Abstract 38: Radiation Exposure And Coronary Atherosclerosis: Differential Effect Of The Radiation Site

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Prerna R Nepali ◽  
Mickael Mathieu ◽  
Sarah Kitz ◽  
Chiharuko Nakauchi ◽  
James Russell ◽  
...  
Keyword(s):  
Radiation Exposure ◽  
Cancer Patients ◽  
Inflammatory Responses ◽  
Differential Sensitivity ◽  
Basal Region ◽  
Atherosclerotic Lesions ◽  
Coronary Artery Atherosclerosis ◽  
Apolipoprotein E Knockout Mice ◽  
Thoracic Radiation ◽  
Whole Heart

Background: Thoracic radiation is commonly used in breast cancer, Hodgkin’s lymphoma, head and neck and lung cancer patients. Accelerated coronary artery atherosclerosis is a common complication of thoracic radiation as a result of unintended cardiac radiation. It is unclear however whether specific areas of the heart are more susceptible to the effects of radiation (RT). In this study we hypothesize that accelerated development of lesions post RT is dependent upon differential sensitivity of specific areas of the heart to the effects of RT. Methods: Male Apolipoprotein E knockout mice on a high fat diet received 16Gy cardiac RT targeted to the whole or partial (apical or basal) region of the heart at 9 or 16 weeks of age (n=5 per group). Atherosclerotic lesions in H&E stained slides and inflammatory infiltrates in the hearts by IHC were assessed 8 weeks following RT and compared to control unirradiated mice. Results: Our studies show that: (1) Subendocardial atherosclerotic lesions at the base of heart in mice irradiated at 9 weeks of age after basal irradiation (7.8±2.49) were comparable to whole heart irradiation (12.2±3.29). (2) A greater number of atherosclerotic lesions were present in the basal coronary arteries (29.33±5.48 vs 9±2.70) and basal subendocardial vasculature (6.66±2.07 vs 0.2±0.2) after irradiation of the cardiac base as compared to unirradiated controls in mice irradiated at 16 weeks of age. (3) Apical or whole heart irradiation had no impact on the development of lesions in the basal region of the hearts of older mice. (4) IL-6 was significantly increased in the serum of mice 6 hours post basal cardiac irradiation (105.10±17.56 pg/ml) when compared to unirradiated controls (29.85±11.63 pg/ml), demonstrating an acute inflammatory response. (5) Infiltration of inflammatory cells (CD45 and CD3) and enhanced expression of endothelial adhesion molecules (CD31) were differentially and locally regulated based upon the site of irradiation. Conclusion: Our results indicate that the base of the heart is more prone to development of RT induced atherosclerotic lesions likely due to acute and delayed inflammatory responses. Avoiding this area from direct radiation exposure may improve the quality of life for cancer patients receiving thoracic RT.

Abstract 15364: Radiation Exposure of the Base of the Heart Accelerates Coronary Atherosclerosis

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Prerna Ramesh Nepali ◽  
Karen Gabriels ◽  
Mickael Mathieu ◽  
James Russell ◽  
Johannes A te Poele ◽  
...  
Keyword(s):  
Radiation Exposure ◽  
Cancer Patients ◽  
Foam Cell ◽  
Heart Function ◽  
Clinical Problem ◽  
Atherosclerotic Plaques ◽  
Cardiovascular Risks ◽  
Macrophage Foam Cell ◽  
Curative Intent ◽  
Whole Heart

Introduction: Radiation therapy (RT) is used in the treatment of approximately 50% of cancer patients. Thoracic RT is commonly used in breast cancer, Hodgkin’s lymphoma, head and neck and lung cancers among others. Unfortunately, the benefits of RT are often out-weighed by the by-stander cardiovascular risks and associated non-relapse mortality in cancer survivors. Hence, the development of cardiovascular disease (CVD) in patients receiving RT remains an important clinical problem. The base of the heart has been shown to be dose-sensitive wherein basal irradiation is associated with lower patient survival in lung-cancer patients treated with curative-intent RT. Although the mechanisms for RT-induced CVD are poorly understood, direct injury to the coronary arteries endothelium has been implicated. Hypothesis and Results: We hypothesized that irradiation harms heart tissue differentially depending upon the specific region that receives radiation. In order to test this hypothesis, we irradiated different regions of the heart and measured the development of atherosclerotic plaques as compared to control unirradiated mice. Apolipoprotein E knockout (ApoE -/- ) mice were irradiated with 16Gy to the base, apex or to the whole heart. Our results demonstrate that the base of the heart has significantly greater sensitivity to irradiation as compared to the apex, and develops atherosclerotic lesions that are equivalent to those produced by whole heart irradiation at 20 weeks post-RT. In addition, a greater number of plaques are present in the base of the heart after whole heart and basal irradiation compared to unirradiated controls at 40 weeks post-RT. Atherosclerotic plaques with subendothelial macrophage foam cell accumulation and fibrin deposits were also observed at 20 and 40 weeks post basal or whole heart RT. Ongoing studies are testing the effect of high-fat diet on the development of differential RT-induced atherosclerotic plaques in ApoE -/- mice and their correlation with heart function. Conclusion: Our studies strengthen the argument for advanced RT techniques to shield the base of the heart from radiation exposure to minimize RT-induced CVD and improve the quality of life and survival of cancer patients receiving RT.

scholarly journals Radiation Exposure of the Base of the Heart Accelerates Coronary Atherosclerosis

2021 ◽  
Author(s):  
Prerna R. Nepali ◽  
Mickael Mathieu ◽  
Sarah Kitz ◽  
Chiharuko Nakauchi ◽  
Karen Gabriels ◽  
...  
Keyword(s):  
Coronary Arteries ◽  
Inflammatory Cells ◽  
Basal Region ◽  
Atherosclerotic Lesions ◽  
Direct Exposure ◽  
Enhanced Expression ◽  
Endothelial Adhesion Molecules ◽  
Whole Heart ◽  
Thoracic Malignancies ◽  
Eicosanoid Mediators

Clinical studies have identified cardiac exposure as an independent predictor for cardiovascular mortality in patients treated with radiation therapy (RT) for thoracic malignancies. Although the mechanisms are not completely understood, the available evidence indicate that direct injury to the coronary arteries endothelium is implicated. In these studies we tested the hypothesis that different areas of the heart are more sensitive to the effects of RT on the formation of atherosclerotic plaque in apolipoprotein E deficient (ApoE-/-) mice, a well validated model of atherosclerosis. Methods: ApoE-/- mice on a high fat diet (HFD) received 16Gy cardiac irradiation targeted to the whole or partial (apical or basal) region of the heart at 9 weeks or 16 weeks of age. Atherosclerotic lesions and inflammatory changes in the hearts as compared to control unirradiated mice were assessed eight weeks following radiation. Results: After either basal or whole heart RT at 9 weeks of age the number of subendocardial atherosclerotic lesions at the heart base was higher as compared to unirradiated mice. Irradiation of the apex did not increase the number of subendocardial atherosclerotic lesions in any region. After basal RT at 16 weeks of age the number of coronary and subendocardial atherosclerotic lesions was higher as compared to controls. Neither apical or whole heart RT had an impact on the development or acceleration of lesions in the basal region of the hearts of 16 week old mice, thus demonstrating the adverse impact of basal irradiation. Infiltration of inflammatory cells (CD45+ and CD3+) and enhanced expression of endothelial adhesion molecules (CD31), were differentially and locally regulated based upon the site of irradiation. In support of a role of eicosanoid mediators for base or whole heart atherogenic irradiation effects, apex irradiation eicosanoid mediators are not clearly atherogenic, in contrast to eicosanoid mediators detected in serum after base heart irradiation. These results indicate that the base of the heart is significantly more prone to the development of atherosclerotic lesions in the coronary arteries post-RT. Conclusion: Our results indicate that the base of the heart is more susuceptible to development of RT-induced atherosclerotic lesions and therefore avoidance from RT direct exposure to this area may reduce the risk for atherosclerotic disease in patients undergoing RT.

Atherosclerotic plaque disruption induced by stress and lipopolysaccharide in apolipoprotein E knockout mice

2009 ◽  
Vol 296 (5) ◽  
pp. H1598-H1606 ◽  
Author(s):  
Mei Ni ◽  
Yan Wang ◽  
Mei Zhang ◽  
Peng Fei Zhang ◽  
Shi Fang Ding ◽  
...  
Keyword(s):  
Apolipoprotein E ◽  
High Fat Diet ◽  
Morphological Analysis ◽  
Fibrous Cap ◽  
Atherosclerotic Lesions ◽  
Plaque Disruption ◽  
Apolipoprotein E Knockout Mice ◽  
Fibrous Cap Thickness ◽  
And Control ◽  
Disruption Rate

To establish an animal model with disruptions of atherosclerotic plaques, 96 male apolipoprotein E knockout (apoE−/−) mice were randomly divided into stress, lipopolysaccharide (LPS), stress+LPS, and control groups ( n = 24 each). All mice were fed a high-fat diet throughout the experiment, and carotid atherosclerotic lesions were induced by placement of a constrictive perivascular collar. Four weeks after surgery, mice in the LPS and stress+LPS groups were intraperitoneally injected with LPS (1 mg/kg twice per week for 8 wk). Eight weeks after surgery, mice in the stress and stress+LPS groups were treated with intermittent physical stress (electric foot shock and noise stimulation) for 4 wk. Morphological analysis revealed a plaque disruption rate of 16.7% in control, 34.8% in LPS, 54.2% in stress, and 60.9% in stress+LPS groups. The disruption rates in stress and stress+LPS groups were both significantly higher than those of controls ( P = 0.007 and P = 0.002, respectively). Luminal thrombosis secondary to plaque disruption was observed only in the stress+LPS group. Both stress and LPS stimulation significantly decreased fibrous cap thickness and increased macrophage and lipid contents in plaques. Moreover, the combination of stress and LPS stimulation further lowered cap thickness and enhanced accumulation of macrophages and expression of inflammatory cytokines and matrix metalloproteinases. Stress activated the sympathetic nervous system, as manifested by increased blood pressure and flow velocity. Plasma fibrinogen levels were remarkably elevated in the stress and stress+LPS groups. In conclusion, stress- and LPS-costimulated apoE−/− mice provide a useful model for studies of plaque vulnerability and interventions.

Abstract 116: Slit-Robo Signaling Regulates Lipopolysaccharide-induced Endothelial Inflammation and Expression of Slit/Robo is Dysregulated During Endotoxemia

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Helong Zhao ◽  
Appakkudal Anand ◽  
Ramesh Ganju
Keyword(s):  
Endothelial Cells ◽  
Cell Adhesion ◽  
Inflammatory Responses ◽  
Umbilical Vein ◽  
Model Studies ◽  
Endothelial Inflammation ◽  
Anti Inflammatory ◽  
Whole Heart

Abstract Introduction: Lipopolysaccharide (LPS) is one of the critical factors which induce endothelial inflammation during the pathogenesis of atherosclerosis, endocarditis and sepsis shock induced heart injury. The secretory Slit2 protein and its endothelial receptors Robo1 and Robo4 have been shown to regulate mobility and permeability of endothelial cells, which could be functional in regulating LPS induced endothelial inflammation. Hypothesis: We hypothesized that in addition to regulating permeability and migration of endothelial cells, Slit2-Robo1/4 signaling might regulate other LPS-induced endothelial inflammatory responses. Methods and Results: Using Human Umbilical Vein Endothelial Cells (HUVEC) culture, we observed that Slit2 treatment suppressed LPS-induced secretion of pro-inflammatory cytokines (including GM-CSF), cell adhesion molecule upregulation and monocyte (THP-1 cell) adhesion. With siRNA knock down techniques, we further confirmed that this anti-inflammatory effect is mediated by the interaction of Slit2 with its dominant receptor in endothelial cells, Robo4, though the much lesser expressed minor receptor Robo1 is pro-inflammatory. Our signaling studies showed that downstream of Robo4, Slit2 suppressed inflammatory gene expression by inhibiting the Pyk2 - NF-kB pathway following LPS-TLR4 interaction. In addition, Slit2 can induce a positive feedback to its expression and downregulate the pro-inflammatory Robo1 receptor via mediation of miR-218. Moreover, both in in vitro studies using HUVEC and in vivo mouse model studies indicated that LPS also causes endothelial inflammation by downregulating the anti-inflammatory Slit2 and Robo4 and upregulating the pro-inflammatory Robo1 during endotoxemia, especially in mouse arterial endothelial cells and whole heart. Conclusions: Slit2-Robo1/4 signaling is important in regulation of LPS induced endothelial inflammation, and LPS in turn causes inflammation by interfering with the expression of Slit2, Robo1 and Robo4. This implies that Slit2-Robo1/4 is a key regulator of endothelial inflammation and its dysregulation during endotoxemia is a novel mechanism for LPS induced cardiovascular pathogenesis.

Inhibitory effects of vasostatin-1 against atherogenesis

2018 ◽  
Vol 132 (23) ◽  
pp. 2493-2507 ◽  
Author(s):  
Yuki Sato ◽  
Rena Watanabe ◽  
Nozomi Uchiyama ◽  
Nana Ozawa ◽  
Yui Takahashi ◽  
...  
Keyword(s):  
Adhesion Molecule ◽  
Inflammatory Responses ◽  
Foam Cell ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cell Formation ◽  
Inhibitory Effects ◽  
Macrophage Foam Cell ◽  
Down Regulation ◽  
Atherosclerotic Lesions

Vasostatin-1, a chromogranin A (CgA)-derived peptide (76 amino acids), is known to suppress vasoconstriction and angiogenesis. A recent study has shown that vasostatin-1 suppresses the adhesion of human U937 monocytes to human endothelial cells (HECs) via adhesion molecule down-regulation. The present study evaluated the expression of vasostatin-1 in human atherosclerotic lesions and its effects on inflammatory responses in HECs and human THP-1 monocyte-derived macrophages, macrophage foam cell formation, migration and proliferation of human aortic smooth muscle cells (HASMCs) and extracellular matrix (ECM) production by HASMCs, and atherogenesis in apolipoprotein E-deficient (ApoE−/−) mice. Vasostatin-1 was expressed around Monckeberg’s medial calcific sclerosis in human radial arteries. Vasostatin-1 suppressed lipopolysaccharide (LPS)-induced up-regulation of monocyte chemotactic protein-1 (MCP-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin in HECs. Vasostatin-1 suppressed inflammatory M1 phenotype and LPS-induced interleukin-6 (IL-6) secretion via nuclear factor-κB (NF-κB) down-regulation in macrophages. Vasostatin-1 suppressed oxidized low-density lipoprotein (oxLDL)-induced foam cell formation associated with acyl-CoA:cholesterol acyltransferase-1 (ACAT-1) and CD36 down-regulation and ATP-binding cassette transporter A1 (ABCA1) up-regulation in macrophages. In HASMCs, vasostatin-1 suppressed angiotensin II (AngII)-induced migration and collagen-3 and fibronectin expression via decreasing ERK1/2 and p38 phosphorylation, but increased elastin expression and matrix metalloproteinase (MMP)-2 and MMP-9 activities via increasing Akt and JNK phosphorylation. Vasostatin-1 did not affect the proliferation and apoptosis in HASMCs. Four-week infusion of vasostatin-1 suppressed the development of aortic atherosclerotic lesions with reductions in intra-plaque inflammation, macrophage infiltration, and SMC content, and plasma glucose level in ApoE−/− mice. These results indicate the inhibitory effects of vasostatin-1 against atherogenesis. The present study provided the first evidence that vasostatin-1 may serve as a novel therapeutic target for atherosclerosis.

scholarly journals Detection of Atherosclerotic Lesions in Apolipoprotein E Knockout Mice Using USPIO-Enhanced Magnetic Resonance Imaging

2011 ◽  
Vol 78 (3) ◽  
pp. 136-137 ◽  
Author(s):  
Mika Murabayashi ◽  
Taku Sugita ◽  
Keiko Hirakawa ◽  
Hideto Kuribayashi ◽  
Ikuo Mori ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Magnetic Resonance ◽  
Apolipoprotein E ◽  
Knockout Mice ◽  
Resonance Imaging ◽  
Atherosclerotic Lesions ◽  
Apolipoprotein E Knockout Mice

Abstract 028: Endothelial Nogo-B Controls Sphingolipid de novo Biosynthesis to Impact Coronary Artery Atherosclerosis

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Yi Zhang ◽  
Linda Sasset ◽  
Ren Xu ◽  
Matthew Blake Greenblatt ◽  
Annarita Di Lorenzo
Keyword(s):  
Myocardial Infarction ◽  
Coronary Artery ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Vascular Inflammation ◽  
High Cholesterol Diet ◽  
Serine Palmitoyltransferase ◽  
Atherosclerotic Lesions ◽  
Coronary Artery Atherosclerosis ◽  
Artery Disease

Coronary artery disease is a leading cause of myocardial infarction (MI) worldwide. Alterations in sphingolipid levels have been linked to atherosclerosis although specific molecular mechanisms are poorly understood. Recently, we discovered that endothelial Nogo-B, a membrane protein of the ER, regulates vascular functions by inhibiting serine palmitoyltransferase (SPT), the rate-limiting enzyme of the de novo sphingolipid biosynthesis. Mice lacking Nogo-B are resistant to hypertension and heart failure. Here, we employed a novel model of coronary atherosclerotic lesions induced by hypercholesterolemia and hypertension, well-known risk factors for atherosclerosis. To this aim, transverse aortic constriction (TAC) surgery was performed in mice lacking endothelial Nogo-B in ApoE -/- background and ApoE -/- mice as control. ApoE -/- mice developed coronary atherosclerotic lesions within 6 weeks following TAC, (without the need of long-term high-cholesterol diet) and 70% of the mice died of MI at 6-week post-TAC. On the contrary, mice lacking Nogo-B specifically in endothelial cells were markedly resistant to the development of coronary atherosclerotic lesions and MI (20%). Mechanistically, in the absence of endothelial Nogo-B, the biosynthesis of sphingolipids, particularly S1P, is upregulated, protecting the endothelium from hypertension and hypercholesterolemia-triggered vascular inflammation and atherogenesis. This study identifies an important and novel role of endothelial Nogo-B-dependent regulation of sphingolipid de novo biosynthesis in the coronary atherosclerosis, a primary cause of myocardial infarction.

Foodborne Gram-Negative Bacteria and Atherosclerosis: Is There a Connection?

1987 ◽  
Vol 50 (9) ◽  
pp. 783-787 ◽  
Author(s):  
DOUGLAS L. ARCHER
Keyword(s):  
Recombinant Dna ◽  
Inflammatory Responses ◽  
Body Burden ◽  
Inflammatory Factors ◽  
Gram Negative ◽  
Atherosclerotic Lesions ◽  
Degrading Bacteria ◽  
Initial Injury ◽  
Recombinant Dna Techniques ◽  
Total Body

There is some evidence that endotoxin-containing bacteria may contribute to atherogenesis. The degree to which bacterial insults contribute to the total body burden of atherosclerotic lesions cannot be determined at this time. It is important to realize that there are other potential sources of injury to the vascular endothelium, mechanical, chemical, immunologic and biological, which may initiate formation of an atherosclerotic plaque. It must also be remembered that the process of atherogenesis is extremely complex and involves many factors other than the initial injury to endothelium. The suggested role for endotoxin, particularly endotoxin from degrading bacteria in macrophages, in concert with the inflammatory factors induced by endotoxin from endothelium and vascular smooth muscle cells, is an attractive hypothesis for several reasons. First, dampening of inflammatory responses by effects of N-3 polyunsaturated fatty acids (omega-3s) is explained, particularly their direct influence on monocyte functions. Second, the hypothesis provides a model system in which the first step in atherogenesis may be studied prospectively, while other factors may be varied to determine their influences on later stages in the process of plaque formation. Recombinant DNA techniques and sophisticated immunologic tools are available to study the entire process, as are animal models in which to conduct studies with relevance to the human. Although at present, the link between foodborne gram-negative bacterial pathogens and atherosclerosis is largely unproven, the possible role of such organisms warrants more research. Additionally, should the link be firmly established, it would further underscore the importance of food safety in the biological sense.

scholarly journals IL-18 binding protein (IL-18BP) as a novel radiation countermeasure after radiation exposure in mice

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Xianghong Li ◽  
Wanchang Cui ◽  
Lisa Hull ◽  
Li Wang ◽  
Tianzheng Yu ◽  
...  
Keyword(s):  
Radiation Exposure ◽  
Tissue Damage ◽  
Inflammatory Responses ◽  
Binding Protein ◽  
Treated Group ◽  
Therapeutic Window ◽  
Mouse Serum ◽  
Mouse Heart ◽  
Cell Counts ◽  
Radiation Induced

Abstract Recent studies suggested that radiation exposure causes local and systemic inflammatory responses and induces cell and tissue damage. We have reported that IL-18 plays an important role in radiation-induced injury. Here, we demonstrate that IL-18 binding protein (IL-18BP), a natural antagonist of IL-18, was significantly increased (1.7–63 fold) in mouse serum on day 1 after 0.5–10 Gy TBI. However, this high level of IL-18BP was not sufficient to neutralize the active IL-18 in irradiated mice, resulting in a radiation dose-dependent free IL-18 increase in these mice’s serum which led to pathological alterations to the irradiated cells and tissues and finally caused animal death. Administration of recombinant human (rh) IL-18BP (1.5 mg/kg) with single (24, 48 or 72 h post-TBI) or double doses (48 h and 5 days post-TBI) subcutaneous (SC) injection increased 30-day survival of CD2F1 mice after 9 Gy TBI 12.5–25% compared with the vehicle control treated group, respectively. Furthermore, the mitigative effects of rhIL-18BP included balancing the ratio of IL-18/IL-18BP and decreasing the free IL-18 levels in irradiated mouse serum and significantly increasing blood cell counts, BM hematopoietic cellularity and stem and progenitor cell clonogenicity in mouse BM. Furthermore, IL-18BP treatment inhibited the IL-18 downstream target interferon (IFN)-γ expression in mouse BM, decreased reactive oxygen species (ROS) level in the irradiated mouse heart tissues, attenuated the stress responsive factor GDF-15 (growth differentiation factor-15) and increased the intestine protector citrulline level in total body irradiated mouse serum, implicating that IL-18BP may protect multiple organs from radiation-induced inflammation and oxidative stress. Our data suggest that IL-18 plays a key role in radiation-induced cell and tissue damage and dysfunction; and for the first time demonstrated that IL-18BP counters IL-18 activation and therefore may mitigate/treat radiation-induced multiple organ injuries and increase animal survival with a wider therapeutic window from 24 h and beyond after lethal doses of radiation exposure.

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