ROS-Based Nanoparticles for Atherosclerosis Treatment

Atherosclerosis (AS), a chronic arterial disease, is the leading cause of death in western developed countries. Considering its long-term asymptomatic progression and serious complications, the early prevention and effective treatment of AS are particularly important. The unique characteristics of nanoparticles (NPs) make them attractive in novel therapeutic and diagnostic applications, providing new options for the treatment of AS. With the assistance of reactive oxygen species (ROS)-based NPs, drugs can reach specific lesion areas, prolong the therapeutic effect, achieve targeted controlled release and reduce adverse side effects. In this article, we reviewed the mechanism of AS and the generation and removal strategy of ROS. We further discussed ROS-based NPs, and summarized their biomedical applications in scavenger and drug delivery. Furthermore, we highlighted the recent advances, challenges and future perspectives of ROS-based NPs for treating AS.

Endothelial Yin Yang 1 Phosphorylation at S118 Induces Atherosclerosis Under Flow

Rationale: Disturbed flow occurring in arterial branches and curvatures induces vascular endothelial cell (EC) dysfunction and atherosclerosis. We postulated that disturbed flow plays important roles in modulating phosphoprotein expression profiles to regulate endothelial functions and atherogenesis. Objective: The goal of this study is to discover novel site-specific phosphorylation alterations induced by disturbed flow in ECs to contribute to atherosclerosis. Methods and Results: Quantitative phosphoproteomics analysis of ECs exposed to disturbed flow with low and oscillatory shear stress (OS, 0.5plusminus4 dynes/cm 2 ) vs. pulsatile flow with high shear stress (PS, 124plusminus dynes/cm 2 ) revealed that OS induces serine (S)118 phosphorylation of Yin Yang 1 (phospho-YY1 S118 ) in ECs. Elevated phospho-YY1 S118 level in ECs was further confirmed to be present in the disturbed flow regions in experimental animals and human atherosclerotic arteries. This disturbed flow-induced EC phospho-YY1 S118 is mediated by casein kinase 2α (CK2α) through its direct interaction with YY1. Yeast two-hybrid library screening and in situ proximity ligation assays demonstrate that phospho-YY1 S118 directly binds zinc finger with KRAB and SCAN domains 4 (ZKSCAN4) to induce promoter activity and gene expression of human double minute 2 (HDM2), which consequently induces EC proliferation through down-regulations of p53 and p21 CIP1 . Administration of apolipoprotein E-deficient (ApoE -/- ) mice with CK2-specific inhibitor tetrabromocinnamic acid or atorvastatin inhibits atherosclerosis formation through down-regulations of EC phospho-YY1 S118 and HDM2. Generation of novel transgenic mice bearing EC-specific overexpression of S118-non-phosphorylatable mutant of YY1 in ApoE -/- mice confirms the critical role of phospho-YY1 S118 in promoting atherosclerosis through EC HDM2. Conclusions: Our findings provide new insights into the mechanisms by which disturbed flow induces endothelial phospho-YY1 S118 to promote atherosclerosis, thus indicating phospho-YY1 S118 as a potential molecular target for atherosclerosis treatment.

Silibinin augments the effect of clopidogrel on atherosclerosis in diabetic ApoE deficiency mice

BACKGROUND: Diabetes mellitus (DM) abolishes the antithrombotic effect of Clopidogrel. Here, we investigated the synergistic effect of Silibinin on Clopidogrel-mediated atherosclerosis treatment in diabetic mice. METHODS: ApoE–/– mice were fed with high-fat diet (HFD) to establish the atherosclerotic model with diabetes. Animals were treated with Clopidogrel, Silibinin, or the combined to evaluate the protective effects on atherosclerosis and diabetes through Oil-red-O staining, qRT-PCR, Western blot, and metabolic measurements. Platelet activation and aggregation ex vivo assays were performed to detect the anti-thrombotic effect of different administrations. RESULTS: Silibinin significantly enhanced the inhibitory effect of Clopidogrel on atherosclerosis in DM mice. Co-administration of Silibinin with Clopidogrel remarkedly reduced the aortic lesion, inflammation, and endothelial dysfunction in aorta roots, and diabetic symptoms were significantly improved by the Silibinin-Clopidogrel treatment in HFD-fed ApoE–/– mice. Interestingly, the anti-thrombotic effect of Clopidogrel was further augmented by the Silibinin treatment in atherosclerotic mice. CONCLUSION: In atherosclerotic mouse model, Silibinin significantly improves the effect of Clopidogrel on atherosclerosis.

Intermittent Fasting Inhibits High-Fat Diet–Induced Atherosclerosis by Ameliorating Hypercholesterolemia and Reducing Monocyte Chemoattraction

Atherosclerosis is a major pathology for cardiovascular diseases (CVDs). Clinically, the intermittent fasting (IF) has been observed to reduce the risk of CVDs. However, the effect of IF on the development of atherosclerosis has not been fully elucidated. Herein, we determined the protection of IF against high-fat diet–induced atherosclerosis in pro-atherogenic low-density lipoprotein receptor deficient (LDLR-/-) mice and the potentially involved mechanisms. The LDLR-/- mice were scheduled intermittent fasting cycles of 3-day HFD feeding ad libitum and 1 day fasting, while the mice in the control group were continuously fed HFD. The treatment was lasted for 7 weeks (∼12 cycles) or 14 weeks (∼24 cycles). Associated with the reduced total HFD intake, IF substantially reduced lesions in the en face aorta and aortic root sinus. It also increased plaque stability by increasing the smooth muscle cell (SMC)/collagen content and fibrotic cap thickness while reducing macrophage accumulation and necrotic core areas. Mechanistically, IF reduced serum total and LDL cholesterol levels by inhibiting cholesterol synthesis in the liver. Meanwhile, HFD-induced hepatic lipid accumulation was attenuated by IF. Interestingly, circulating Ly6Chigh monocytes but not T cells and serum c-c motif chemokine ligand 2 levels were significantly reduced by IF. Functionally, adhesion of monocytes to the aortic endothelium was decreased by IF via inhibiting VCAM-1 and ICAM-1 expression. Taken together, our study indicates that IF reduces atherosclerosis in LDLR-/- mice by reducing monocyte chemoattraction/adhesion and ameliorating hypercholesterolemia and suggests its potential application for atherosclerosis treatment.

Mitochondrial Dysfunction in Vascular Wall Cells and Its Role in Atherosclerosis

Altered mitochondrial function is currently recognized as an important factor in atherosclerosis initiation and progression. Mitochondrial dysfunction can be caused by mitochondrial DNA (mtDNA) mutations, which can be inherited or spontaneously acquired in various organs and tissues, having more or less profound effects depending on the tissue energy status. Arterial wall cells are among the most vulnerable to mitochondrial dysfunction due to their barrier and metabolic functions. In atherosclerosis, mitochondria cause alteration of cellular metabolism and respiration and are known to produce excessive amounts of reactive oxygen species (ROS) resulting in oxidative stress. These processes are involved in vascular disease and chronic inflammation associated with atherosclerosis. Currently, the list of known mtDNA mutations associated with human pathologies is growing, and many of the identified mtDNA variants are being tested as disease markers. Alleviation of oxidative stress and inflammation appears to be promising for atherosclerosis treatment. In this review, we discuss the role of mitochondrial dysfunction in atherosclerosis development, focusing on the key cell types of the arterial wall involved in the pathological processes. Accumulation of mtDNA mutations in isolated arterial wall cells, such as endothelial cells, may contribute to the development of local inflammatory process that helps explaining the focal distribution of atherosclerotic plaques on the arterial wall surface. We also discuss antioxidant and anti-inflammatory approaches that can potentially reduce the impact of mitochondrial dysfunction.

Biological Activities of Paeonol in Cardiovascular Diseases: A Review

Paeonol is a naturally existing bioactive compound found in the root bark of Paeonia suffruticosa and it is traditionally used in Chinese medicine for the prevention and management of cardiovascular diseases. To date, a great deal of studies has been reported on the pharmacological effects of paeonol and its mechanisms of action in various diseases and conditions. In this review, the underlying mechanism of action of paeonol in cardiovascular disease has been elucidated. Recent studies have revealed that paeonol treatment improved endothelium injury, demoted inflammation, ameliorated oxidative stress, suppressed vascular smooth muscle cell proliferation, and repressed platelet activation. Paeonol has been reported to effectively protect the cardiovascular system either employed alone or in combination with other traditional medicines, thus, signifying it could be a hypothetically alternative or complementary atherosclerosis treatment. This review summarizes the biological and pharmacological activities of paeonol in the treatment of cardiovascular diseases and its associated underlying mechanisms for a better insight for future clinical practices.