Thrombospondin 1 in Metabolic Diseases

Abstract

The thrombospondin family comprises of five multifunctional glycoproteins, whose best-studied member is thrombospondin 1 (TSP1). This matricellular protein is a potent antiangiogenic agent that inhibits endothelial migration and proliferation, and induces endothelial apoptosis. Studies have demonstrated a regulatory role of TSP1 in cell migration and in activation of the latent transforming growth factor beta 1 (TGFβ1). These functions of TSP1 translate into its broad modulation of immune processes. Further, imbalances in immune regulation have been increasingly linked to pathological conditions such as obesity and diabetes mellitus. While most studies in the past have focused on the role of TSP1 in cancer and inflammation, recently published data have revealed new insights about the role of TSP1 in physiological and metabolic disorders. Here, we highlight recent findings that associate TSP1 and its receptors to obesity, diabetes, and cardiovascular diseases. TSP1 regulates nitric oxide, activates latent TGFβ1, and interacts with receptors CD36 and CD47, to play an important role in cell metabolism. Thus, TSP1 and its major receptors may be considered a potential therapeutic target for metabolic diseases.

Keywords: TGFβ1; angiogenesis; atherosclerosis; cardiovascular disease; diabetes; nitric oxide; obesity.

Figure 1

Schematic diagram representing the structure of TSP1, its major ligands and functions. TSP1 displays an amino terminus that interacts with integrins and proteoglycans. The type I, II, and III repeats and the carboxyl-terminal end are also represented herein. The type I repeats also named TSRs contain the binding domain for CD36, responsible for endothelial apoptosis. The sequence RFK that activates the latent form of transforming growth factor beta1(TGFβ1) is also found within these repeats. The type III repeats of TSP1 contain domains that interact with neutrophil elastase and inhibit FGF2. Finally, the carboxyl-terminal domain of TSP1 binds to CD47. This domain interacts with integrins modulating cell adhesion, spreading and migration. TSP1 binds to a diversity of relevant proteins and growth factors not shown in this figure in lieu of clarity.

Figure 2

Mechanisms mediated by TSP1 in cardiovascular diseases. The interaction of TSP1 with CD47 inhibits nitric-oxide (NO) levels, thereby decreasing vasodilation and compromising organ perfusion. Hypertension and endothelial injury can in turn, activate the coagulation system, promoting the initiation of thrombus. CD47 suppresses the activation of phagocytic and natural killer (NK) cells during atherogenesis, dampening the inflammatory response and efferocytosis by interacting with signal regulatory protein alpha (SIRPα) and inhibiting integrins. TSP1 activates the latent transforming growth factor beta1 (TGFβ1) enhancing inflammation and fibrosis in the heart and vascular system. Additionally, this growth factor activates matrix metalloproteinases (MMPs), thereby contributing to matrix remodeling in atherosclerosis. Inflammation-induced hypoxia activates hypoxia inducible factor-1 and 2 alpha (HIF1/2α) and increases the levels of interleukin 6 (IL6) and tumor necrosis factor alpha (TNFα) promoting even more the inflammatory process and atherosclerosis. Inflammation also enhances the production of reactive oxygen species (ROS) and cell damage. CD36, as a scavenger receptor B, promotes cellular uptake of lipoproteins and formation of foamy macrophages, which are part of the atherosclerotic plaque. Additionally, by interacting with TSP1, CD36 stabilizes the thrombus in the arterial wall and stimulates the proliferation and migration of smooth muscle cells (SMCs), contributing even further to the atherosclerotic process.

Figure 3

Effects of TSP1 and ligands in glucose metabolism and diabetes mellitus. TSP1 protects the pancreatic endothelium and controls angiogenesis by enhancing insulin production and release. TSP1 also blocks the formation of uncoupling protein 2 (UCP2), a mitochondrial protein involved in oxidation and reactive oxygen species (ROS) metabolism. Under normal glycemic conditions, TSP1 inhibits glycolysis promoting the production of more ATP and pro-insulin. However, under hyperglycemic conditions and by activating TGFβ1, TSP1 accelerates the inflammation and fibrotic changes in multiple organs, especially in the kidney, leading to diabetic nephropathy and other diabetic complications. The TSP1 receptors CD36 and CD47 can inhibit the proliferation and migration of endothelial and smooth muscle cells, thereby contributing to endothelial dysfunction in diabetes. In this context, CD47 regulates SMC migration by binding mainly to TSP1 while limiting its association with SIRP1α. Activation of the hexosamine pathway and glycosylated products can induce further endothelial damage, with generation of ROS and delay of the wound-healing process in diabetes. Hyperglycemia will inhibit PKG and induce upstream stimulatory factor 2 (USF2), promoting the upregulation of TSP1 in diabetes. However, all these effects mediated by TSP1 in the glucose metabolism may be regulated by microRNAs.

Figure 4

TSP1 in adipose metabolism and obesity. TSP1 activates the latent form of transforming growth factor beta1 (TGFβ1), consequently promoting the recruitment of leukocytes, the influx of macrophages to the adipose tissue, and the release of inflammatory cytokines and adipokines. TGFβ1 will also contribute to fibrosis of adipose tissues by inducing the transcription of pro-fibrotic genes. By interacting with TSP1, CD47 suppresses the mitochondrial metabolism in brown adipose cells, therefore exhibiting a pro-obesity effect. TSP1 interacts with the hormone leptin by activating the JAK/STATs pathway. Increased plasma levels of leptin are correlated with high body fatness. The dashed arrow indicates a probable but yet unexplained association with obesity. CD36 facilitates the uptake of free fatty acids (FFA) into adipose cells, but it can also promote the apoptosis of endothelial cells, decreasing angiogenesis. Perhaps, this could contribute to the lower vascularization observed in white adipose tissues during the progression of this condition (dashed arrow). Finally, CD36 can regulate adipogenesis and expansion of adipose cells by activating the signal transducer and activator of transcription 3 (STAT3) signaling.