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SHR Neuro Krebs Kardio Lipid Stoffw 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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Co-Autor*innen der Med Uni Graz

Wallner Markus

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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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