RATIONALE: Possible beneficial effects of GDF11 (growth differentiation factor 11) on the normal, diseased, and aging heart have been reported, including reversing aging-induced hypertrophy. These effects have not been well validated. High levels of GDF11 have also been shown to cause cardiac and skeletal muscle wasting. These controversies could be resolved if dose-dependent effects of GDF11 were defined in normal and aged animals as well as in pressure overload-induced pathological hypertrophy. OBJECTIVE: To determine dose-dependent effects of GDF11 on normal hearts and those with pressure overload-induced cardiac hypertrophy. METHODS AND RESULTS: Twelve- to 13-week-old C57BL/6 mice underwent transverse aortic constriction (TAC) surgery. One-week post-TAC, these mice received rGDF11 (recombinant GDF11) at 1 of 3 doses: 0.5, 1.0, or 5.0 mg/kg for up to 14 days. Treatment with GDF11 increased plasma concentrations of GDF11 and p-SMAD2 in the heart. There were no significant differences in the peak pressure gradients across the aortic constriction between treatment groups at 1 week post-TAC. Two weeks of GDF11 treatment caused dose-dependent decreases in cardiac hypertrophy as measured by heart weight/tibia length ratio, myocyte cross-sectional area, and left ventricular mass. GDF11 improved cardiac pump function while preventing TAC-induced ventricular dilation and caused a dose-dependent decrease in interstitial fibrosis (in vivo), despite increasing markers of fibroblast activation and myofibroblast transdifferentiation (in vitro). Treatment with the highest dose (5.0 mg/kg) of GDF11 caused severe body weight loss, with significant decreases in both muscle and organ weights and death in both sham and TAC mice. CONCLUSIONS: Although GDF11 treatment can reduce pathological cardiac hypertrophy and associated fibrosis while improving cardiac pump function in pressure overload, high doses of GDF11 cause severe cachexia and death. Use of GDF11 as a therapy could have potentially devastating actions on the heart and other tissues.
RATIONALE: Possible beneficial effects of GDF11 (growth differentiation factor 11) on the normal, diseased, and aging heart have been reported, including reversing aging-induced hypertrophy. These effects have not been well validated. High levels of GDF11 have also been shown to cause cardiac and skeletal muscle wasting. These controversies could be resolved if dose-dependent effects of GDF11 were defined in normal and aged animals as well as in pressure overload-induced pathological hypertrophy. OBJECTIVE: To determine dose-dependent effects of GDF11 on normal hearts and those with pressure overload-induced cardiac hypertrophy. METHODS AND RESULTS: Twelve- to 13-week-old C57BL/6 mice underwent transverse aortic constriction (TAC) surgery. One-week post-TAC, these mice received rGDF11 (recombinant GDF11) at 1 of 3 doses: 0.5, 1.0, or 5.0 mg/kg for up to 14 days. Treatment with GDF11 increased plasma concentrations of GDF11 and p-SMAD2 in the heart. There were no significant differences in the peak pressure gradients across the aortic constriction between treatment groups at 1 week post-TAC. Two weeks of GDF11 treatment caused dose-dependent decreases in cardiac hypertrophy as measured by heart weight/tibia length ratio, myocyte cross-sectional area, and left ventricular mass. GDF11 improved cardiac pump function while preventing TAC-induced ventricular dilation and caused a dose-dependent decrease in interstitial fibrosis (in vivo), despite increasing markers of fibroblast activation and myofibroblast transdifferentiation (in vitro). Treatment with the highest dose (5.0 mg/kg) of GDF11 caused severe body weight loss, with significant decreases in both muscle and organ weights and death in both sham and TACmice. CONCLUSIONS: Although GDF11 treatment can reduce pathological cardiac hypertrophy and associated fibrosis while improving cardiac pump function in pressure overload, high doses of GDF11 cause severe cachexia and death. Use of GDF11 as a therapy could have potentially devastating actions on the heart and other tissues.
Authors: Norimichi Koitabashi; Thomas Danner; Ari L Zaiman; Yigal M Pinto; Janelle Rowell; Joseph Mankowski; Dou Zhang; Taishi Nakamura; Eiki Takimoto; David A Kass Journal: J Clin Invest Date: 2011-05-02 Impact factor: 14.808
Authors: Shavonn C Smith; Xiaoxiao Zhang; Xiaoying Zhang; Polina Gross; Timothy Starosta; Sadia Mohsin; Michael Franti; Priyanka Gupta; David Hayes; Maria Myzithras; Julius Kahn; James Tanner; Steven M Weldon; Ashraf Khalil; Xinji Guo; Abdelkarim Sabri; Xiongwen Chen; Scott MacDonnell; Steven R Houser Journal: Circ Res Date: 2015-09-17 Impact factor: 17.367
Authors: Nadine Biesemann; Luca Mendler; Astrid Wietelmann; Sven Hermann; Michael Schäfers; Marcus Krüger; Thomas Boettger; Thilo Borchardt; Thomas Braun Journal: Circ Res Date: 2014-05-07 Impact factor: 17.367
Authors: David W Hammers; Melissa Merscham-Banda; Jennifer Ying Hsiao; Stefan Engst; James J Hartman; H Lee Sweeney Journal: EMBO Mol Med Date: 2017-04 Impact factor: 12.137
Authors: Jill M Goldstein; Hilal Sengul; Kathleen A Messemer; Marcos Fernández-Alfara; Jessica C Garbern; Amy C Kristl; Richard T Lee; Amy J Wagers Journal: Blood Date: 2019-11-14 Impact factor: 22.113
Authors: Jawed A Siddiqui; Ramesh Pothuraju; Maneesh Jain; Surinder K Batra; Mohd W Nasser Journal: Biochim Biophys Acta Rev Cancer Date: 2020-03-25 Impact factor: 10.680
Authors: Ryan G Walker; Ornella Barrandon; Tommaso Poggioli; Sezin Dagdeviren; Shannon H Carroll; Melanie J Mills; Kourtney R Mendello; Yanet Gomez; Francesco S Loffredo; James R Pancoast; Claudio Macias-Trevino; Colin Marts; Katherine B LeClair; Hye-Lim Noh; Taekyoon Kim; Alexander S Banks; Jason K Kim; David E Cohen; Amy J Wagers; Douglas A Melton; Richard T Lee Journal: Sci Rep Date: 2020-03-12 Impact factor: 4.379
Authors: Jill M Goldstein; Austin Valido; Jordan P Lewandowski; Ryan G Walker; Melanie J Mills; Kathleen A Messemer; Paul Besseling; Kyu Ha Lee; Samuel J Wattrus; Miook Cho; Richard T Lee; Amy J Wagers Journal: Sci Rep Date: 2019-12-09 Impact factor: 4.379