METHODS: cRGD-platelet@MnO/MSN@PPARα/LXRα nanoparticles were synthesized by a chemical method. Dynamic light scattering (DLS) was utilized to detect the size distribution and polydispersity index (PDI) of the nanoparticles. The safety of the nanoparticles was detected by CCK8 in vitro and HE staining and kidney function in vivo. Cell apoptosis was detected by flow cytometry detection and TUNEL staining. Oxidative stress responses (ROS, SOD, MDA, and NOX levels) were tested via a DCFH-DA assay and commercial kits. Immunofluorescence and phagocytosis experiments were used to detect the targeting of nanoparticles. Magnetic resonance imaging (MRI) was used to detect the imaging performance of cRGD-platelet@MnO/MSN@PPARα/LXRα nanoparticles. Using western blotting, the expression changes in LXRα and ABCA1 were identified.
RESULTS: cRGD-platelet@MnO/MSN@PPARα/LXRα nanoparticles were successfully established, with a particle size of approximately 150 nm and PDI less than 0.3, and showed high safety both in vitro and in vivo. cRGD-platelet@MnO/MSN@PPARα/LXRα nanoparticles showed good targeting properties and better MRI imaging performance in AS. cRGD-platelet@MnO/MSN@PPARα/LXRα nanoparticles showed better antioxidative capacities, MRI imaging performance, and diagnostic and therapeutic effects on AS by regulating the expression of LXRα and ABCA1.
CONCLUSION: In the present study, cRGD-platelet@MnO/MSN@PPARα/LXRα nanoparticles with high safety and the capacity to target vulnerable plaques of AS were successfully established. They showed better performance on MRI images and treatment effects on AS by promoting cholesterol efflux through the regulation of ABCA1. These findings might address the problems of off-target effects and side effects of nanoparticle-mediated drug delivery, which will enhance the efficiency of AS treatment and provide new ideas for the clinical treatment of AS.
APPROACH AND RESULTS: Human atherosclerotic plaques showed marked mitochondrial dysfunction, manifested as reduced mtDNA copy number and oxygen consumption rate in fibrous cap and core regions. Vascular smooth muscle cells derived from plaques showed impaired mitochondrial respiration, reduced complex I expression, and increased mitophagy, which was induced by oxidized low-density lipoprotein. Apolipoprotein E-deficient (ApoE-/-) mice showed decreased mtDNA integrity and mitochondrial respiration, associated with increased mitochondrial reactive oxygen species. To determine whether alleviating mtDNA damage and increasing mitochondrial respiration affects atherogenesis, we studied ApoE-/- mice overexpressing the mitochondrial helicase Twinkle (Tw+/ApoE-/-). Tw+/ApoE-/- mice showed increased mtDNA integrity, copy number, respiratory complex abundance, and respiration. Tw+/ApoE-/- mice had decreased necrotic core and increased fibrous cap areas, and Tw+/ApoE-/- bone marrow transplantation also reduced core areas. Twinkle increased vascular smooth muscle cell mtDNA integrity and respiration. Twinkle also promoted vascular smooth muscle cell proliferation and protected both vascular smooth muscle cells and macrophages from oxidative stress-induced apoptosis.
CONCLUSIONS: Endogenous mtDNA damage in mouse and human atherosclerosis is associated with significantly reduced mitochondrial respiration. Reducing mtDNA damage and increasing mitochondrial respiration decrease necrotic core and increase fibrous cap areas independently of changes in reactive oxygen species and may be a promising therapeutic strategy in atherosclerosis.
MATERIALS AND METHODS: Six control and five DM Wistar rats were evaluated. DM was induced at 11 weeks of age using streptozotocin (STZ; 60 mg/kg, intraperitoneal). Animals were monitored up to 38 weeks of age, when plasma glucose, lipid profile, and markers specific for systemic inflammation, endothelial dysfunction, and oxidative stress were measured. The amount of fat within the aortic wall was assessed semiquantitatively using Oil Red O staining.
RESULTS: Diabetic rats presented significantly higher plasma glucose (p < 0.001), total cholesterol and triglycerides (both p = 0.02), high-sensitivity C-reactive protein (p = 0.01), and vascular endothelial growth factor (p = 0.04) levels, and significantly lower interleukin-10 (p = 0.04), superoxide dismutase (p < 0.01), and glutathione peroxidase (p = 0.01) levels than the control rats. Mild (grade 1) atherosclerotic lesions were observed in the aortic wall of 80% of the diabetic rats and in none of the control rats.
CONCLUSIONS: This study presents a STZ-induced type 1 DM rat model with one of the longest follow-ups in the literature. In this model, long-term DM created a highly pro-atherogenic environment characterised by hyperglycemia, dyslipidemia, systemic inflammation, endothelial dysfunction, and oxidative stress that resulted in the development of early aortic atherosclerotic lesions.
MATERIALS AND METHODS: This cross-sectional study included 150 subjects aged 30 years and above who attended a health screening in a Malaysian tertiary institution. Sociodemographics, clinical characteristics and laboratory parameters (lipids, glucose, and sdLDL) were obtained. Lipoprotein subfraction was analysed using the polyacrylamide gel electrophoresis method.
RESULTS: Malays and females made up the majority of subjects and the median age was 37 years. Normolipidaemic Pattern B was significantly higher in women (p=0.008). Significant independent predictors of Pattern B were gender (p=0.02), race (p=0.01), body mass index (BMI) [p=0.02] and lipid status (p=0.01). Triglyceride was the only independent predictor of sdLDL (p=0.001).
CONCLUSION: The prevalence of Pattern B of 33% in this study was comparatively high, of which 6.7% were normolipidaemic. Chinese males with dyslipidaemia and increased BMI independently predicted Pattern B. Differences in triglyceride levels alone among these ethnic groups do not fully explain the differences in the prevalence of Pattern B although it was the only lipid parameter to independently predict sdLDL. Individuals with atherogenic normolipidaemia are at greater risk for a CVD event as they are not included in the protective measures of primary CVD prevention.
METHODS: From October 2015 to September 2016, 202 patients with chronic kidney disease (CKD), stages 4 and 5, underwent arteriovenous fistula creation at the Universiti Sains Malaysia Hospital, Malaysia. Nine patients, with severe atherosclerosis of the distal artery, but with satisfactory veins, underwent forearm loop arteriovenous fistula creation. Maturation of the fistula was based on the classification by the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI).
RESULTS: All nine patients who underwent forearm loop arteriovenous fistula have had diabetes mellitus for more than 10 years. Only one fistula failed to mature within 6 weeks. Two arteriovenous fistulas thrombosed at 3 and 5 months, respectively, after the commencement of haemodialysis. However, the other six matured fistulas are still functioning well after a year of regular usage.
CONCLUSIONS: Distal forearm arteries in diabetics may be severely atherosclerotic. Forearm loop arteriovenous fistula can be considered as the primary access for cases decided as inconvenient for fistula creation due to severe occlusive atherosclerotic disease of the forearm arteries; in order to preserve upper arm veins for future access procedures.