Abstract
Intraplaque hemorrhage (IPH) plays a major role in the aggressive progression of vulnerable plaque, leading to acute cardiovascular events. We previously demonstrated that sonodynamic therapy (SDT) inhibits atherosclerotic plaque progression. In this study, we investigated whether SDT could also be applied to treat more advanced hemorrhagic plaque and addressed the underlying mechanism. SDT decreased atherosclerotic burden, positively altered atherosclerotic lesion composition, and alleviated iron retention in rabbit hemorrhagic plaques. Furthermore, SDT reduced iron retention by stimulating ferroportin 1 (Fpn1) expression in apolipoprotein E (ApoE)−/− mouse plaques with high susceptibility to IPH. Subsequently, SDT inhibited iron‐overload‐induced foam‐cell formation and pro‐inflammatory cytokines secretion in vitro. Moreover, SDT reduced levels of the labile iron pool and ferritin expression via the reactive oxygen species (ROS)‐nuclear factor erythroid 2‐related factor 2 (Nrf2)‐FPN1 pathway. SDT exerted therapeutic effects on hemorrhagic plaques and reduced iron retention via the ROS‐Nrf2‐FPN1 pathway in macrophages, thereby suggesting that it is a potential translational strategy for patients with advanced atherosclerosis in clinical practice.
Highlights
MATERIALS AND METHODSCurrently, an existing challenge to antithrombotic treatment for atherosclerotic vascular diseases is the higher frequencies of intraplaque hemorrhage (IPH).[1,2] IPH plays a major role in the aggressive progression of atherosclerotic plaque, leading to acute cardiovascular events.[3]The potent atherogenic stimulus caused by IPH is attributed to the deposition of erythrocyte lysis products,[4] which cause cholesterol deposits and iron retention in plaques.[3]
We observed a significant decrease in nonheme iron content in rabbit hemorrhagic plaques after sonodynamic therapy (SDT) treatment (Figure 1(d))
These data demonstrated that SDT reduced iron retention and positively altered the composition of rabbit hemorrhagic plaque
Summary
An existing challenge to antithrombotic treatment for atherosclerotic vascular diseases is the higher frequencies of intraplaque hemorrhage (IPH).[1,2] IPH plays a major role in the aggressive progression of atherosclerotic plaque, leading to acute cardiovascular events.[3]. The ultrasonic transducer parameters were as follows: diameter, 35 mm; and resonance frequency, 1.0 MHz. DVDMS was used as the sonosensitizer for SDT. At 4 h after intravenous DVDMS (4 mg/kg) administration, anesthetized animals were subjected to ultrasound for 15 min with an ultrasonic intensity of 1.5 W/cm[2] for rabbits and 0.4 W/cm[2] for mice, as previously described.[17,22] Mice in the hepcidin + SDT group were intraperitoneally administered 25 μg human hepcidin-25 dissolved in 100 μl PBS 1 h before SDT treatment, whereas mice in the hepcidin group received only hepcidin-25. Based on the optimized SDT parameters (Figure S2(a)–(c)), ILMs were incubated with 0.2 μM DVDMS for 4 h, followed by irradiation with an ultrasound intensity of 0.2 W/cm[2] for 5 min. Statistical analyses were performed using GraphPad Prism 7.0 (GraphPad Software, San Diego, CA, USA), and p < 0.05 was considered statistically significant
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
