Cardiovascular Changes in Atherosclerotic ApoE-Deficient Mice Exposed to Co60 (γ) Radiation

Abstract

BackgroundThere is evidence for a role of ionizing radiation in cardiovascular diseases. The goal of this work was to identify changes in oxidative and nitrative stress pathways and the status of the endothelinergic system during progression of atherosclerosis in ApoE-deficient mice after single and repeated exposure to ionizing radiation.Methods and ResultsB6.129P2-ApoE tmlUnc mice on a low-fat diet were acutely exposed (whole body) to Co60 (γ) (single dose 0, 0.5, and 2 Gy) at a dose rate of 36.32 cGy/min, or repeatedly (cumulative dose 0 and 2 Gy) at a dose-rate of 0.1 cGy/min for 5 d/wk, over a period of 4 weeks. Biological endpoints were investigated after 3–6 months of recovery post-radiation. The nitrative stress marker 3-nitrotyrosine and the vasoregulator peptides endothelin-1 and endothelin-3 in plasma were increased (p<0.05) in a dose-dependent manner 3–6 months after acute or chronic exposure to radiation. The oxidative stress marker 8-isoprostane was not affected by radiation, while plasma 8-hydroxydeoxyguanosine and L-3,4-dihydroxyphenylalanine decreased (p<0.05) after treatment. At 2Gy radiation dose, serum cholesterol was increased (p = 0.008) relative to controls. Percent lesion area increased (p = 0.005) with age of animal, but not with radiation treatment.ConclusionsOur observations are consistent with persistent nitrative stress and activation of the endothelinergic system in ApoE−/− mice after low-level ionizing radiation exposures. These mechanisms are known factors in the progression of atherosclerosis and other cardiovascular diseases.

Nitrative stress, oxidative stress and plasma endothelin levels after inhalation of particulate matter and ozone

“…Interestingly, disruption of the endothelinergic system and formation of 3-nitrotyrosine are two well documented central mechanisms in many disease processes including atherosclerosis, pulmonary hypertension, asthma, neurological disorders, cancer and with air pollution and radiation exposure (ozone is known as radiomimetic gas) [ 57 – 67 ]. It is therefore feasible that air pollutants can potentially influence such pathologies through these mechanistic pathways.…”

“…This analysis method is based on the thermolysis of all NO-related compounds in vivo such as nitrosyl metal complexes, nitrite/nitrate, S-nitroso compounds in plasma to nitrate, followed by enzymatic reduction to nitrite that was derivatized using a fluorescent probe for detection by fluorescence. Nitrite analysis was conducted following a previously reported procedure [ 67 ]. In essence, plasma samples (50 μL) treated with DETPA and BHT were thermolyzed at 86 °C, cooled and filtered via 10 kDa molecular weight cut-off filters.…”

Gamma Radiation-Induced Disruption of Cellular Junctions in HUVECs Is Mediated through Affecting MAPK/NF-κB Inflammatory Pathways

“…Recent studies suggested a causality between the development of cardiovascular disease and radiation exposure [1, 2]. Endothelial cells, as the most sensitive cell type in the vascular system, are the critical targets in cardiovascular damage induced by radiation, which plays a key role in the development of vascular pathologies, such as endothelial barrier damage and permeability changes [3, 4], premature senescence [5, 6], angiogenic defects [7], and the development of atherosclerosis [8–10]. The endothelial integrity is closely associated with the barrier functions of intercellular junctions.…”

Endothelial Dysfunction Under Influence of Ionizing Radiation: Pathogenetic Basis and Opportunities of Pharmacological Correction

“…Патофизиологический базис эндотелиальной дисфункции, индуцированной радиоактивным излучением, связан с активацией свободнорадикального окисления, активацией провоспалительных иммунологических каскадов, повреждением эндокринной системы, нарушением работы клеток сосудистой стенки на уровне генетической и эпигенетической регуляции [6]. При этом системные изменения, связанные с полиорганными нарушениями и массивным выбросом широкого спектра гуморальных факторов, суммируются с непосредственным действием ионизирующей радиации на эндотелиоциты и их микроокружение.…”

“…Было показано, что при остром воздействии ионизирующего излучения (36, 32 кДж/мин) на мышей с гиперлипопротеинемией происходит повышение маркеров нитрозативного стресса (пероксинитрит, 3-нитротирозин), вазоконстрикторных пептидов (эндотелин-1, эндотелин-3) и эндотелин-конвертирующего фермента, а также еще большее увеличение концентрации холестерина при относительно низком уровне классических маркеров оксидативного стресса в плазме [6].…”