Adipocytokines in atherothrombosis: focus on platelets and vascular smooth muscle cells

Abstract

Visceral obesity is a relevant pathological condition closely associated with high risk of atherosclerotic vascular disease including myocardial infarction and stroke. The increased vascular risk is related also to peculiar dysfunction in the endocrine activity of adipose tissue responsible of vascular impairment (including endothelial dysfunction), prothrombotic tendency, and low-grade chronic inflammation. In particular, increased synthesis and release of different cytokines, including interleukins and tumor necrosis factor-alpha (TNF-alpha), and adipokines-such as leptin-have been reported as associated with future cardiovascular events. Since vascular cell dysfunction plays a major role in the atherothrombotic complications in central obesity, this paper aims at focusing, in particular, on the relationship between platelets and vascular smooth muscle cells, and the impaired secretory pattern of adipose tissue.

Figure 1

Mechanisms involved in platelet adhesion to subendothelial layer and activation. The diagram illustrates the role of von Willebrand factor (vWF), collagen and other proteins in platelet adhesion by linking to exposure of membrane glycoprotein receptors including GPIb//V/IX complex, GPIIb/IIIa, and GPVI which ensures a stable anchorage with subendothelial matrix by interaction with collagen. Platelet activation and aggregation are triggered by thrombin, endogenous mediators released from storage granules, and synthesis of platelet activating factor (PAF), and thromboxane A₂ (TXA₂). P2Y1/12, purinergic P2Y receptors; TPα, thromboxane α receptor; 5HT-2A, serotonin (5-hydroxytryptamine)-2A receptor; PAR-1, protease-activated receptor-1; PAR-4, protease-activated receptor-4; α ₂ AR, α ₂ adrenoreceptor.

Figure 2

Platelet components involved in the coagulation cascade and the atherosclerotic process. PDGF, platelet-derived growth factor; TGFβ, transforming growth factor β; EGF, endothelial growth factor; bFGF, fibroblast growth factor; VEGF, vascular endothelial growth factor; IGF, insulin-like growth factor; IL-1β, interleukin-1β; PAI-1, plasminogen activator inhibitor 1; vWF, von Willebrand factor; GP, glycoproteins; PECAM, platelet and endothelial cell adhesion molecule; CD40L, CD40 ligand (CD154); RANTES, regulated on activation, normal T-cell expressed and secreted; MIP-1α, macrophage inflammation protein 1α; IL-8, interleukin-8; PF4, platelet factor 4.

Figure 3

General features of circulating platelet microparticles (PMPs). PMPs are phospholipid microvesicles of 0.1–1 micron in size, sheded from parental cell fragments after stimulation with physiological agonists such as thrombin or collagen or exposure to shear stress (i.e., in severe stenosis). PMPs express functional adhesion receptors, including GPIIb/IIIa (CD41), P-selectin (CD62P), CXCR4, and PAR-1 and contain different proteins and coagulation factors, thus exerting a role in the hemostatic response and in the interplay between coagulation and inflammation. PMPs also simulate cytokine release and adhesion molecule expression in endothelial cells and contraction of VSMC. Elevated levels of circulating PMPs have been described in patients with arteriosclerosis, acute vascular syndromes, diabetes mellitus, as well as central obesity. GPIIb/IIIa, glycoprotein IIb/IIIa; GP Ib, glycoprotein Ib; CXCR4, chemokine (C-X-C motif) receptor 4; PAR-1, protease-activated receptor-1; RANTES, regulated on activation, normal T-cell expressed and secreted.

Figure 4

Mechanisms involved in the alterations of the coagulative balance induced by interleukin-6 (IL-6). IL-1, interleukin-1; IL-4, interleukin-4; TNF-α, tumor necrosis factor-α; IFN-γ, interferon-γ; f VIII, factor VIII, vWF, von Willebrand factor; AT III, antithrombin III.

Figure 5

Acute and chronic cardiovascular effects of visfatin. VEGF, vascular endothelial growth factor; MMP-2, matrix metalloproteinase-2; MMP-9, matrix metalloproteinase-9; PBEF, pre-B cell colony-enhancing factor I-R, ischemia-reperfusion.

Figure 6

Potential vascular effects of resistin. IL-6, interleukin-6; IL-8, interleukin-8; TNF-α, tumor necrosis factor-α; ET-1, endothelin-1; MCP-1, monocyte chemoattractant protein-1; VCAM-1, Vascular Cell Adhesion Molecule-1; ICAM-1, Intercellular Adhesion Molecule-1; MMPs, matrix metalloproteinases.