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SHR Neuro Cancer Cardio Lipid Metab Microb

Harper, SC; Johnson, J; Borghetti, G; Zhao, H; Wang, T; Wallner, M; Kubo, H; Feldsott, EA; Yang, Y; Joo, Y; Gou, X; Sabri, AK; Gupta, P; Myzithras, M; Khalil, A; Franti, M; Houser, SR.
GDF11 Decreases Pressure Overload-Induced Hypertrophy, but Can Cause Severe Cachexia and Premature Death.
Circ Res. 2018; 123(11):1220-1231 Doi: 10.1161/CIRCRESAHA.118.312955 [OPEN ACCESS]
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Abstract:
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. To determine dose-dependent effects of GDF11 on normal hearts and those with pressure overload-induced cardiac hypertrophy. 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. 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.
Find related publications in this database (using NLM MeSH Indexing)
Animals -
Cachexia - etiology
Cardiomegaly - drug therapy
Growth Differentiation Factors - administration & dosage
Growth Differentiation Factors - adverse effects
Growth Differentiation Factors - pharmacology
Growth Differentiation Factors - therapeutic use
Injections, Intraperitoneal -
Male -
Mice -
Mice, Inbred C57BL -
Myocardial Contraction - drug effects
Myocytes, Cardiac - drug effects
Myocytes, Cardiac - metabolism

Find related publications in this database (Keywords)
cachexia
cardiomegaly
fibrosis
growth differentiation factors
hypertrophy
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