Growth differentiation factor-15 and cardiovascular dysfunction and disease: malefactor or innocent bystander?

Abstract

It is widely recognized that around 20% of cardiovascular events occurring in the general population cannot be inferred from conventional risk factors.1 This led to a growing interest in novel measurable humoral biomarkers, hopefully leading to an improvement of global cardiovascular risk stratification. Growth differentiation factor-15 (GDF-15) is the latest promising marker in this field. Growth differentiation factor-15 is a protein belonging to the transforming growth factor-β (TGF-β) superfamily, which includes more than 40 proteins with crucial functions in adult tissue homeostasis by modulating cell survival, proliferation, differentiation, and tissue repair in different organs. Initially cloned from an activated macrophage cell line, GDF-15 has been proposed as a cell death promoter in several tumour cell lines, highlighting its potential role as an inductor of apoptosis in some cancer cells.2 Expression of GDF-15 is rapidly induced by IL-1, TNF-α, and TGF-β in macrophages, thereby limiting macrophage activation and inflammation.3 Results of analysis from human tissues evidenced the presence of GDF-15 also in the kidney, prostate and placenta, breast and colon, as well as in the heart.3 Since GDF-15 is a product of activated macrophages, its serum or plasma concentration might be useful in the identification of atherosclerosis. Several studies documented that activated macrophages are greatly involved in the pathogenesis of atherosclerosis and vascular thrombosis, which is often the final endpoint of atherosclerotic disease.4 An increased expression of GDF-15 has been identified in atherosclerotic lesions5 and within the myocardium of mice with acute myocardial infarction.6 The first clinical trial which assessed any association between plasma concentration of GDF-15, also known as macrophage inhibitory cytokine-1 (MIC-1), and risk of cardiovascular events derives from a prospective, nested, case–control study, conducted in apparently healthy elderly women, with no previous evidence of cardiovascular disease, participating in the Women's Health …