Roles of Growth Differentiation Factor 15 in Atherosclerosis and Coronary Artery Disease.

Abstract

The majority of acute cardiovascular events (CVE) in patients are caused by occlusive thrombosis because of rupture or erosion of atherosclerotic plaques.1 Growth differentiation factor 15 (GDF‐15), a stress‐responsive member of the transforming growth factor‐β (TGF‐β) cytokine superfamily, has been shown to be a strong and independent predictor of mortality and disease progression in patients with atherosclerosis and coronary artery disease (CAD), such as acute coronary syndromes (ACS) and stable angina pectoris.2 The development of atherosclerosis is dependent upon a high‐inflammatory content, which has been shown to modulate lesion initiation, progression, and potentially devastating thrombotic complications.3 Angiogenesis plays an important role in the progression of atherosclerotic plaque and complications.4, 5, 6 Atherosclerosis and cancer arise from multiple factors and are consolidated from the very early stages of development up to the advanced forms in inflammatory processes. Uncontrolled cell proliferation and oxidative stress and angiogenesis appear to be unifying causal factors in both diseases.7 A local inflammatory state occurring in atherosclerotic lesions has been implicated in angiogenesis through activation of endothelial cells, release of chemokines, cytokines, growth factors, lipid mediators, proteases, and increase of endothelial metabolic rate. The angiogenesis allows extravasation of the plasma component, leading to future thromboembolic events.8, 9, 10, 11 GDF‐15 might be an acute phase modifier of TGF‐βRII‐dependent proinflammatory responses to atherosclerotic plaque rupture and thrombus formation12 (Figure). Although the exact biological functions of GDF‐15 are still poorly understood, it has been shown to regulate inflammatory and angiogenesis pathways (Figure). GDF‐15 exhibits differing and even opposing functions under various circumstances. For instance, GDF‐15 has proapoptosis, antiapoptosis, proangiogenesis, antiangiogenesis, proinflammatory, and anti‐inflammatory properties.12, 13 Therefore, GDF‐15 exhibits a complex pattern with beneficial and harmful functions. GDF‐15 promoter contains p53‐transcription factor binding sites that are required and sufficient for the induction of GDF‐15 expression.14 Activation of p53 is a fundamental cellular response to inflammation, oxidative stress, hypoxia, telomere erosion, and oncogene activation. The circulating levels of GDF‐15 reflect these acute and chronic inflammatory conditions linked with atherosclerosis and CAD. Open in a separate window Figure 1 Schematic overview of a vulnerable plaque in advanced atherosclerosis. Plaque formation is initiated by endothelial cell dysfunction and subsequent angiogenesis and release of proinflammatory factors mediated by GDF‐15, contributing to the progression of atherosclerotic lesions and the development of plaque rupture and thrombus formation in atherosclerotic status. CRP indicates C‐reactive protein; GDF‐15, growth differentiation factor 15; MAPK, mitogen‐activated protein kinase; M‐CSF, macrophage colony‐stimulating factor; TGF‐βRII, transforming growth factor‐βRII; TNF‐α, tumor necrosis factor‐α.