GDF-15 as a Target and Biomarker for Diabetes and Cardiovascular Diseases: A Translational Prospective

Abstract

Growth differentiation factor-15 (GDF-15) is a stress responsive cytokine. It is highly expressed in cardiomyocytes, adipocytes, macrophages, endothelial cells, and vascular smooth muscle cells in normal and pathological condition. GDF-15 increases during tissue injury and inflammatory states and is associated with cardiometabolic risk. Increased GDF-15 levels are associated with cardiovascular diseases such as hypertrophy, heart failure, atherosclerosis, endothelial dysfunction, obesity, insulin resistance, diabetes, and chronic kidney diseases in diabetes. Increased GDF-15 level is linked with the progression and prognosis of the disease condition. Age, smoking, and environmental factors are other risk factors that may increase GDF-15 level. Most of the scientific studies reported that GDF-15 plays a protective role in different tissues. However, few reports show that the deficiency of GDF-15 is beneficial against vascular injury and inflammation. GDF-15 protects heart, adipose tissue, and endothelial cells by inhibiting JNK (c-Jun N-terminal kinase), Bad (Bcl-2-associated death promoter), and EGFR (epidermal growth factor receptor) and activating Smad, eNOS, PI3K, and AKT signaling pathways. The present review describes the different animal and clinical studies and patent updates of GDF-15 in diabetes and cardiovascular diseases. It is a challenge for the scientific community to use GDF-15 information for patient monitoring, clinical decision-making, and replacement of current treatment strategies for diabetic and cardiovascular diseases.

Figure 1

Role of GDF-15 in different diseases conditions. GDF-15 plays an important role to modulate metabolic, cardiovascular, obesity, cancer, and chronic disease.

Figure 2

GDF-15 regulates signaling pathways essential for cardioprotection. GDF-15 shows cardioprotective effect through activation of ALK type 1 receptors (ALK 1–7) and phosphorylation of Smad2/3 and Smad1/5/8. After phosphorylation, Smad translocates to the nucleus in the form of heteromeric complex with Smad 4 and activates antihypertrophic pathway. GDF-15 also activates PI3 K/AKT/eNOS/NO pathway and shows cardioprotection. GDF-15 inhibits epidermal growth factor receptor (EGFR) transactivation and NF-κB/JNK/caspase-3 pathway to show its cardioprotective effect.