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1.
Radiother Oncol ; 110(3): 455-60, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24630533

ABSTRACT

BACKGROUND AND PURPOSE: Recent studies have shown an increased incidence of localized atherosclerosis and subsequent cardiovascular events in cancer patients treated with thoracic radiotherapy. We previously demonstrated that irradiation accelerated the development of atherosclerosis and predisposed to an inflammatory plaque phenotype in young hypercholesterolemic ApoE(-/-) mice. However, as older cancer patients already have early or advanced stages of atherosclerosis at the time of radiotherapy, we investigated the effects of irradiation on the progression of existing atherosclerotic lesions in vivo. MATERIAL AND METHODS: ApoE(-/-) mice (28 weeks old) received local irradiation with 14 or 0 Gy (sham-treated) at the aortic arch and were examined after 4 and 12 weeks for atherosclerotic lesions, plaque size and phenotype. Moreover, we investigated the impact of irradiation on macrophage phenotype (pro- or anti-inflammatory) and function (efferocytotic capacity, i.e. clearance of apoptotic cells) in vitro. RESULTS: Irradiation of existing lesions in the aortic arch resulted in smaller, macrophage-rich plaques with intraplaque hemorrhage and increased apoptosis. In keeping with the latter, in vitro studies revealed augmented polarization toward pro-inflammatory macrophages after irradiation and reduced efferocytosis by anti-inflammatory macrophages. In addition, considerably more lesions in irradiated mice were enriched in pro-inflammatory macrophages. CONCLUSIONS: Irradiation of existing atherosclerotic lesions led to smaller but more inflamed plaques, with increased numbers of apoptotic cells, most likely due to a shift toward pro-inflammatory macrophages in the plaque.


Subject(s)
Atherosclerosis/pathology , Inflammation/etiology , Macrophages/radiation effects , Animals , Aorta, Thoracic/pathology , Aorta, Thoracic/radiation effects , Apolipoproteins E/genetics , Apoptosis , Disease Progression , Macrophages/physiology , Mice , Mice, Inbred C57BL , Mice, Knockout
2.
Radiother Oncol ; 105(3): 358-64, 2012 Dec.
Article in English | MEDLINE | ID: mdl-22959484

ABSTRACT

BACKGROUND AND PURPOSE: Radiotherapy of thoracic and chest-wall tumors increases the long-term risk of radiation-induced heart disease, like a myocardial infarct. Cancer patients commonly have additional risk factors for cardiovascular disease, such as hypercholesterolemia. The goal of this study is to define the interaction of irradiation with such cardiovascular risk factors in radiation-induced damage to the heart and coronary arteries. MATERIAL AND METHODS: Hypercholesterolemic and atherosclerosis-prone ApoE(-/-) mice received local heart irradiation with a single dose of 0, 2, 8 or 16 Gy. Histopathological changes, microvascular damage and functional alterations were assessed after 20 and 40 weeks. RESULTS: Inflammatory cells were significantly increased in the left ventricular myocardium at 20 and 40 weeks after 8 and 16 Gy. Microvascular density decreased at both follow-up time-points after 8 and 16 Gy. Remaining vessels had decreased alkaline phosphatase activity (2-16 Gy) and increased von Willebrand Factor expression (16 Gy), indicative of endothelial cell damage. The endocardium was extensively damaged after 16 Gy, with foam cell accumulations at 20 weeks, and fibrosis and protein leakage at 40 weeks. Despite an accelerated coronary atherosclerotic lesion development at 20 weeks after 16 Gy, gated SPECT and ultrasound measurements showed only minor changes in functional cardiac parameters at 20 weeks. CONCLUSIONS: The combination of hypercholesterolemia and local cardiac irradiation induced an inflammatory response, microvascular and endocardial damage, and accelerated the development of coronary atherosclerosis. Despite these pronounced effects, cardiac function of ApoE(-/-) mice was maintained.


Subject(s)
Apolipoproteins E/deficiency , Coronary Artery Disease/etiology , Endocardium/radiation effects , Heart/radiation effects , Animals , Apolipoproteins E/genetics , Coronary Artery Disease/metabolism , Coronary Artery Disease/pathology , Dose-Response Relationship, Radiation , Endocardium/metabolism , Endocardium/pathology , Mice , Mice, Knockout , Radiation Dosage , Radiation Injuries, Experimental , Time Factors
3.
Radiother Oncol ; 103(2): 143-50, 2012 May.
Article in English | MEDLINE | ID: mdl-22112779

ABSTRACT

BACKGROUND: Radiotherapy of thoracic and chest wall tumors increases the long-term risk of cardiotoxicity, but the underlying mechanisms are unclear. METHODS: Single doses of 2, 8, or 16 Gy were delivered to the hearts of mice and damage was evaluated at 20, 40, and 60 weeks, relative to age matched controls. Single photon emission computed tomography (SPECT/CT) and ultrasound were used to measure cardiac geometry and function, which was related to histo-morphology and microvascular damage. RESULTS: Gated SPECT/CT and ultrasound demonstrated decreases in end diastolic and systolic volumes, while the ejection fraction was increased at 20 and 40 weeks after 2, 8, and 16 Gy. Cardiac blood volume was decreased at 20 and 60 weeks after irradiation. Histological examination revealed inflammatory changes at 20 and 40 weeks after 8 and 16 Gy. Microvascular density in the left ventricle was decreased at 40 and 60 weeks after 8 and 16 Gy, with functional damage to remaining microvasculature manifest as decreased alkaline phosphatase (2, 8, and 16 Gy), increased von Willebrand Factor and albumin leakage from vessels (8 and 16 Gy), and amyloidosis (16 Gy). 16 Gy lead to sudden death between 30 and 40 weeks in 38% of mice. CONCLUSIONS: Irradiation with 2 and 8 Gy induced modest changes in murine cardiac function within 20 weeks but this did not deteriorate further, despite progressive structural and microvascular damage. This indicates that heart function can compensate for significant structural damage, although higher doses, eventually lead to sudden death.


Subject(s)
Heart/radiation effects , Microvessels/radiation effects , Animals , Dose-Response Relationship, Radiation , Heart/physiology , Male , Mice , Mice, Inbred C57BL , Multimodal Imaging , Myocardium/pathology , Organ Size/radiation effects , Positron-Emission Tomography , Radiotherapy/adverse effects , Tomography, X-Ray Computed
4.
Radiother Oncol ; 101(1): 100-8, 2011 Oct.
Article in English | MEDLINE | ID: mdl-22001104

ABSTRACT

BACKGROUND AND PURPOSE: We previously showed that irradiating the carotid arteries of ApoE(-/-) mice accelerated the development of macrophage-rich, inflammatory and thrombotic atherosclerotic lesions. In this study we investigated the potential of anti-inflammatory (atorvastatin, CD40L knockout) and anti-thrombotic (clopidogrel) intervention strategies to inhibit radiation-induced atherosclerosis. MATERIAL AND METHODS: ApoE(-/-) mice were given 0 or 14 Gy to the neck and the carotid arteries were harvested at 4 or 28 weeks after irradiation. Atorvastatin (15 mg/kg/day) or clopidogrel (20 mg/kg/day) was given in the chow; control groups received regular chow. Clopidogrel inhibited platelet aggregation by 50%. CD40L(-/-)/ApoE(-/-) and ApoE(-/-) littermates were also given 0 or 14 Gy to the neck and the carotid arteries were harvested after 30 weeks. RESULTS: Clopidogrel decreased MCP-1 expression in the carotid artery at 4 weeks after irradiation. Expression of VCAM-1, ICAM-1, thrombomodulin, tissue factor and eNOS was unchanged in atorvastatin and clopidogrel-treated mice. Neither drug inhibited either age-related or radiation-induced atherosclerosis. Furthermore, loss of the inflammatory mediator CD40L did not influence the development of age-related and radiation-induced atherosclerosis. CONCLUSIONS: The effects of radiation-induced atherosclerosis could not be circumvented by these specific anti-inflammatory and anti-coagulant therapies. This suggests that more effective drug combinations may be required to overcome the radiation stimulus, or that other underlying mechanistic pathways are involved compared to age-related atherosclerosis.


Subject(s)
Apolipoproteins E/deficiency , Atherosclerosis/drug therapy , Atherosclerosis/etiology , Heptanoic Acids/pharmacology , Pyrroles/pharmacology , Radiation Injuries, Experimental/complications , Ticlopidine/analogs & derivatives , Animals , Anti-Inflammatory Agents/pharmacology , Apolipoproteins E/metabolism , Atherosclerosis/pathology , Atorvastatin , CD40 Antigens/radiation effects , Carotid Arteries/pathology , Carotid Arteries/radiation effects , Clopidogrel , Disease Models, Animal , Immunohistochemistry , Mice , Mice, Inbred C57BL , Mice, Knockout , Platelet Aggregation Inhibitors/pharmacology , Radiation Dosage , Random Allocation , Reference Values , Statistics, Nonparametric , Ticlopidine/pharmacology
5.
PLoS One ; 5(9): e12874, 2010 Sep 21.
Article in English | MEDLINE | ID: mdl-20877628

ABSTRACT

BACKGROUND: We previously showed that irradiation to the carotid arteries of ApoE(-/-) mice accelerated the development of macrophage-rich, inflammatory atherosclerotic lesions, prone to intra-plaque hemorrhage. In this study we investigated the potential of anti-inflammatory and anti-coagulant intervention strategies to inhibit age-related and radiation-induced atherosclerosis. METHODOLOGY/PRINCIPAL FINDINGS: ApoE(-/-) mice were given 0 or 14 Gy to the neck and the carotid arteries and aortic arches were harvested at 4 or 30 weeks after irradiation. Nitric oxide releasing aspirin (NCX 4016, 60 mg/kg/day) or aspirin (ASA, 30 or 300 mg/kg/day) were given continuously in the chow. High dose ASA effectively blocked platelet aggregation, while the low dose ASA or NCX 4016 had no significant effect on platelet aggregation. High dose ASA, but not NCX 4016, inhibited endothelial cell expression of VCAM-1 and thrombomodulin in the carotid arteries at 4 weeks after irradiation; eNOS and ICAM-1 levels were unchanged. After 30 weeks of follow-up, NCX 4016 significantly reduced the total number of lesions and the number of initial macrophage-rich lesions in the carotid arteries of unirradiated mice, but these effects were not seen in the brachiocephalic artery of the aortic arch (BCA). In contrast, high dose ASA lead to a decrease in the number of initial lesions in the BCA, but not in the carotid artery. Both high dose ASA and NCX 4016 reduced the collagen content of advanced lesions and increased the total plaque burden in the BCA of unirradiated mice. At 30 weeks after irradiation, neither NCX 4016 nor ASA significantly influenced the number or distribution of lesions, but high dose ASA lead to formation of collagen-rich "stable" advanced lesions in carotid arteries. The total plaque area of the irradiated BCA was increased after ASA, but the plaque burden was very low compared with the carotid artery. CONCLUSIONS/SIGNIFICANCE: The development and characteristics of radiation-induced atherosclerosis varied between different arteries but could not be circumvented by anti-inflammatory and anti-coagulant therapies. This implicates other underlying mechanistic pathways compared to age-related atherosclerosis.


Subject(s)
Apolipoproteins E/deficiency , Aspirin/analogs & derivatives , Aspirin/administration & dosage , Atherosclerosis/drug therapy , Carotid Arteries/radiation effects , Down-Regulation , X-Rays/adverse effects , Age Factors , Animals , Apolipoproteins E/genetics , Atherosclerosis/etiology , Atherosclerosis/genetics , Atherosclerosis/immunology , Carotid Arteries/drug effects , Carotid Arteries/immunology , Disease Models, Animal , Female , Gene Expression/drug effects , Gene Expression/radiation effects , Humans , Intercellular Adhesion Molecule-1/genetics , Intercellular Adhesion Molecule-1/immunology , Male , Mice , Mice, Inbred C57BL , Platelet Aggregation/drug effects , Platelet Aggregation/radiation effects , Vascular Cell Adhesion Molecule-1/genetics , Vascular Cell Adhesion Molecule-1/immunology
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