Growth differentiation factor 15 acts anti‐apoptotic and pro‐hypertrophic in adult cardiomyocytes

Abstract

Growth differentiation factor 15 (GDF15) is induced during heart failure development, and may influence different processes in cardiac remodeling. While its anti-apoptotic action under conditions of ischemia-reperfusion have been shown, it remained unclear if this is a broadly protective effect applicable to other apoptotic stimuli. Furthermore, effects on cardiac hypertrophy remained obscure. Therefore, we investigated the effects of GDF15 on induction of hypertrophy and apoptosis in ventricular cardiomyocytes. GDF15 (3 ng/ml) enhanced hypertrophic growth of cardiomyocytes as determined by an increase in cell size by 27 +/- 5% and rate of protein synthesis by 47 +/- 15%. In addition, a time and dose-dependent increase in SMAD-binding affinity was found, as well as enhanced phosphorylation of R-SMAD1. Inhibition of SMADs by transformation of cardiomyocytes with SMAD-decoy oligonucleotides abolished the hypertrophic growth effect. Specific inhibitors of PI3K (10 microM LY290042 or 10 nM wortmannin) or ERK (10 microM PD98059) also blocked GDF15-induced hypertrophy and SMAD activation. Apoptosis induction by three different agents, 100 nM angiotensin II, 1 ng/ml TGFbeta(1), or the NO-donor SNAP (100 microM) was blocked by addition of GDF15 (3 ng/ml). Scavenging of SMADs by transformation of cardiomyocytes with SMAD-decoy oligonucleotides abolished the anti-apoptotic effect of GDF15. In conclusion, GDF15 protects ventricular cardiomyocytes against different apoptotic stimuli and enhances hypertrophic growth. Hypertrophic signaling is thereby mediated via the kinases PI3K and ERK and the transcription factor R-SMAD1. Thus, GDF15 may influence cardiac remodeling via two different mechanisms, apoptosis protection and induction of hypertrophy.

GDF15 contributes to radioresistance and cancer stemness of head and neck cancer by regulating cellular reactive oxygen species via a SMAD-associated signaling pathway

“…In the present study, we found that GDF15 facilitated cancer stemness and radioresistance via activation of Smad1/5, as demonstrated in both cellular (Figure 6C-6F) and animal studies (Figure 7B-7D). Consistently, this Smad-associated pathway has been shown to be induced by GDF15 with anti-apoptotic effects in cardiomyocytes [58, 59]. Thus, GDF15 may have multiple functions in cells through distinctive signaling pathways depending on the specific tissue types.…”

Growth Differentiation Factor (GDF)-15 Blocks Norepinephrine-induced Myocardial Hypertrophy via a Novel Pathway Involving Inhibition of Epidermal Growth Factor Receptor Transactivation

“…GDF-15 was found to inhibit myocardial hypertrophy through a Smad2/3 pathway in a pressure-induced hypertrophy model (18), whereas directly treating cultured cardiomyocytes with GDF-15 results in pro-hypertrophic effect through a Smad1 pathway (19). It seems that the exact effect differs in different conditions.…”

“…These results suggested that GDF-15 could play a role in the process of myocardial hypertrophy. So far, both pro-and anti-hypertrophic effects have been characterized (18,19); however, whether GDF-15 acts as an injury factor or a protector, as well as its precise function and mechanism of action, remains unclear.…”

Inflammation and cardiac outcome

“…But how GDF-15 might interact with the different macrophage subsets during MI and HF needs clarification. GDF-15 was recently shown to have a direct action on cardiac myocytes themselves by promoting hypertrophic growth and acting anti apoptotic in cultured cardiac myocytes [52]. It remains currently unknown whether the increase in GDF-15 levels seen in HF is a protective mechanism of the body in response to injury or if such high GDF-15 levels might be detrimental and cause disease progression.…”