Characterization of atherosclerotic plaques in blood vessels with low oxygenated blood and blood pressure (Pulmonary trunk): role of growth differentiation factor-15 (GDF-15).

BACKGROUND

Growth 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.

METHODS

GDF-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.

RESULTS

After CED the body weight of GDF-15ApoE 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-15ApoE 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-15ApoE) lower LS in the PT. Immunohistomorphometry of atherosclerotic lesions in PT of GDF-15ApoE 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-15ApoE 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 GDF15ApoE mice the necrotic area was 10% and 6.5% lower than in ApoE. In BT and PT of GDF15ApoE we found 40% and 57% less unstable plaques than ApoE mice.

CONCLUSIONS

Atherosclerotic 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.