BackgroundThe incidental use of statins during radiation therapy has been associated with a reduced long-term risk of developing atherosclerotic cardiovascular disease. However, the mechanisms by which statins protect the vasculature from irradiation injury remain poorly understood.ObjectivesIdentify the mechanisms by which the hydrophilic and lipophilic statins pravastatin and atorvastatin preserve endothelial function after irradiation.MethodsCultured human coronary and umbilical vein endothelial cells irradiated with 4 Gy and mice subjected to 12 Gy head-and-neck irradiation were pretreated with statins and tested for endothelial dysfunction, nitric oxide production, oxidative stress, and various mitochondrial phenotypes at 24 and 240 h after irradiation.ResultsBoth pravastatin (hydrophilic) and atorvastatin (lipophilic) were sufficient to prevent the loss of endothelium-dependent relaxation of arteries after head-and-neck irradiation, preserve the production of nitric oxide by endothelial cells, and suppress the cytosolic reactive oxidative stress associated with irradiation. However, only pravastatin inhibited irradiation-induced production of mitochondrial superoxide; damage to the mitochondrial DNA; loss of electron transport chain activity; and expression of inflammatory markers.ConclusionsOur findings reveal some mechanistic underpinnings of the vasoprotective effects of statins after irradiation. Whereas both pravastatin and atorvastatin can shield from endothelial dysfunction after irradiation, pravastatin additionally suppresses mitochondrial injury and inflammatory responses involving mitochondria. Clinical follow-up studies will be necessary to determine whether hydrophilic statins are more effective than their lipophilic counterparts in reducing the risk of cardiovascular disease in patients undergoing radiation therapy.
Background Up to 90% of brain cancer survivors develop radiation‐induced cognitive dysfunction following treatment. Damage to neurovascular endothelium contributes to cognitive decline through increased blood‐brain barrier (BBB) permeability. In our preliminary studies of endothelial cells (ECs) and mice, increased mitochondrial reactive oxygen species (mtROS), inducing heightened mitochondrial DNA (mtDNA) damage and release as cell‐free DNA are detected following irradiation (IR). This cell‐free mtDNA is known to activate Toll‐like receptor 9 (TLR9), triggering an immune response and further ROS. These endothelial responses are prevented with TLR9 inhibition and mtROS scavenging, suggesting a key role for TLR9 in sustained IR‐induced endothelial damage and dysfunction. Here, we posit that specific inhibition of TLR9 in cerebral ECs during radiation treatment will prevent subsequent BBB permeability and cognitive decline. Thus, the objective of this study is to examine the role of TLR9 in IR‐induced cognitive decline using TLR‐specific loaded nanoparticles (NP). Methods and Results To target TLR9 in irradiated ECs, poly (lactic‐co‐glycolic acid)‐based NP coated with cyclic Arg‐Gly‐Asp (cRGD)‐peptide were designed and loaded with TLR9 inhibitor (ODN‐2088, 2.23ug/mg particle). cRGD‐peptide is a ligand for integrin αvβ3, which is highly expressed in ECs post‐IR. cRGD‐NP loaded with coumarin‐6 were used to first evaluate specificity in vitro and in vivo. ECs 24h post‐IR (4 Gy) displayed higher fluorescence than non‐IR, indicating selective uptake. Moreover, in C57Bl6 mice 24h post unilateral cerebral IR (12Gy) with cRGD‐NP, uptake accumulated in endothelium of the IR hemisphere. Mice were administered NP‐ODN‐2088 or empty NP (3mg injection) and subjected to IR as described above. 30 days post‐IR, they were tested for memory and learning ability using the Novel Object Recognition test. IR induced a significant impairment in the memory ability of empty NP treated mice compared to NP‐ODN‐2088. BBB permeability was analyzed in the same mice 30 days post‐IR with immunohistochemistry using anti‐mouse IgG. Significant BBB permeability was detected in the IR hemisphere of empty NP mice compared to the non‐IR hemisphere. However, the IR hemisphere of NP‐ODN‐2088 mice showed attenuated permeability compared to empty NP treated mice. Conclusion Inhibition of TLR9 in irradiated ECs was observed to protect against BBB disruption and cognitive decline. These data support a pathway of radiation‐induced endotheliopathy through which TLR9 activation links vascular mitochondrial injury to neuropathology. Currently there are no pharmacological options for treating radiation‐induced normal tissue injury and targeting TLR9 poses a promising strategy.
Introduction: The incidental use of statins during radiation therapy has been associated with a decreased risk of long-term atherosclerotic cardiovascular (CV) disease. However, the mechanisms by which statins protect the vasculature from irradiation injury remain poorly understood. Hypothesis: Establish the mechanisms by which lipophilic and hydrophilic statins preserve endothelial function after irradiation. Methods: Cultured human coronary and umbilical vein endothelial cells irradiated with 4 Gy and mice on day 1 and 10 after head and neck irradiation with 12 Gy were assessed for endothelial dysfunction, nitric oxide and reactive oxidative stress production and various mitochondrial phenotypes. Results: Pretreatment of mice with pravastatin or atorvastatin prevented the loss of endothelium-dependent relaxation on day 1 and 10 after head and neck irradiation. Both statins inhibit the loss of nitric oxide, and the increase in cytosolic reactive oxidative stress in endothelial cells. However, only pravastatin blocked mitochondrial superoxide production, mitochondrial DNA damage and loss of electron complex activity. In contrast to atorvastatin, pravastatin also significantly reduced the expression of inflammatory markers TNF-α, NFκB p65 and p50 after irradiation. Conclusions: Our findings provide mechanistic underpinnings for the vasoprotective effects of statins after irradiation. While lipo- and hydrophilic statins shield from endothelial dysfunction after irradiation, pravastatin also prevents mitochondrial injury and decreases an inflammatory response by actions in mitochondria. A correlation with clinical studies is necessary to determine whether hydrophilic statins, such as pravastatin reduce the risk of CV disease after irradiation in humans to a greater extent than lipophilic statins.
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