The transforming growth factor beta (TGF-beta) family of proteins are a set of pleiotropic secreted signaling molecules with unique and potent immunoregulatory properties. TGF-beta 1 is produced by every leukocyte lineage, including lymphocytes, macrophages, and dendritic cells, and its expression serves in both autocrine and paracrine modes to control the differentiation, proliferation, and state of activation of these immune cells. TGF-beta can modulate expression of adhesion molecules, provide a chemotactic gradient for leukocytes and other cells participating in an inflammatory response, and inhibit them once they have become activated. Increased production and activation of latent TGF-beta have been linked to immune defects associated with malignancy and autoimmune disorders, to susceptibility to opportunistic infection, and to the fibrotic complications associated with chronic inflammatory conditions. In addition to these roles in disease pathogenesis, TGF-beta is now established as a principal mediator of oral tolerance and can be recognized as the sine qua non of a unique subset of effector cells that are induced in this process. The accumulated knowledge gained through extensive in vitro functional analyses and from in vivo animal models, including newly established TGF-beta gene knockout and transgenic mice, supports the concept that clinical therapies based on modulation of this cytokine represent an important new approach to the treatment of disorders of immune function.

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REGULATION OF IMMUNE RESPONSES BY TGF-β*

Blood high-density lipoprotein (HDL) levels are inversely related to risk for cardiovascular disease, implying that factors associated with HDL metabolism are atheroprotective. One of these factors is ATP-binding cassette transporter A1 (ABCA1), a cell membrane protein that mediates the transport of cholesterol, phospholipids, and other metabolites from cells to lipid-depleted HDL apolipoproteins. ABCA1 transcription is highly induced by sterols, a major substrate for cellular export, and its expression and activity are regulated posttranscriptionally by diverse processes. Liver ABCA1 initiates formation of HDL particles, and macrophage ABCA1 protects arteries from developing atherosclerotic lesions. ABCA1 mutations can cause a severe HDL deficiency syndrome characterized by cholesterol deposition in tissue macrophages and prevalent atherosclerosis. Genetic manipulations of ABCA1 expression in mice also affect plasma HDL levels and atherogenesis. Metabolites elevated in individuals with the metabolic syndrome and diabetes destabilize ABCA1 protein and decrease cholesterol export from macrophages. Moreover, oxidative modifications of HDL found in patients with cardiovascular disease reduce the ability of apolipoproteins to remove cellular cholesterol by the ABCA1 pathway. These observations raise the possibility that an impaired ABCA1 pathway contributes to the enhanced atherogenesis associated with common inflammatory and metabolic disorders. The ABCA1 pathway has therefore become an important new therapeutic target for treating cardiovascular disease.

https://www.physiology.org/doi/pdf/10.1152/physrev.00005.2005

ATP-Binding Cassette Transporter A1: A Cell Cholesterol Exporter That Protects Against Cardiovascular Disease

Lipid abnormalities are among the key risk factors for cardiovascular disease. Indeed, lipid-modifying drugs - in particular, the statins, which primarily lower plasma levels of low-density lipoprotein (LDL) cholesterol - considerably reduce the risk of cardiovascular events, leading to their widespread use. Nevertheless, it seems that there might be limits to the degree of benefit that can be achieved by lowering LDL-cholesterol levels alone, which has led to increased interest in targeting other lipid-related risk factors for cardiovascular disease, such as low levels of high-density lipoprotein (HDL) cholesterol. In this article, we first consider the mechanisms that underlie the protective effect of HDL cholesterol, and then discuss several strategies that have recently emerged to increase levels of HDL cholesterol to treat cardiovascular disease, including nuclear receptor modulation, inhibition of cholesteryl ester transfer protein and infusion of apolipoprotein/phospholipid complexes.

HDL as a target in the treatment of atherosclerotic cardiovascular disease

Apolipoprotein-mediated removal of cellular cholesterol and phospholipids

Background—The ability of apolipoprotein (apo)A-I to induce regression of preexisting atherosclerotic lesions has not been determined, and a mouse model of atherosclerosis regression has not yet been reported. Methods and Results—LDL receptor–deficient mice were fed a western-type diet for 5 weeks to induce atherosclerotic lesions. A second-generation recombinant adenovirus encoding human apoA-I or a control adenovirus were injected intravenously in order to express apoA-I in the liver. Three days after injection, total apoA-I levels in mice injected with the apoA-I–expressing adenovirus were 216±16.0 mg/dL, compared with 68.0±3.0 mg/dL in control virus–injected mice (P<0.001). HDL cholesterol levels in mice injected with the AdhapoA-I vector 7 days after injection were 189±21.0 mg/dL, compared with 123±8.0 mg/dL in control virus-injected mice (P<0.02). Total and non-HDL cholesterol levels did not differ between the 2 groups. Atherosclerotic lesion area was quantified by en face analysis of the aorta and ...

Regression of Atherosclerosis Induced by Liver-Directed Gene Transfer of Apolipoprotein A-I in Mice

The effects of intravenous injection of purified rabbit apoA-I on the progression of aortic atherosclerosis in cholesterol-fed rabbits were examined. In experiment 1, 28 rabbits were equally divided into groups A and B and fed a 0.5% cholesterol diet for 90 days. For the last 30 days, group B received 40 mg apoA-I every week. The fatty streak lesions in group B (23.9±15.6%) were significantly suppressed compared with those in group A (46.0±24.9%) ( P <.05). In experiment 2, 33 rabbits were divided into four groups (8 or 9 rabbits per group) and fed a 0.5% cholesterol diet. Group A was killed on day 105, while groups B, C, and D were maintained for an additional 60 days on a normal diet, during which time groups C and D received 1 mg apoA-I every other day or 40 mg apoA-I every week, respectively. The lesions in group C (70.2±15.4%) and group D (65.7±20.0%) were significantly suppressed compared with those in group B (86.2±13.7%) ( P <.05) but were not reduced to the level of group A (50.0±22.9%). Although apparent regression was not observed under these conditions, the present study provided the first evidence for the antiatherogenic effect of homologous apoA-I on the progression of atherosclerosis in cholesterol-fed rabbits.

Intravenous Injection of Rabbit Apolipoprotein A-I Inhibits the Progression of Atherosclerosis in Cholesterol-Fed Rabbits

Lipoprotein(a) induces cell growth in rat peritoneal macrophages through inhibition of transforming growth factor-β activation

Reconstituted high density lipoprotein reduces the capacity of oxidatively modified low density lipoprotein to accumulate cholesteryl esters in mouse peritoneal macrophages

Endocytic Uptake of Lysophosphatidylcholine Mediated by Macrophage Scavenger Receptor Plays a Major Role in Oxidized Low Density Lipoprotein-induced Macrophage Growth

We recently demonstrated that macrophage growth was induced by oxidized LDL (Ox-LDL)' and its lysophosphatidylcholine (lyso-PC), a major phospholipid component of Ox-LDL, plays an essential role in Ox-LDL-induced macrophage growth.2,3 Because several lines of evidence have verified that the foam cells that proliferated in the early atherosclerotic lesions in situ are derived from mono~ytes/macrophages,4.~ the macrophage growth induced by Ox-LDL might potentially be linked to an enhanced progression of atherosclerosis. In contrast to the cell-growth capacity of Ox-LDL, acetyl-LDL, which served as an efficient ligand for the macrophage scavenger receptor (MSR), but contained a negligible amount of lyso-PC, did not show any mitogenic effect on mouse resident peritoneal macrophages2 nor on human monocyte-derived macro phage^.^ Similarly, lyso-PC alone did not show any mitogenic effect. However, incubation of macrophages with acetyl-LDL and lyso-PC or phospholipase A2-treated acetyl-LDL, resulted in a significant induction of macrophage g r o ~ t h . ~ , ~ These results taken together suggest that the combination of lyso-PC and a modified LDL is essential for induction of macrophage growth. Two routes are possible for the transfer of lyso-PC from Ox-LDL to macrophages. One is the direct transfer from Ox-LDL to plasma membranes of the macrophages by aqueous diffusion or lipid exchange reaction. The other pathway is the endocytic uptake of Ox-LDL by MSR and subsequent intracellular delivery of lyso-PC. It is not known which route is important for Ox-LDL-induced macrophage growth. To resolve

Seikoh Horiuchi

Papers

Intravenous Injection of Rabbit Apolipoprotein A-I Inhibits the Progression of Atherosclerosis in Cholesterol-Fed Rabbits

Lipoprotein(a) induces cell growth in rat peritoneal macrophages through inhibition of transforming growth factor-β activation

Reconstituted high density lipoprotein reduces the capacity of oxidatively modified low density lipoprotein to accumulate cholesteryl esters in mouse peritoneal macrophages

Endocytic Uptake of Lysophosphatidylcholine Mediated by Macrophage Scavenger Receptor Plays a Major Role in Oxidized Low Density Lipoprotein-induced Macrophage Growth

Role of the Macrophage Scavenger Receptor for Internalization of Lysophosphatidylcholine in Oxidized Low Density Lipoprotein‐Induced Macrophage Growth