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

Abstract

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-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. 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.

Overview of growth differentiation factor 15 in metabolic syndrome

“… 68 Under normal physiological conditions, GDF15 is rarely expressed in the heart, whereas in response to cardiovascular injuries, such as pressure overload, infarction, 69 ischemia reperfusion, or heart failure, its expression is dramatically increased, being primarily derived from defective endothelial cells, hypoxic cardiomyocytes, activated macrophages and atherosclerotic plaques (Figure 2A ). 70 The property of GDF15 to capture discrete aspects in the progression and prognosis of varying CVD with differentially expressed features has led to GDF15 becoming a potent and independent biomarker for distinct CVD with high specificity, relevance and predictability, 71 even allowing prediction of cardiovascular outcomes and all‐cause mortality, 72 which are not reflected by clinical risk predictors or other biomarkers.…”

Clinical features and metabolic reprogramming of atherosclerotic lesions in patients with chronic thromboembolic pulmonary hypertension

“…However, the common risk factors of atherosclerosis in the systemic and coronary circulation, such as smoking, altered blood lipid, and pulmonary emphysema, were not found in CTEPH patients with atherosclerotic lesions in the present study. It is well known that the major pulmonary artery and its branches are rarely affected by atherosclerotic lesions due to their relatively low blood pressure and high flow ( 12 ). In contrast, during the development of PH, atherosclerotic lesions may occur in the main pulmonary artery ( 9 , 12 , 23 ).…”

“…It is well known that the major pulmonary artery and its branches are rarely affected by atherosclerotic lesions due to their relatively low blood pressure and high flow ( 12 ). In contrast, during the development of PH, atherosclerotic lesions may occur in the main pulmonary artery ( 9 , 12 , 23 ). Atherosclerotic lesions in the pulmonary vascular bed have also been noted in pulmonary arterial hypertension, revealed by autopsy, possibly as a result of shear stress-induced endothelial injury and subsequent inflammation ( 24 , 25 ).…”

“…Atherosclerotic lesions do not develop in pulmonary arteries under the normal environment of low pressure and high flow, but they may form during the development of PH ( 9 , 12 ). Atherosclerotic lesions were found in approximately 30% of CTEPH cases ( 7 , 13 ).…”

Role of the Stress- and Inflammation-Induced Cytokine GDF-15 in Cardiovascular Diseases: From Basic Research to Clinical Relevance

“…In addition to macrophages and ECs, as cellular sources of GDF-15 production, VSMCs also secrete GDF-15 in response to metabolic and/or oxidative stress or stimulation by pro-inflammatory cytokines [28]. In studies concerning atherosclerotic plaques of the pulmonary trunk of GDF-15 deficient ApoE −/− mice after 20 weeks cholesterol-enriched diet, Bonaterra et al [50] found an increase in the percentage of α-actin + SMCs with a higher percentage of CD68 + macrophages and a decreased necrotic core area compared to ApoE −/− mice.…”