Role of the Stress- and Inflammation-Induced Cytokine GDF-15 in Cardiovascular Diseases: From Basic Research to Clinical Relevance.

Stress- and inflammation-induced growth differentiation factor-15 (GDF-15) is proposed as a biomarker for mortality and disease progression in patients with atherosclerosis and/or cardiovascular disease (CVD). The development of atherosclerotic lesions depends, among other factors, on inflammatory processes, oxidative stress, and impaired lipid homeostasis. As a consequence, activation and dysfunction of endothelial cells, release of chemokines, growth factors and lipid mediators occur. GDF-15 is suggested as an acute-phase modifier of transforming growth factor (TGF)-ßRII-dependent pro-inflammatory responses leading to rupture of atherosclerotic plaques, although the exact biological function is poorly understood to date. GDF-15 is upregulated in many disease processes, and its effects may be highly context-dependent. To date, it is unclear whether the upregulation of GDF-15 leads to disease progression or provides protection against disease. Concerning CVD, cardiomyocytes are already known to produce and release GDF-15 in response to angiotensin II stimulation, ischemia, and mechanical stretch. Cardiomyocytes, macrophages, vascular smooth muscle cells, endothelial cells, and adipocytes also release GDF-15 in response to oxidative as well as metabolic stress or stimulation with pro-inflammatory cytokines. Given the critically discussed pathophysiological and cellular functions and the important clinical significance of GDF-15 as a biomarker in CVD, we have summarized here the basic research findings on different cell types. In the context of cellular stress and inflammation, we further elucidated the signaling pathway of GDF-15 in coronary artery disease (CAD), the most common CVD in developing and industrial nations.