Growth and Differentiation Factor 11 and its role in cardiac homeostasis

Schoemaker, H. (Henk) (2016) Growth and Differentiation Factor 11 and its role in cardiac homeostasis. thesis, Medicine.

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Abstract

Heart failure accounts for about one third of all deaths worldwide. With lower birth-rates and changing demographics, it is crucial to understand the principals of heart failure with age and which physiological systems affect it. GDF11 has been identified as a possible candidate to help understand the cardiac ageing system. It is a member of the TGF-beta superfamily and is a circulating protein that decreases with age. Old animals exposed to youthful levels of this circulating protein showed regression in age-related cardiac hypertrophy. As GDF11 -/- knockout embryos are not feasible with life, we utilised the tamoxifen-inducible Cre lox system to generate knockdown models of GDF11 that could be initiated later in life. Mice with the suitable “Cre/+; GDF11 flox/flox” genotype were injected with hydroxytamoxifen, inducing partial recombination and knockdown of GDF11. We evaluated two different knockdown models: a total inducible knockdown and a cardiac specific knockdown of GDF11. Through our (5-7 month old) total inducible knockdown model, we showed that the spleen had the highest relative expression of GDF11 when compared to other organs, suggesting that it might play a role in the regulation of GDF11. Through qPCR analysis, we showed that the total knockdown animals had 40% less expression of GDF11 in the spleen after 10 days of hydroxytamoxifen injections. These same animals showed a trend with increased heart weight to tibia length ratios (p=0.11) after the knockdown of the protein. In our aged (18-22 month old) total inducible knockdown model, no significant reduction of GDF11 expression could be noted in any organ after hydroxytamoxifen injections. As opposed to the younger cohort, statistical testing could not be conducted between treatment groups as a high mortality rate affected the sample sizes. Calculations using echocardiographic parameters, did however, show a significant increase in left ventricular mass to tibia length ratios in GDF11 knockdown animals. This significant increase was found when comparing post-treatment to baseline values. In the cardiac specific knockdown model, no significant reduction could be noted in the relative expression of GDF11 in the harvested organs. This was probably the result of the low sample numbers in certain groups, but may also suggest that the heart is a less prominent regulator of total circulating GDF11 levels in vivo. All in all, these have been important steps towards fully understanding GDF11’s function in vivo, as well as how it affects cardiac ageing. Even though the results were not always as comprehensible - the supporting trends were - and future experiments with larger sample numbers could indeed shed more light on GDF11’s full potential.

Item Type:	Thesis (Thesis)
Supervisor name:	Supervisors Groningen, the Netherlands and Harmsen, Prof. Martin C. PhD and Department of Cell Biology and University Medical Center Groningen and Welling, Gjalt W. MD PhD and GIPS-M
Supervisor name:	Supervisors Boston, USA: and Garbern, Jessica C. MD PhD and Fellow in Pediatric Cardiology, Children’s Hospital Boston and Harvard Medical School and Lee, MD Brigham and Women's Hospital and HarvProf. Richard T. and Harvard University Department of Stem Cell & Regenerative Bi and Harvard Medical School
Faculty:	Medical Sciences
Date Deposited:	25 Jun 2020 10:47
Last Modified:	25 Jun 2020 10:47
URI:	https://umcg.studenttheses.ub.rug.nl/id/eprint/875

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