Abstract
BackgroundGrowth differentiation factor (GDF)-15 is linked to inflammation, cancer, and atherosclerosis. GDF-15 is expressed in most tissues but is extremely induced under pathological conditions. Elevated serum levels are suggested as a risk factor and a marker for cardiovascular diseases. However, the cellular sources and the effects of GDF-15 on the cardiovascular system have not been completely elucidated including progression, and morphology of atherosclerotic plaques. Thus, this work aimed to characterize the influence of GDF-15 deficiency on the morphology of atherosclerotic plaques in blood vessels with low-oxygen blood and low blood pressure as the pulmonary trunk (PT), in hypercholesterolemic ApoE−/− mice.MethodsGDF-15−/− ApoE−/− mice were generated by crossbreeding of ApoE−/−- and GDF-15−/− mice. After feeding a cholesterol-enriched diet (CED) for 20 weeks, samples of the brachiocephalic trunk (BT) and PT were dissected and lumen stenosis (LS) was measured. Furthermore, changes in the cellularity of the PT, amounts of apoptosis-, autophagy-, inflammation- and proliferation-relevant proteins were immunohisto-morphometrically analyzed. Additionally, we examined an atherosclerotic plaque in a human post mortem sample of the pulmonary artery.ResultsAfter CED the body weight of GDF-15−/−ApoE−/− was 22.9% higher than ApoE−/−. Double knockout mice showed also an 35.3% increase of plasma triglyceride levels, whereas plasma cholesterol was similar in both genotypes. LS in the BT and PT of GDF-15−/−ApoE−/− mice was significantly reduced by 19.0% and by 6.7% compared to ApoE−/−. Comparing LS in PT and BT of the same genotype revealed a significant 38.8% (ApoE−/−) or 26.4% (GDF-15−/−ApoE−/−) lower LS in the PT. Immunohistomorphometry of atherosclerotic lesions in PT of GDF-15−/−ApoE−/− revealed significantly increased levels (39.8% and 7.3%) of CD68 + macrophages (MΦ) and α-actin + smooth muscle cells than in ApoE−/−. The density of TUNEL + , apoptotic cells was significantly (32.9%) higher in plaques of PT of GDF-15−/−ApoE−/− than in ApoE−/−. Analysis of atherosclerotic lesion of a human pulmonary artery showed sm-α-actin, CD68+, TUNEL+, Ki67+, and APG5L/ATG+ cells as observed in PT. COX-2+ and IL-6+ immunoreactivities were predominantly located in endothelial cells and subendothelial space. In BT and PT of GDF15−/−ApoE−/− mice the necrotic area was 10% and 6.5% lower than in ApoE−/−. In BT and PT of GDF15−/−ApoE−/− we found 40% and 57% less unstable plaques than ApoE−/− mice.ConclusionsAtherosclerotic lesions occur in both, BT and PT, however, the size is smaller in PT, possibly due to the effect of the low-oxygen blood and/or lower blood pressure. GDF-15 is involved in atherosclerotic processes in BT and PT, although different mechanisms (e.g. apoptosis) in these two vessels seem to exist.
Highlights
Growth differentiation factor (GDF)-15 is linked to inflammation, cancer, and atherosclerosis
growth differentiation factor-15 (GDF-15) is involved in atherosclerotic processes in brachiocephalic trunk (BT) and pulmonary trunk (PT), different mechanisms in these two vessels seem to exist
Whether the gain of weight in the absence of GDF-15 relates to lipid metabolism, total plasma cholesterol, and triglyceride levels were determined: After 20 weeks cholesterol-enriched diet (CED), plasma triglyceride significantly (p < 0.05) increased by 35.3% in GDF-15−/−Apolipoprotein E (ApoE)−/− mice compared with ApoE−/− mice, whereas plasma cholesterol levels were similar in both genotypes (Fig. 1C and D)
Summary
Growth differentiation factor (GDF)-15 is linked to inflammation, cancer, and atherosclerosis. There are limited data on the use of biomarkers in predicting morbidity in populations of patients e.g. with atherosclerosis or acute PE In this context, growth differentiation factor-15 (GDF-15) is linked to e.g. cardiovascular diseases and is related to mortality in older adults [8, 9]. Hypoxia contributes to the formation of many pathologies of the blood vessel wall, like atherosclerosis, aortic aneurysms, pulmonary artery stenosis, and chronic venous disease [25, 28, 29]. In this context, elevated GDF-15 levels have been recently found during early chronic obstructive pulmonary disease (COPD) [29,30,31,32]. A recent study has demonstrated elevated serum levels of GDF-15 in patients with idiopathic pulmonary arterial hypertension (IPAH) [41]
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