GDF15, a Cardioprotective TGF-β Superfamily Protein

he transforming growth factor-␤ (TGF-␤) superfamily proteins, comprising more than 40 members (broadly divided into the TGF-␤s/activins/nodal family and the bone morphogenetic proteins [BMPs]/Mu ¨llerrian inhibiting substance/growth and differentiation factors [GDFs] family), were originally identified as molecules important for regulating development, differentiation, and tissue repair in various organs. 1 TGF-␤1, a founding member of the TGF-␤ superfamily, plays a key role in mediating cardiac hypertrophy 2 and remodeling after myocardial infarction (MI) as an autocrine/paracrine factor. 3Increased TGF-␤1 expression is considered one of the few molecular markers that potentially discriminate between compensated and decompensated cardiac hypertrophy. 3Although TGF-␤1 may function protectively after MI by promoting scar formation, inhibiting neutrophil infiltration, and facilitating cardiomyogenic differentiation of adult hematopoietic stem cells, 4 such beneficial effects last only briefly and sustained activation of TGF-␤1 causes structural remodeling, eventually leading to cardiac failure. 5Thus, TGF-␤1 is generally regarded as detrimental, inducing cardiac hypertrophy and failure in the adult heart.Compared with the wealth of knowledge regarding the effects of TGF-␤1 on the heart, much less is known as to how other members of the TGF-␤ superfamily affect cardiac hypertrophy and failure. 6In this issue of Circulation Research, two companion articles report the effect of growth and differentiation factor 15 (GDF15), a 12-kDa secreted protein (and a 25-kDa disulfide-linked dimer) belonging to the TGF-␤ superfamily, on cardiac hypertrophy and apoptosis. 7,8GDF15 is highly expressed in the placenta and the prostate, but not normally in many other organs, including the heart. 9,10However, expression of GDF15 is induced rapidly by IL-1, TNF␣, and TGF-␤ in macrophages, thereby limiting macrophage activation and inflammation (Figure 1). 9 In addition, p53, a tumor suppressor protein, induces expression of GDF15, which acts as a growth inhibitory molecule in tumor cells (Figure 1). 10 Such growth inhibitory actions of GDF15 are unique compared with those of other targets of p53, such as p21/Waf-1, because GDF15 can act on neighboring cells as an "extracellular" messenger after being