Abstract
BackgroundTransient early-life perturbations in glucocorticoids (GC) are linked with cardiovascular disease risk in later life. Here the impact of early life manipulations of GC on adult heart structure, function and gene expression were assessed. Methods and resultsZebrafish embryos were incubated in dexamethasone (Dex) or injected with targeted glucocorticoid receptor (GR) morpholino knockdown (GR Mo) over the first 120 h post fertilisation (hpf); surviving embryos (>90%) were maintained until adulthood under normal conditions. Cardiac function, heart histology and cardiac genes were assessed in embryonic (120 hpf) and adult (120 days post fertilisation (dpf)) hearts.GR Mo embryos (120 hpf) had smaller hearts with fewer cardiomyocytes, less mature striation pattern, reduced cardiac function and reduced levels of vmhc and igf mRNA compared with controls. GR Mo adult hearts were smaller with diminished trabecular network pattern, reduced expression of vmhc and altered echocardiographic Doppler flow compared to controls. Dex embryos had larger hearts at 120 hpf (Dex 107.2 ± 3.1 vs. controls 90.2 ± 1.1 μm, p < 0.001) with a more mature trabecular network and larger cardiomyocytes (1.62 ± 0.13 cells/μm vs control 2.18 ± 0.13 cells/μm, p < 0.05) and enhanced cardiac performance compared to controls. Adult hearts were larger (1.02 ± 0.07 μg/mg vs controls 0.63 ± 0.06 μg/mg, p = 0.0007), had increased vmhc and gr mRNA levels. ConclusionPerturbations in GR activity during embryonic development results in short and long-term alterations in the heart.
Highlights
Epidemiological studies in humans indicate that prenatal glucocorticoid (GC) excess is associated with increased risk of cardio-metabolic disease in later life (Seckl and Meaney, 2004)
Ventricles from glucocorticoid receptor (GR) Mo treated embryos showed reduced cross-sectional area compared to controls (Fig. 2B) and reduced number of ventricular cardiomyocytes per unit heart volume (Fig. 2C)
Alterations in cardiac developmental genes in whole GR Mo treated embryos has been reported previously, using microarray techniques (Nesan and Vijayan, 2013b), The findings reported here are concordant with this study we have further refined the approach by demonstrating gene changes in isolated embryonic hearts
Summary
Epidemiological studies in humans indicate that prenatal glucocorticoid (GC) excess is associated with increased risk of cardio-metabolic disease in later life (Seckl and Meaney, 2004). Rodents exposed to excess GCs during foetal life are more likely to be hypertensive, obese and display impaired glucose tolerance as adults (Nyirenda et al, 1998). While these observations suggest a link between transient changes in early life GCs and cardiovascular risk factors it remains unclear whether this risk includes changes in the structure and function of the heart itself. GR Mo embryos (120 hpf) had smaller hearts with fewer cardiomyocytes, less mature striation pattern, reduced cardiac function and reduced levels of vmhc and igf mRNA compared with controls. Adult hearts were larger (1.02 ± 0.07 mg/mg vs controls 0.63 ± 0.06 mg/mg, p 1⁄4 0.0007), had increased vmhc and gr mRNA levels
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