Therapy Of Atherosclerosis Research Articles

Nature-inspired nanocarriers for improving drug therapy of atherosclerosis.

Atherosclerosis (AS) has emerged as one of the prevalent arterial vascular diseases characterized by plaque and inflammation, primarily causing disability and mortality globally. Drug therapy remains the main treatment for AS. However, a series of obstacles hinder effective drug delivery. Nature, from natural micro-/nano-structural biological particles like natural cells and extracellular vesicles to the distinctions between the normal and pathological microenvironment, offers compelling solutions for efficient drug delivery. Nature-inspired nanocarriers of synthetic stimulus-responsive materials and natural components, such as lipids, proteins and membrane structures, have emerged as promising candidates for fulfilling drug delivery needs. These nanocarriers offer several advantages, including prolonged blood circulation, targeted plaque delivery, targeted specific cells delivery and controlled drug release at the action site. In this review, we discuss the nature-inspired nanocarriers which leverage the natural properties of cells or the microenvironment to improve atherosclerotic drug therapy. Finally, we provide an overview of the challenges and opportunities of applying these innovative nature-inspired nanocarriers.

M1/M2 re-polarization of kaempferol biomimetic NPs in anti-inflammatory therapy of atherosclerosis.

Atherosclerosis (AS), a leading cause of death worldwide, involves chronic macrophage inflammation from its initiation to the emergence of complications. Targeting plaque inflammation by re-polarizing pro-inflammatory M1 to anti-inflammatory M2 could therefore provide a promising strategy to treat AS, but currently available anti-inflammatory drugs limit clinical outcomes. In this study, we found that kaempferol (KPF) is capable of potential anti-inflammation as a novel drug candidate, which has been scarcely reported. Building upon these findings, we fabricated a macrophage-biomimetic KPF delivery platform, abbreviated as KPF@MM-NPs to potentiate therapeutic payloads, wherein the designed ROS-responsive Dextran-g-PBMEO NPs with π-π stacking were coated with macrophage membrane (MM) for effective target and accumulation in atherosclerotic lesions. Therapy of KPF@MM-NPs afforded significant decrease in proliferating macrophage inflammation while went with the reduction of key pro-inflammatory cytokines and re-polarization M1 to M2 phenotype, inducing excellent anti-AS responses in ApoE-/- mice after i.p. delivery. The mechanism of KPF@MM-NPs was further investigated and found it related to block the ROS/NF-κB signaling pathways. Together with as well demonstrated biosafety profiles, this proof-of-concept opens an instructive door for the study of KPF-mediated nanodrugs in treatment of AS based on biomimetic NPs.

Novel peptide inhibitors targeting CD40 and CD40L interaction: A potential for atherosclerosis therapy

Atherosclerosis is a chronic inflammatory disease characterized by plaque build-up in the arteries, leading to the obstruction of blood flow. Macrophages are the primary immune cells found in the atherosclerotic lesions and are directly involved in atherosclerosis progression. Macrophages are derived from extravasating blood monocytes. The monocytic CD40 receptor is important for monocyte recruitment on the endothelium expressing the CD40 ligand (CD40L). Thus, targeting monocyte/macrophage interaction with the endothelium by inhibiting CD40-CD40L interaction may be a promising strategy for attenuating atherosclerosis. Monoclonal antibodies have been used against this target but shows various complications. We used an array of computer-aided drug discovery tools and molecular docking approaches to design a therapeutic inhibitory peptide that could efficiently bind to the critical residues (82Y, 84D, and 86N) on the CD40 receptor essential for the receptor's binding to CD40L. The initial screen identified a parent peptide with a high binding affinity to CD40, but the peptide exhibited a positive hepatotoxicity score. We then designed several novel peptidomimetic derivatives with higher binding affinities to CD40, good physicochemical properties, and negative hepatotoxicity as compared to the parent peptide. Furthermore, we conducted molecular dynamics simulations for both the apo and complexed forms of the receptor with ligand, and screened peptides to evaluate their stability. The designed peptidomimetic derivatives are promising therapeutics targeting the CD40-CD40L interaction and may potentially be used to attenuate atherosclerosis.

Advances in imaging and treatment of atherosclerosis based on organic nanoparticles.

Atherosclerosis, a systemic chronic inflammatory disease, can lead to thrombosis and vascular occlusion, thereby inducing a series of serious vascular diseases. Currently, distinguishing unstable plaques early and achieving more effective treatment are the two main clinical concerns in atherosclerosis. Organic nanoparticles have great potential in atherosclerotic imaging and treatment, showing superior biocompatibility, drug-loading capacity, and synthesis. This article illustrates the process of atherosclerosis onset and the key targeted cells, then systematically summarizes recent progress made in organic nanoparticle-based imaging of different types of targeted cells and therapeutic methods for atherosclerosis, including optical and acoustic-induced therapy, drug delivery, gene therapy, and immunotherapy. Finally, we discuss the major impediments that need to be addressed in future clinical practice. We believe this article will help readers to develop a comprehensive and in-depth understanding of organic nanoparticle-based atherosclerotic imaging and treatment, thus advancing further development of anti-atherosclerosis therapies.

Imaging-guided gene delivery: seeing is delivering

Imaging-guided gene delivery: seeing is delivering

Déjà vu: Plaque morphology revisited.

The impact of plaque morphology on the risk of stroke in patients with atherosclerosis of the carotid bifurcation has been a matter of interest for more than 40 years…. nearly as long as carotid endarterectomy (CEA) has been in existence!1 In the era of modern medical therapy for atherosclerosis, there are some who continue to believe that asymptomatic carotid disease should always be treated with optimal medical management as opposed to any carotid artery intervention. Although most vascular surgeons would agree that plaque morphology is exceedingly important, we continue to make our decisions regarding carotid artery intervention primarily based on the degree of stenosis.

Dual-responsive targeted atherosclerosis therapy through a multi-effective nanoplatform with anti-inflammatory, lipid-regulating and autophagy

The traditional treatment of atherosclerosis (AS) is mainly focused on lipid-lowering therapy, through oral statins to reduce blood lipid levels and control the progress of AS. However, current oral drug therapy has suffered from poor targeting and single efficacy. Here, a pH-responsive magnetic nanoplatforms (MMNS@AT-CS-DS) was developed. The dextran sulfate (DS) was encapsulated on MMNS@AT-CS to endow the nanoplatforms with the property of targeting atherosclerotic plaques. In vitro and in vivo results showed that MMNS@AT-CS-DS could target lesion areas and release statins to slow the progression of AS due to the magnetocaloric effect under alternating magnetic field (AMF) and dissolution of chitosan (CS) in the AS induced low pH environment. More importantly, its magneto-thermal responsiveness could induce protective autophagy to treat AS synergistically. In addition, the magnetic nanoplatforms could perform magnetic resonance (MR) imaging of atherosclerotic plaques, which shed new light on the integration of diagnosis and treatment of AS.

Living Macrophage-Delivered Tetrapod PdH Nanoenzyme for Targeted Atherosclerosis Management by ROS Scavenging, Hydrogen Anti-inflammation, and Autophagy Activation.

Atherosclerosis, driven by chronic inflammation in the artery walls, underlies several severe cardiovascular diseases. However, currently available anti-inflammatory-based strategies for atherosclerosis treatment suffer from compromised therapeutic efficacy and undesirable therapeutic outcome. Herein, a distinct tetrapod needle-like PdH nanozyme was designed and engineered for efficient atherosclerosis treatment by the combinatorial reactive oxygen species (ROS) scavenging, hydrogen anti-inflammation, and autophagy activation. After loading into macrophages and targeted delivery to arterial plaques, these multifunctional nanozymes efficiently decreased the ROS levels and significantly suppressed the inflammation-related pathological process, exerting the distinct antioxidation and anti-inflammatory performance for alleviating atherosclerosis development. Especially and importantly, the specific spiky morphology of the PdH nanoenzyme further triggered a strong autophagy response in macrophages, synergistically maintaining the cellular homeostasis and alleviating atherosclerosis development. Both in vitro and in vivo results confirmed the synergy among the antioxidation, anti-inflammatory, and autophagy activation, suggesting that the combinatorial engineering of nanomedicines with intrinsic multiple therapeutic functions and topology-induced biological effects is highly preferable and effective for achieving the high therapeutic performance and desirable therapeutic outcome on atherosclerosis management and therapy.

ATF3 in atherosclerosis: a controversial transcription factor.

Atherosclerosis, the pathophysiological basis of most malignant cardiovascular diseases, remains a global concern. Transcription factors play a key role in regulating cell function and disease progression in developmental signaling pathways involved in atherosclerosis. Activated transcription factor (ATF) 3 is an adaptive response gene in the ATF/cAMP response element binding (CREB) protein family that acts as a transcription suppressor or activator by forming homodimers or heterodimers with other ATF/CREB members. Appropriate ATF3 expression is vital for normal physiological cell function. Notably, ATF3 exhibits distinct roles in vascular endothelial cells, macrophages, and the liver, which will also be described in detail. This review provides a new perspective for atherosclerosis therapy by summarizing the mechanism of ATF3 in atherosclerosis, as well as the structure and pathophysiological properties of ATF3. KEY MESSAGES: • In endothelial cells, ATF3 overexpression aggravates oxidative stress and inflammation. • In macrophages and liver cells, ATF3 can act as a negative regulator of inflammation and promote cholesterol metabolism. • ATF3 can be used as a potential therapeutic factor in the treatment of atherosclerosis.

Molecular mechanisms of myocardial damage in the hypertensive rats and hypertensive rats with metabolic disorders (diabetes mellitus, atherosclerosis)

Introduction: Despite the success which was achieved in the treatment of arterial hypertension, for optimization of the treatment, it is necessary to study the pathogenesis of primary arterial hypertension and target organ damage on the molecular level. Materials and methods: Our team studied the molecular mechanisms of myocardial damage during arterial hypertension and metabolic disorders. We used the spontaneously hypertensive rats (SHR) as an experimental model, and, additionally, we modeled diabetes mellitus and atherosclerosis in these rats. Results and discussion: Our study obtained evidence of a much higher level of the energy imbalance in the cardiomyocytes and more intensive production of reactive oxygen species in the SHRs with diabetes mellitus and atherosclerosis compared with the healthy animals and the animals with only hypertension. The indicated defections create an environment for further cellular damage – mitochondrial dysfunction, depletion in the thiol-disulfide system, and formation of highly reactive NO products. At the same time, we have noticed a higher activity of the Hsp70 in the hypertensive groups compared with the normotensive animals. The source of these deviations is in the formation of mitochondrial dysfunction of cardiocytes, the cause of which is oxidative modification of the protein structures of mitochondria under conditions of activation of oxidative stress reactions, insufficiency of mPT pores, and impaired mitochondrial chaperone function. The presented data give reason to believe that mitochondrial dysfunction, which develops against the background of deficient HSP70, is an integral aspect of arterial hypertension, contributes to its aggravation, and triggers a cascade of molecular and biochemical mechanisms of myocardial damage. These mechanisms include disturbances in the L-arginine-NO-synthase-NO system, production of mitochondrial iNOS oxygen radicals, neutralization of the vasorelaxant effect of NO and its transformation into an active participant in nitrous stress due to reduced intermediates of the thiol-disulfide system. The question of cause-and-effect relationships of oxidative stress remains open for discussion. Conclusion: We envisage that studies in this direction may lead to a better insight into a pathogenetic therapy of essential hypertension, diabetes mellitus, and atherosclerosis. Graphical abstract:

Bilateral ocular ischemic syndrome following treatment for laryngeal carcinoma

A 72-year-old male with a history of atherosclerosis and radiation therapy for laryngeal cancer presented with complaints of decreased vision. The exam of the right eye was notable for neovascularization of the iris and significant vaso-occlusive disease of the retina, with non-perfusion of the peripheral retina (Figure 1A). Classical large dot-blot hemorrhages were present in the mid-periphery of left retina consistent with the diagnosis of bilateral Ocular Ischemia Syndrome (OIS) (Figure 1B). Fluorescein angiography demonstrated more severe OIS of the right retina, with global peripheral capillary drop out and optic disc and diffuse vascular leakage (Figure 1C). Far peripheral capillary drop out was seen in the left eye with leaking neovascular vessels near the disc (Figure 1D). CT angiography showed arterial occlusive disease with impairment of carotid artery perfusion of the clinoid segment of the right internal carotid artery on axial CT angiogram, mirroring the severity of retinal ischemia between the two eyes (Figure 2).

A new approach of statin therapy in carotid atherosclerosis: Targeting indices of plaque vulnerability on the top of lipid-lowering. A narrative review.

Novel imaging techniques and biomarkers have emerged as surrogate markers of carotid plaque vulnerability. In parallel, statin administration in patients with established carotid atherosclerosis not requiring revascularization has reduced the number of consequent cerebrovascular events. This reduction is not only attributed to the lipid-lowering properties of statins but also to their pleiotropic actions. The present literature review aimed to summarize the stabilizing effects of statins on carotid plaques based on imaging modalities and biomarkers and propose an alternative approach to their implementation. Moreover, we assessed the perioperative use of statins in patients undergoing carotid revascularization and the impact of aggressive vs. conventional statin therapy. Recent studies using: (1) ultrasound indices of plaque echogenicity; (2) fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) scans for plaque inflammation assessment; or (3)magnetic resonance imaging (MRI) scans quantifying intraplaque hemorrhage, and lipid-rich necrotic core (LRNC) have shown quite promising results in evaluation of carotid plaque vulnerability. Based on those imaging modalities, a growing number of studies have demonstrated a very modest carotid plaque regression due to/induced by statins, while their stabilizing impact is disproportionally higher. Other studies assaying several biomarkers (e.g. inflammation, etc.) have confirmed a statin-induced carotid plaque stabilization. All the aforementioned benefits followed a dose-dependent pattern of statins, on top of the low-density lipoprotein cholesterol (LDL-C) target in current guidelines. In the case of symptomatic patients with carotid atherosclerosis suitable for revascularization, robust evidence implicates a significant statin-related reduction of perioperative cardiovascular risk only in patients undergoing endarterectomy.

Synthesis and Characterization of Fucoidan-Chitosan Nanoparticles Targeting P-Selectin for Effective Atherosclerosis Therapy.

Atherosclerosis is the key pathogenesis of cardiovascular diseases; oxidative stress, which is induced by the generated excess reactive oxygen species (ROS), has been a crucial mechanism underlying this pathology. Nanoparticles (NPs) represent a novel strategy for the development of potential therapies against atherosclerosis, and multifunctional NPs possessing antioxidative capacities hold promise for amelioration of vascular injury caused by ROS and for evading off-target effects; materials that are currently used for NP synthesis often serve as vehicles that do not possess intrinsic biological activities; however, they may affect the surrounding healthy environment due to decomposition of products. Herein, we used nontoxic fucoidan, a sulfated polysaccharide derived from a marine organism, to develop chitosan–fucoidan nanoparticles (CFNs). Then, by binding to P-selectin, an inflammatory adhesion exhibited molecule expression on the endothelial cells and activated platelets, blocking leukocyte recruitment and rolling on platelets and endothelium. CFNs exhibit antioxidant and anti-inflammatory properties. Nevertheless, by now, the application of CFNs for the target delivery regarding therapeutics specific to atherosclerotic plaques is not well investigated. The produced CFNs were physicochemically characterized using transmission electron microscopy (TEM), together with Fourier transform infrared spectroscopy (FTIR). Evaluations of the in vitro antioxidant as well as anti-inflammatory activities exhibited by CFNs were based on the measurement of their ROS scavenging abilities and investigating inflammatory mediator levels. The in vivo pharmacokinetics and binding efficiency of the CFNs to atherosclerotic plaques were also evaluated. The therapeutic effects indicated that CFNs effectively suppressed local oxidative stress and inflammation by targeting P-selectin in atheromatous plaques and thereby preventing the progression of atherosclerosis.

The TBK1/IKKε inhibitor amlexanox improves dyslipidemia and prevents atherosclerosis.

Cardiovascular diseases, especially atherosclerosis and its complications, are a leading cause of death. Inhibition of the noncanonical IκB kinases TANK-binding kinase 1 and IKKε with amlexanox restores insulin sensitivity and glucose homeostasis in diabetic mice and human patients. Here we report that amlexanox improves diet-induced hypertriglyceridemia and hypercholesterolemia in Western diet–fed (WD-fed) Ldlr–/– mice and protects against atherogenesis. Amlexanox ameliorated dyslipidemia, inflammation, and vascular dysfunction through synergistic actions that involve upregulation of bile acid synthesis to increase cholesterol excretion. Transcriptomic profiling demonstrated an elevated expression of key bile acid synthesis genes. Furthermore, we found that amlexanox attenuated monocytosis, eosinophilia, and vascular dysfunction during WD-induced atherosclerosis. These findings demonstrate the potential of amlexanox as a therapy for hypercholesterolemia and atherosclerosis.

Targeted delivery of platelet membrane modified extracellular vesicles into atherosclerotic plaque to regress atherosclerosis

Atherosclerosis is a major underlying cause of cardiovascular disease. Although certain success has been achieved in treatment for atherosclerosis, the risk of cardiovascular diseases still remains high. Anti-inflammation therapy was proved to halt atherosclerosis progression, but their clinical application was hindered by the systemic immunosuppressive effect. Since macrophages play a key role in the development of atherosclerosis, targeted delivery of anti-inflammatory therapeutics to lesional macrophages might be an effective therapeutic strategy to resolve localized inflammation while reducing the adverse effects. Mesenchymal stem cells derived extracellular vesicles (MSC-EVs) are believed to possess anti-atherosclerosis effects by reducing inflammation. In this study, we fabricated platelet mimetic MSC-EVs (P-EVs) by decorating EVs with platelets membranes. P-EVs inherited the natural homing ability of platelets to plaques and therapeutic effects of MSC-EVs. When injected into atherosclerotic mice, P-EVs were recruited to injured endothelium, then penetrated into plaques followed with endocytosis by inflammatory macrophages through the interaction between platelet membranes proteins and macrophages surface proteins. Subsequently, P-EVs delivered miRNAs into the cytoplasm of macrophages through lysosomal escape, which attenuated the progression of atherosclerosis eventually by switching the macrophage into anti-inflammatory phenotype, scavenging the overproduced ROS and reducing lipid deposition in lesional macrophages. In general, our study demonstrated the pro-resolving potential of P-EVs for targeted anti-inflammation therapy of atherosclerosis.

LncRNAs in Inflammation: Lessons From a Preclinical Investigation of Mexis Therapy in Atherosclerosis

LncRNAs in Inflammation: Lessons From a Preclinical Investigation of Mexis Therapy in Atherosclerosis

Overexpressed PKM2 promotes macrophage phagocytosis and atherosclerosis.

The expression of pyruvate kinase muscle 2 (PKM2) is augmented in macrophages of patients with atherosclerotic coronary artery disease. The role of PKM2 in atherosclerosis is to be determined. Global and myeloid cell-specific PKM2 knock-in mice with ApoE-/- background (ApoE-/- , PKM2KI/KI and Lyz2-cre, ApoE-/- , and PKM2flox/flox ) were produced to evaluate the clinical significance of PKM2 in atherosclerosis development. Wild-type and PKM2 knock-in macrophages were isolated to assess the function of PKM2 in macrophage phagocytosis. Atherosclerotic mice were treated with PKM2 inhibitor shikonin (SKN) to evaluate the therapeutic potential of PKM2 suppression in atherosclerosis. Oxidized low-density lipoprotein (oxLDL) upregulated PKM2 in macrophages. PKM2 in return promoted the uptake of oxLDL by macrophages. Overexpressed PKM2 accelerated atherosclerosis in mice. SKN blocked the progress of mouse atherosclerosis. PKM2 accelerates macrophage phagocytosis and atherosclerosis. Targeting PKM2 is a potential therapy for atherosclerosis.

Inhibiting vascular smooth muscle cell proliferation mediated by osteopontin via regulating gut microbial lipopolysaccharide: A novel mechanism for paeonol in atherosclerosis treatment.

Background: Although the gut microbiota is involved in metabolic disease such as atherosclerosis, the underlying mechanism remains elusive. Paeonol (Pae) is a natural phenolic compound isolated from Cortex Moutan, which exhibits anti-atherosclerotic effects. Our previous research demonstrated gut microbiota as a site of Pae action. However, the mechanism by which Pae exerts its anti-atherosclerotic effect by the regulation of gut microbiota remains unclear. Objective: To investigate a potential mechanistic link between the gut microbial lipopolysaccharide (LPS) and vascular smooth muscle cell (VSMC) proliferation in atherosclerosis progression and explore the possible role of Pae. Methods: Experimental atherosclerosis was established in ApoE-/- mice, and the atherosclerosis mice were treated with Pae for 4weeks before being sacrificed for analyses while conducting fecal microbiota transplantation (FMT). The plaque area, levels of serum LPS, expressions of inflammatory factors in serum or aorta, and intestinal barrier permeability were determined. VSMCs were co-cultured with THP-1 cells. CCK-8 assay and EdU staining were performed to assess the proliferative capacity of VSMCs. Immunofluorescence staining was performed to observe the nuclear transfer of p65. Western blotting was used to detect the candidate protein expression level, and quantitative real-time PCR (qRT-PCR) was used to detect the mRNA expression level in tissues or cells of each group. Results: During atherosclerosis progression, gut dysbiosis leads to the peripheral accumulation of gut microbial LPS, which acts as a trigger to stimulate osteopontin (OPN) production from circulating monocytes, inducing cell-to-cell crosstalk to promote VSMC proliferation in the aorta. Importantly, the elevation of LPS and OPN concentrations in the blood was also observed in patients with atherosclerosis. Pae could significantly improve atherosclerosis, suppress gut microbial LPS accumulation, and inhibit monocyte/macrophage activation and VSMC proliferation. Conclusions: The present study provides a mechanistic scenario for how long-term stimulation of gut microbial LPS in circulating blood generates a pathological secondary response that leads to abnormal proliferation of VSMCs using high OPN expression in circulating monocytes and suggests a novel strategy for atherosclerosis therapy by remodeling the gut microbiota.

MiR-99a-5p: A Potential New Therapy for Atherosclerosis by Targeting mTOR and Then Inhibiting NLRP3 Inflammasome Activation and Promoting Macrophage Autophagy.

Objective MicroRNAs have been revealed to be involved in the development of atherosclerosis. The present study is aimed at exploring the potential of miR-99a-5p as a therapy for atherosclerosis. We suspected that miR-99a-5p might inhibit NLRP3 inflammasome activation and promote macrophage autophagy via constraining mTOR, therefore, alleviating atherosclerosis. Methods The cell viability in ox-LDL-induced THP-1 macrophages was assessed by CCK-8 assay. Bioinformatic analysis was used to predict the target genes of miR-99a-5p. The binding between miR-99a-5p and mTOR was confirmed by luciferase reporter assay. In vivo, a high-fat-diet-induced atherosclerosis model was established in apolipoprotein E knockout mice. Hematoxylin-eosin, oil red O, and Sirius red staining were performed for the determination of atherosclerotic lesions. MTOR and associated protein levels were detected by Western blot analysis. Results miR-99a-5p inhibited NLRP3 inflammasome activation and promoted macrophage autophagy by targeting mTOR. Enforced miR-99a-5p significantly reduced the levels of inflammasome complex and inflammatory cytokines. Furthermore, miR-99a-5p overexpression inhibited the expression of mTOR, whereas mTOR overexpression reversed the trend of the above behaviors. In vivo, the specific overexpression of miR-99a-5p significantly reduced atherosclerotic lesions, accompanied by a significant downregulation of autophagy marker CD68 protein expression. Conclusion We demonstrated for the first time that miR-99a-5p may be considered a therapy for atherosclerosis. The present study has revealed that miR-99a-5p might inhibit NLRP3 inflammasome activation and promote macrophage autophagy by targeting mTOR, therefore, alleviating atherosclerosis.

An Ultrasound‐Responsive Theranostic Cyclodextrin‐Loaded Nanoparticle for Multimodal Imaging and Therapy for Atherosclerosis (Small 31/2022)

Atherosclerosis Imaging and Therapy In article number 2200967, Xiaowei Wang, Karlheinz Peter, and co-workers show that theranostic nanoparticles made of air can deliver a near-infrared fluorescence dye, cyclodextrin, to be used as a contrast agent for ultrasound and fluorescence imaging and as ultrasound-responsive anti-atherosclerotic drug, achieving reduction of cholesterol in plaques after ingestion of nanoparticle by monocytes/macrophages.