scholarly journals Signaling Pathways and Key Genes Involved in Regulation of foam Cell Formation in Atherosclerosis

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 584 ◽  
Author(s):  
Anastasia V. Poznyak ◽  
Wei-Kai Wu ◽  
Alexandra A. Melnichenko ◽  
Reinhard Wetzker ◽  
Vasily Sukhorukov ◽  
...  
Keyword(s):  
Foam Cell ◽  
Low Density Lipoprotein ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cells ◽  
Foam Cell Formation ◽  
Beneficial Effects ◽  
Complex Process ◽  
Experimental Therapies ◽  
Inflammatory Drugs

Atherosclerosis is associated with acute cardiovascular conditions, such as ischemic heart disease, myocardial infarction, and stroke, and is the leading cause of morbidity and mortality worldwide. Our understanding of atherosclerosis and the processes triggering its initiation is constantly improving, and, during the last few decades, many pathological processes related to this disease have been investigated in detail. For example, atherosclerosis has been considered to be a chronic inflammation triggered by the injury of the arterial wall. However, recent works showed that atherogenesis is a more complex process involving not only the immune system, but also resident cells of the vessel wall, genetic factors, altered hemodynamics, and changes in lipid metabolism. In this review, we focus on foam cells that are crucial for atherosclerosis lesion formation. It has been demonstrated that the formation of foam cells is induced by modified low-density lipoprotein (LDL). The beneficial effects of the majority of therapeutic strategies with generalized action, such as the use of anti-inflammatory drugs or antioxidants, were not confirmed by clinical studies. However, the experimental therapies targeting certain stages of atherosclerosis, among which are lipid accumulation, were shown to be more effective. This emphasizes the relevance of future detailed investigation of atherogenesis and the importance of new therapies development.

scholarly journals Koala Biovar of Chlamydia pneumoniae Infects Human and Koala Monocytes and Induces Increased Uptake of Lipids In Vitro

2001 ◽  
Vol 69 (12) ◽  
pp. 7894-7897 ◽  
Author(s):  
Katie A. Coles ◽  
Peter Timms ◽  
David W. Smith
Keyword(s):  
Chlamydia Pneumoniae ◽  
Foam Cell ◽  
Low Density Lipoprotein ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cells ◽  
Foam Cell Formation ◽  
Low Density ◽  
Human Monocytes

ABSTRACT We examined the ability of the koala biovar of Chlamydia pneumoniae to infect both Hep-2 cells and human monocytes and the effect of infection on the formation of foam cells. The koala biovar produced large inclusions in both human and koala monocytes and in Hep-2 cells. Koala C. pneumoniae induced foam cell formation with and without added low-density lipoprotein, in contrast to TW183, which produced increased foam cell formation only in the presence of low-density lipoprotein.

scholarly journals Dihydrotestosterone Suppresses Foam Cell Formation and Attenuates Atherosclerosis Development

2010 ◽  
Vol 31 (3) ◽  
pp. 401-401
Author(s):  
Yang Qiu ◽  
Toshihiko Yanase ◽  
Haidi Hu ◽  
Tomoko Tanaka ◽  
Yoshihiro Nishi ◽  
...  
Keyword(s):  
Placebo Group ◽  
Foam Cell ◽  
Low Density Lipoprotein ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cells ◽  
Foam Cell Formation ◽  
Sham Operation ◽  
Low Density ◽  
Oxidized Low Density Lipoprotein

ABSTRACT The role of testosterone in atherosclerosis remains unclear because it is aromatized to estrogen. We investigated the effect of the nonaromatized natural androgen 5α-dihydrotestosterone (DHT) on the rabbit atherogenesis in relation to the proatherogenic molecule lectin-like oxidized-low-density lipoprotein receptor-1 (LOX-1) and its downstream molecules. Thirty-nine male New Zealand white rabbits were divided into four groups: 1) noncastrated group with normal chow diet (n = 6); 2) noncastrated group with high-cholesterol diet (HCD) (n = 10); 3) castrated group with HCD plus sc placebo pellet (n = 11); and 4) castrated group with HCD plus sc 150 mg DHT pellet (n = 12). Implantation of sc DHT or placebo pellet was performed at the time of castration. After castration or sham operation, the rabbits were fed the HCD for 8 wk, and plaque areas were assessed in the entire aorta. The HCD-induced increase in plaque area, which was most aggravated in the castration plus placebo group, was attenuated in the castration plus DHT group. Microscopic examination of the proximal descending aorta revealed that DHT significantly reduced HCD-induced foam cell formation, which was mostly composed of macrophages in the intima layer, compared with the placebo group. The decreased accumulation of foam cells with DHT treatment was accompanied by a marked reduction in the expression of LOX-1 mRNA in these cells. In cultured macrophages prepared from male wild-type mice that express the androgen receptor (AR), 1 × 10−8m and 1 × 10−9m DHT inhibited the formation of foam cells induced by oxidized low-density lipoprotein. Moreover, the expression of LOX-1 and inflammatory cytokines in the cultured macrophages was significantly suppressed by DHT. Such suppressive effects of DHT on foam cell formation and cytokine expression were not observed in cultured macrophages prepared from male AR-null mice, suggesting an involvement of AR in the mechanism. In conclusion, physiological levels of DHT attenuated the development of atherosclerosis in rabbits through the suppression of intimal foam cell formation of macrophage partly via the suppression of LOX-1 expression.

scholarly journals Dihydrotestosterone Suppresses Foam Cell Formation and Attenuates Atherosclerosis Development

Endocrinology ◽  
2010 ◽  
Vol 151 (7) ◽  
pp. 3307-3316 ◽  
Author(s):  
Yang Qiu ◽  
Toshihiko Yanase ◽  
Haidi Hu ◽  
Tomoko Tanaka ◽  
Yoshihiro Nishi ◽  
...  
Keyword(s):  
Placebo Group ◽  
Foam Cell ◽  
Low Density Lipoprotein ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cells ◽  
Foam Cell Formation ◽  
Sham Operation ◽  
Low Density ◽  
Oxidized Low Density Lipoprotein

The role of testosterone in atherosclerosis remains unclear because it is aromatized to estrogen. We investigated the effect of the nonaromatized natural androgen 5α-dihydrotestosterone (DHT) on the rabbit atherogenesis in relation to the proatherogenic molecule lectin-like oxidized-low-density lipoprotein receptor-1 (LOX-1) and its downstream molecules. Thirty-nine male New Zealand white rabbits were divided into four groups: 1) noncastrated group with normal chow diet (n = 6); 2) noncastrated group with high-cholesterol diet (HCD) (n = 10); 3) castrated group with HCD plus sc placebo pellet (n = 11); and 4) castrated group with HCD plus sc 150 mg DHT pellet (n = 12). Implantation of sc DHT or placebo pellet was performed at the time of castration. After castration or sham operation, the rabbits were fed the HCD for 8 wk, and plaque areas were assessed in the entire aorta. The HCD-induced increase in plaque area, which was most aggravated in the castration plus placebo group, was attenuated in the castration plus DHT group. Microscopic examination of the proximal descending aorta revealed that DHT significantly reduced HCD-induced foam cell formation, which was mostly composed of macrophages in the intima layer, compared with the placebo group. The decreased accumulation of foam cells with DHT treatment was accompanied by a marked reduction in the expression of LOX-1 mRNA in these cells. In cultured macrophages prepared from male wild-type mice that express the androgen receptor (AR), 1 × 10−8m and 1 × 10−9m DHT inhibited the formation of foam cells induced by oxidized low-density lipoprotein. Moreover, the expression of LOX-1 and inflammatory cytokines in the cultured macrophages was significantly suppressed by DHT. Such suppressive effects of DHT on foam cell formation and cytokine expression were not observed in cultured macrophages prepared from male AR-null mice, suggesting an involvement of AR in the mechanism. In conclusion, physiological levels of DHT attenuated the development of atherosclerosis in rabbits through the suppression of intimal foam cell formation of macrophage partly via the suppression of LOX-1 expression.

Abstract 306: Deficiency of ROCK1 in Macrophages Protects Against Atherosclerosis

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Hong-Wei Wang ◽  
Naotsugu Oyama ◽  
Yoshiyuki Rikitake ◽  
Shiro Kitamoto ◽  
Jonathan Gitlin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Foam Cell ◽  
Vascular Inflammation ◽  
Low Density Lipoprotein ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cells ◽  
Foam Cell Formation ◽  
Low Density ◽  
Lipid Uptake

Background: Rho kinases (ROCKs) are serine-threonine protein kinases that regulate various cellular functions. There is increasing evidence that the RhoA/ROCK pathway plays an important pathophysiological role in cardiovascular diseases. However, direct evidence of which ROCK isoforms or target tissues are involved in the atherogenic process is still lacking. Objective: The aim of this study was to determine the effect of ROCK1 deficiency on atherogenesis and how ROCK1 affects key atherosclerosis-related macrophage function such as lipid uptake and chemotaxis. Methods: We utilized ROCK1 −/− mice and the atherosclerosis-prone apolipoprotein E knockout (apoE −/− ) mice or low-density lipoprotein receptor knockout (LDLR −/− ) mice to investigate the role of ROCK1 in the pathogenesis of atherosclerotic plaque formation. Bone marrow-derived macrophages from ROCK1 −/− and ROCK1 +/+ mice were used to investigate acetylated (Ac)LDL-mediated foam cell formation and chemotaxis. Results: Compared to atherosclerosis-prone apoE −/− mice, apoE −/− ROCK1 +/− mice had substantially less fatty streaks foam cells and atherosclerosis (77.0 ± 12.9 × 10 3 μm 2 versus 166.4 ± 14.6 × 10 3 μm 2 , P < 0.01). Atherosclerotic lesions were reduced also in LDLR −/− mice, whose bone marrow were replaced with bone marrow derived from ROCK1 −/− mice compared to ROCK1 +/+ recipients (181.5 ± 15.6 × 10 3 μm 2 versus 448.5 ± 33.3 × 10 3 μm 2 , P < 0.05). Bone marrow-derived ROCK1-deficient macrophages exhibited impaired chemotaxis to monocyte chemotactic protein-1 and showed reduced ability to take up lipids and to develop into foam cells when exposed to modified low density lipoprotein. Conclusion: These findings indicate that ROCK1 in macrophages is a critical mediator of foam cell formation, macrophage chemotaxis and atherogenesis, and suggest that macrophage ROCK1 may be an important therapeutic target for vascular inflammation and atherosclerosis.

scholarly journals Naoxintong Retards Atherosclerosis by Inhibiting Foam Cell Formation Through Activating Pparα Pathway

2019 ◽  
Vol 18 (10) ◽  
pp. 698-710 ◽  
Author(s):  
Zeng Wang ◽  
Huairui Shi ◽  
Huan Zhao ◽  
Zhen Dong ◽  
Buchang Zhao ◽  
...  
Keyword(s):  
Cholesterol Efflux ◽  
Foam Cell ◽  
Low Density Lipoprotein ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cell Formation ◽  
Oxidized Low Density Lipoprotein ◽  
Beneficial Effects ◽  
Cell Accumulation ◽  
Ldl Uptake

Background: We recently reported that Naoxintong (NXT), a China Food and Drug Administration (FDA)-approved cardiac medicine, could reduce the plaque size, but the underlying mechanism remains elusive now. Objective: In this study, we investigated the effects of NXT on foam cell accumulation both in vivo and in vitro and explored related mechanisms. Method: THP-1 cells and bone marrow-derived macrophages were incubated with oxidized low-density lipoprotein (ox-LDL) with/without Naoxintong. ApoE-/- mice fed an atherogenic diet were administered to receive NXT for eight weeks. Macrophage-derived foam cell formation in plaques was measured by immunohistochemical staining. Expression of proteins was evaluated by Western blot. Lentivirus was used to knockdown PPARα in THP-1 cells. Results: After NXT treatment, foam cell accumulation was significantly reduced in atherosclerotic plaques. Further investigation revealed that oxidized low-density lipoprotein (ox-LDL) uptake was significantly decreased and expression of scavenger receptor class A (SR-A) and class B (SR-B and CD36) was significantly downregulated post-NXT treatment. On the other hand, NXT increased cholesterol efflux and upregulated ATP-binding cassette (ABC) transporters (ABCA-1 and ABCG-1) in macrophages. Above beneficial effects of NXT were partly abolished after lentiviral knockdown of PPARα. Conclusion: Our findings suggest that NXT could retard atherosclerosis by inhibiting foam cell formation through reducing ox-LDL uptake and enhancing cholesterol efflux and above beneficial effects are partly mediated through PPARα pathway.

ClC-3: A Novel Promising Therapeutic Target for Atherosclerosis

2021 ◽  
pp. 107424842110236
Author(s):  
Dun Niu ◽  
Lanfang Li ◽  
Zhizhong Xie
Keyword(s):  
Therapeutic Target ◽  
Chloride Channels ◽  
Foam Cell ◽  
Low Density Lipoprotein ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Molecular Structures ◽  
Foam Cell Formation ◽  
Endothelium Dysfunction ◽  
Atherosclerotic Process

Chloride channel 3 (ClC-3), a Cl−/H+ antiporter, has been well established as a member of volume-regulated chloride channels (VRCCs). ClC-3 may be a crucial mediator for activating inflammation-associated signaling pathways by regulating protein phosphorylation. A growing number of studies have indicated that ClC-3 overexpression plays a crucial role in mediating increased plasma low-density lipoprotein levels, vascular endothelium dysfunction, pro-inflammatory activation of macrophages, hyper-proliferation and hyper-migration of vascular smooth muscle cells (VSMCs), as well as oxidative stress and foam cell formation, which are the main factors responsible for atherosclerotic plaque formation in the arterial wall. In the present review, we summarize the molecular structures and classical functions of ClC-3. We further discuss its emerging role in the atherosclerotic process. In conclusion, we explore the potential role of ClC-3 as a therapeutic target for atherosclerosis.

scholarly journals Protective Effect of Lusianthridin on Hemin-Induced Low-Density Lipoprotein Oxidation

2021 ◽  
Vol 14 (6) ◽  
pp. 567
Author(s):  
Su Wutyi Thant ◽  
Noppawan Phumala Morales ◽  
Visarut Buranasudja ◽  
Boonchoo Sritularak ◽  
Rataya Luechapudiporn
Keyword(s):  
Foam Cell ◽  
Low Density Lipoprotein ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cell Formation ◽  
Raw 264.7 ◽  
Low Density ◽  
Lipoprotein Oxidation ◽  
Raw 264.7 Macrophage Cells ◽  
Low Density Lipoprotein Oxidation

Oxidation of low-density lipoprotein (LDL) plays a crucial role in the pathogenesis of atherosclerosis. Hemin (iron (III)-protoporphyrin IX) is a degradation product of hemoglobin that can be found in thalassemia patients. Hemin is a strong oxidant that can cause LDL oxidation and contributes to atherosclerosis in thalassemia patients. Lusianthridin from Dendrobium venustrum is a phenolic compound that possesses antioxidant activity. Hence, lusianthridin could be a promising compound to be used against hemin-induced oxidative stress. The major goal of this study is to evaluate the protective effect of lusianthridin on hemin-induced low-density lipoprotein oxidation (he-oxLDL). Here, various concentrations of lusianthridin (0.25, 0.5, 1, and 2 µM) were preincubated with LDL for 30 min, then 5 µM of hemin was added to initiate the oxidation, and oxidative parameters were measured at various times of incubation (0, 1, 3, 6, 12, 24 h). Lipid peroxidation of LDL was measured by thiobarbituric reactive substance (TBARs) assay and relative electrophoretic mobility (REM). The lipid composition of LDL was analyzed by using reverse-phase HPLC. Foam cell formation with he-oxLDL in RAW 264.7 macrophage cells was detected by Oil Red O staining. The results indicated that lusianthridin could inhibit TBARs formation, decrease REM, decrease oxidized lipid products, as well as preserve the level of cholesteryl arachidonate and cholesteryl linoleate. Moreover, He-oxLDL incubated with lusianthridin for 24 h can reduce the foam cell formation in RAW 264.7 macrophage cells. Taken together, lusianthridin could be a potential agent to be used to prevent atherosclerosis in thalassemia patients.

Abstract 3691: Deletion of Suppressor Of Cytokine Signaling-1 in a Murine Model of Atherosclerosis Results in a Lethal Systemic Inflammation

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Christina Grothusen ◽  
Harald Schuett ◽  
Stefan Lumpe ◽  
Andre Bleich ◽  
Silke Glage ◽  
...  
Keyword(s):  
Foam Cell ◽  
Low Density Lipoprotein ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cell Formation ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
The Impact

Introduction: Atherosclerosis is a chronic inflammatory disease of the cardiovascular system which may result in myocardial infarction and sudden cardiac death. While the role of pro-inflammatory signaling pathways in atherogenesis has been well characterized, the impact of their negative regulators, e.g. suppressor of cytokine signaling (SOCS)-1 remains to be elucidated. Deficiency of SOCS-1 leads to death 3 weeks post-partum due to an overwhelming inflammation caused by an uncontrolled signalling of interferon-gamma (IFNγ). This phenotype can be rescued by generating recombination activating gene (rag)-2, SOCS-1 double knock out (KO) mice lacking mature lymphocytes, the major source of IFNγ. Since the role of SOCS-1 during atherogenesis is unknown, we investigated the impact of a systemic SOCS-1 deficiency in the low-density lipoprotein receptor (ldlr) KO model of atherosclerosis. Material and Methods: socs-1 −/− /rag-2 −/− deficient mice were crossed with ldlr-KO animals. Mice were kept under sterile conditions on a normal chow diet. For in-vitro analyses, murine socs-1 −/− macrophages were stimulated with native low density lipoprotein (nLDL) or oxidized (ox)LDL. SOCS-1 expression was determined by quantitative PCR and western blot. Foam cell formation was determined by Oil red O staining. Results: socs-1 −/− /rag-2 −/− /ldlr −/− mice were born according to mendelian law. Tripel-KO mice showed a reduced weight and size, were more sensitive to bacterial infections and died within 120 days (N=17). Histological analyses revealed a systemic, necrotic, inflammation in Tripel-KO mice. All other genotypes developed no phenotype. In-vitro observations revealed that SOCS-1 mRNA and protein is upregulated in response to stimulation with oxLDL but not with nLDL. Foam cell formation of socs-1 −/− macrophages was increased compared to controls. Conclusion: SOCS-1 seemingly controls critical steps of atherogenesis by modulating foam cell formation in response to stimulation with oxLDL. SOCS-1 deficiency in the ldlr-KO mouse leads to a lethal inflammation. These observations suggest a critical role for SOCS-1 in the regulation of early inflammatory responses in atherogenesis.

scholarly journals Epac1 regulates cellular SUMOylation by promoting the formation of SUMO-activating nuclear condensates

2022 ◽  
Author(s):  
Wenli Yang ◽  
William G Robichaux ◽  
Fang C Mei ◽  
Wel Lin ◽  
Li Li ◽  
...  
Keyword(s):  
Molecular Mechanism ◽  
Stress Responses ◽  
Foam Cell ◽  
Low Density Lipoprotein ◽  
Cellular Stress ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cell Formation ◽  
Intracellular Camp ◽  
Protein Sumoylation

Protein SUMOylation plays an essential role in maintaining cellular homeostasis when cells are under stress. However, precisely how SUMOylation is regulated, and a molecular mechanism linking cellular stress to SUMOylation remains elusive. Herein, we report that cAMP, a major stress-response second messenger, acts through Epac1 as a regulator of cellular SUMOylation. The Epac1-associated proteome is highly enriched with components of the SUMOylation pathway. Activation of Epac1 by intracellular cAMP triggers phase separation and the formation of nuclear condensates containing Epac1 and general components of the SUMOylation machinery to promote cellular SUMOylation. Furthermore, genetic knockout of Epac1 obliterates oxidized low-density lipoprotein induced cellular SUMOylation in macrophages, leading to suppression of foam cell formation. These results provide a direct nexus connecting two major cellular stress responses to define a molecular mechanism in which cAMP regulates the dynamics of cellular condensates to modulate protein SUMOylation.

Sign in / Sign up

Export Citation Format

Share Document