, increasing evidence points toward a role for NADPH oxidase as a source of oxidative stress in the pathogenesis of AAA.

Atherosclerosis is increasingly recognized as a chronic inflammatory disease. Although a variety of inflammatory markers (ie, C-reactive protein) have been associated with atherosclerosis and its consequences, it is important to identify principal mediators of the inflammatory responses. One potentially important source of vascular inflammation in atherosclerosis is bacterial endotoxin. Mutations in Toll-like receptor 4 (TLR-4), an integral component of the endotoxin signaling complex, are fairly common in the Caucasian population and have recently been associated with reduced incidence of atherosclerosis and other cardiovascular diseases in some studies. Moreover, epidemiological studies suggest that endotoxemia at levels as low as 50 pg/mL constitutes a strong risk factor for the development of atherosclerosis. Endotoxin concentrations in this range may be produced by a variety of common subclinical Gram-negative infections. In this article, we outline the main elements of the endotoxin signaling receptor complex that initiates proinflammatory signaling (lipopolysaccharide binding protein [LBP], CD14, TLR-4, and MD-2) and discuss how changes in expression of these molecules may affect proatherogenic responses in the vessel wall. We also describe some of the proinflammatory effects of endotoxin that may be relevant to atherosclerosis, and discuss how serum lipoproteins, especially high-density lipoprotein, may modulate endotoxin-induced inflammatory responses. Further, we discuss recent findings suggesting that the lipid-lowering statins may have an additional protective role in blocking at least some of these proinflammatory signaling pathways. Finally, we discuss species diversity with regard to endotoxin signaling that should be considered when extrapolating experimental data from animal models to humans.

Non-phagocytic NAD(P)H oxidases have been implicated as major sources of reactive oxygen species in blood vessels. These oxidases can be activated by cytokines, thereby generating O⨪₂, which is subsequently converted to H₂O₂ and other oxidant species. The oxidants, in turn, act as important second messengers in cell signaling cascades. We hypothesized that reactive oxygen species, themselves, can activate the non-phagocytic NAD(P)H oxidases in vascular cells to induce oxidant production and, consequently, cellular injury. The current report demonstrates that exogenous exposure of non-phagocytic cell types of vascular origin (smooth muscle cells and fibroblasts) to H₂O₂ activates these cell types to produce O⨪₂ via an NAD(P)H oxidase. The ensuing endogenous production of O⨪₂ contributes significantly to vascular cell injury following exposure to H₂O₂. These results suggest the existence of a feed-forward mechanism, whereby reactive oxygen species such as H₂O₂ can activate NAD(P)H oxidases in non-phagocytic cells to produce additional oxidant species, thereby amplifying the vascular injury process. Moreover, these findings implicate the non-phagocytic NAD(P)H oxidase as a novel therapeutic target for the amelioration of the biological effects of chronic oxidant stress.