Metformin, Macrophage Dysfunction and Atherosclerosis.
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ABSTRACT:
SUBMITTER: Feng X
PROVIDER: S-EPMC8215340 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Autophagy dysfunction in mouse atherosclerosis models has been associated with increased lipid accumulation, apoptosis and inflammation. Expression of cystatin C (CysC) is decreased in human atheroma, and CysC deficiency enhances atherosclerosis in mice. Here, we first investigated the association of autophagy and CysC expression levels with atheroma plaque severity in human atherosclerotic lesions. We found that autophagy proteins Atg5 and LC3? in advanced human carotid atherosclerotic lesions are decreased, while markers of dysfunctional autophagy p62/SQSTM1 and ubiquitin are increased together with elevated levels of lipid accumulation and apoptosis. The expressions of LC3? and Atg5 were positively associated with CysC expression. Second, we investigated whether CysC expression is involved in autophagy in atherosclerotic apoE-deficient mice, demonstrating that CysC deficiency (CysC(-/-) ) in these mice results in reduction of Atg5 and LC3? levels and induction of apoptosis. Third, macrophages isolated from CysC(-/-) mice displayed increased levels of p62/SQSTM1 and higher sensitivity to 7-oxysterol-mediated lysosomal membrane destabilization and apoptosis. Finally, CysC treatment minimized oxysterol-mediated cellular lipid accumulation. We conclude that autophagy dysfunction is a characteristic of advanced human atherosclerotic lesions and is associated with reduced levels of CysC. The deficiency of CysC causes autophagy dysfunction and apoptosis in macrophages and apoE-deficient mice. The results indicate that CysC plays an important regulatory role in combating cell death via the autophagic pathway in atherosclerosis.
| S-EPMC4988293 | biostudies-literature
Project description:Dysfunction in the macrophage lysosomal system including reduced acidity and diminished degradative capacity is a hallmark of atherosclerosis, leading to blunted clearance of excess cellular debris and lipids in plaques and contributing to lesion progression. Devising strategies to rescue this macrophage lysosomal dysfunction is a novel therapeutic measure. Nanoparticles have emerged as an effective platform to both target specific tissues and serve as drug delivery vehicles. In most cases, administered nanoparticles are taken up non-selectively by the mononuclear phagocyte system including monocytes/macrophages leading to the undesirable degradation of cargo in lysosomes. We took advantage of this default route to target macrophage lysosomes to rectify their acidity in disease states such as atherosclerosis. Herein, we develop and test two commonly used acidic nanoparticles, poly-lactide-co-glycolic acid (PLGA) and polylactic acid (PLA), both in vitro and in vivo. Our results in cultured macrophages indicate that the PLGA-based nanoparticles are the most effective at trafficking to and enhancing acidification of lysosomes. PLGA nanoparticles also provide functional benefits including enhanced lysosomal degradation, promotion of macroautophagy/autophagy and protein aggregate removal, and reduced apoptosis and inflammasome activation. We demonstrate the utility of this system in vivo, showing nanoparticle accumulation in, and lysosomal acidification of, macrophages in atherosclerotic plaques. Long-term administration of PLGA nanoparticles results in significant reductions in surrogates of plaque complexity with reduced apoptosis, necrotic core formation, and cytotoxic protein aggregates and increased fibrous cap formation. Taken together, our data support the use of acidic nanoparticles to rescue macrophage lysosomal dysfunction in the treatment of atherosclerosis.Abbreviations: BCA: brachiocephalic arteries; FACS: fluorescence activated cell sorting; FITC: fluorescein-5-isothiocyanatel; IL1B: interleukin 1 beta; LAMP: lysosomal associated membrane protein; LIPA/LAL: lipase A, lysosomal acid type; LSDs: lysosomal storage disorders; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MFI: mean fluorescence intensity; MPS: mononuclear phagocyte system; PEGHDE: polyethylene glycol hexadecyl ether; PLA: polylactic acid; PLGA: poly-lactide-co-glycolic acid; SQSTM1/p62: sequestosome 1.
| S-EPMC9980706 | biostudies-literature
Project description:PurposeHIV infection is consistently associated with an increased risk of atherosclerotic cardiovascular disease, but the underlying mechanisms remain elusive. HIV protein Tat, a transcriptional activator of HIV, has been shown to activate NF-κB signaling and promote inflammation in vitro. However, the atherogenic effects of HIV Tat have not been investigated in vivo. Macrophages are one of the major cell types involved in the initiation and progression of atherosclerosis. We and others have previously revealed the important role of IκB kinase β (IKKβ), a central inflammatory coordinator through activating NF-κB, in the regulation of macrophage functions and atherogenesis. This study investigated the impact of HIV Tat exposure on macrophage functions and atherogenesis.MethodsTo investigate the effects of Tat on macrophage IKKβ activation and atherosclerosis development in vivo, myeloid-specific IKKβ-deficient LDLR-deficient (IKKβΔMyeLDLR-/-) mice and their control littermates (IKKβF/FLDLR-/-) were exposed to recombinant HIV protein Tat.ResultsExposure to Tat significantly increased atherosclerotic lesion size and plaque vulnerability in IKKβF/FLDLR-/- but not IKKβΔMyeLDLR-/- mice. Deficiency of myeloid IKKβ attenuated Tat-elicited macrophage inflammatory responses and atherosclerotic lesional inflammation in IKKβΔMyeLDLR-/- mice. Further, RNAseq analysis demonstrated that HIV protein Tat affects the expression of many atherosclerosis-related genes in vitro in an IKKβ-dependent manner.ConclusionsOur findings reveal atherogenic effects of HIV protein Tat in vivo and demonstrate a pivotal role of myeloid IKKβ in Tat-driven atherogenesis.
| S-EPMC8286272 | biostudies-literature
Project description:Formation of foam cells is a hallmark at the initial stages of atherosclerosis. Monocytes attracted by pro-inflammatory stimuli attach to the inflamed vascular endothelium and penetrate to the arterial intima where they differentiate to macrophages. Intimal macrophages phagocytize oxidized low-density lipoproteins (oxLDL). Several scavenger receptors (SR), including CD36, SR-A1 and lectin-like oxLDL receptor-1 (LOX-1), mediate oxLDL uptake. In late endosomes/lysosomes of macrophages, oxLDL are catabolysed. Lysosomal acid lipase (LAL) hydrolyses cholesterol esters that are enriched in LDL to free cholesterol and free fatty acids. In the endoplasmic reticulum (ER), acyl coenzyme A: cholesterol acyltransferase-1 (ACAT1) in turn catalyses esterification of cholesterol to store cholesterol esters as lipid droplets in the ER of macrophages. Neutral cholesteryl ester hydrolases nCEH and NCEH1 are involved in a secondary hydrolysis of cholesterol esters to liberate free cholesterol that could be then out-flowed from macrophages by cholesterol ATP-binding cassette (ABC) transporters ABCA1 and ABCG1 and SR-BI. In atherosclerosis, disruption of lipid homoeostasis in macrophages leads to cholesterol accumulation and formation of foam cells.
| S-EPMC4717859 | biostudies-other
Project description:Accumulation of cholesteryl esters (CE) stored as cytoplasmic lipid droplets is the main characteristic of macrophage foam cells that are central to the development of atherosclerotic plaques. Since only unesterified or free cholesterol (FC) can be effluxed from the cells to extracellular cholesterol acceptors, hydrolysis of CE is the obligatory first step in CE mobilization from macrophages. This reaction, catalyzed by neutral cholesteryl ester hydrolase (CEH), is increasingly being recognized as the rate-limiting step in FC efflux. CEH, therefore, regulates the process of reverse cholesterol transport and ultimate elimination of cholesterol from the body. In this review, we summarize the earlier controversies surrounding the identity of CEH in macrophages, discuss the characteristics of the various candidates recognized to date and examine their role in mobilizing cellular CE and thus regulating atherogenesis. In addition, physiological requirements to hydrolyze lipid droplet-associated substrate and complexities of interfacial catalysis are also discussed to emphasize the importance of evaluating the biochemical characteristics of candidate enzymes that may be targeted in the future to attenuate atherosclerosis.
| S-EPMC2823947 | biostudies-literature
Project description:Although various types of drugs and therapies are available to treat atherosclerosis, it remains a major cause of mortality throughout the world. Macrophages are the major source of foam cells, which are hallmarks of atherosclerotic lesions. Consequently, the roles of macrophages in the pathophysiology of atherosclerosis are increasingly investigated. Autophagy is a self-protecting cellular catabolic pathway. Since its discovery, autophagy has been found to be associated with a variety of diseases, including cardiovascular diseases, malignant tumors, neurodegenerative diseases, and immune system disorders. Accumulating evidence demonstrates that autophagy plays an important role in inhibiting inflammation and apoptosis, and in promoting efferocytosis and cholesterol efflux. These facts suggest the induction of autophagy may be exploited as a potential strategy for the treatment of atherosclerosis. In this review we mainly discuss the relationship between macrophage autophagy and atherosclerosis and the molecular mechanisms, as well as the recent advances in targeting the process of autophagy to treat atherosclerosis.
| S-EPMC4753375 | biostudies-other
Project description:OBJECTIVE:Defective autophagy in macrophages leads to pathological processes that contribute to atherosclerosis, including impaired cholesterol metabolism and defective efferocytosis. Autophagy promotes the degradation of cytoplasmic components in lysosomes and plays a key role in the catabolism of stored lipids to maintain cellular homeostasis. microRNA-33 (miR-33) is a post-transcriptional regulator of genes involved in cholesterol homeostasis, yet the complete mechanisms by which miR-33 controls lipid metabolism are unknown. We investigated whether miR-33 targeting of autophagy contributes to its regulation of cholesterol homeostasis and atherogenesis. APPROACH AND RESULTS:Using coherent anti-Stokes Raman scattering microscopy, we show that miR-33 drives lipid droplet accumulation in macrophages, suggesting decreased lipolysis. Inhibition of neutral and lysosomal hydrolysis pathways revealed that miR-33 reduced cholesterol mobilization by a lysosomal-dependent mechanism, implicating repression of autophagy. Indeed, we show that miR-33 targets key autophagy regulators and effectors in macrophages to reduce lipid droplet catabolism, an essential process to generate free cholesterol for efflux. Notably, miR-33 regulation of autophagy lies upstream of its known effects on ABCA1 (ATP-binding cassette transporter A1)-dependent cholesterol efflux, as miR-33 inhibitors fail to increase efflux upon genetic or chemical inhibition of autophagy. Furthermore, we find that miR-33 inhibits apoptotic cell clearance via an autophagy-dependent mechanism. Macrophages treated with anti-miR-33 show increased efferocytosis, lysosomal biogenesis, and degradation of apoptotic material. Finally, we show that treating atherosclerotic Ldlr-/- mice with anti-miR-33 restores defective autophagy in macrophage foam cells and plaques and promotes apoptotic cell clearance to reduce plaque necrosis. CONCLUSIONS:Collectively, these data provide insight into the mechanisms by which miR-33 regulates cellular cholesterol homeostasis and atherosclerosis.
| S-EPMC5494696 | biostudies-literature
Project description:Background: Macrophage foam cells (FCs) play a crucial role in the initiation and progression of atherosclerosis. Reducing the formation or inducing the removal of FCs could ameliorate atherosclerosis. The present study examined whether the whole-cell vaccination using FCs could be used as novel prevention and treatment strategies to battle atherosclerosis. Methods: ApoE-/- mice with initial or established atherosclerosis were subcutaneously immunized three times with FCs in Freund's adjuvant. Results: Immunization with FCs resulted in an overt reduction of atherosclerotic lesion in the whole aorta and the aortic root with enhanced lesion stability. Subsequent study in mechanism showed that FCs vaccination dramatically increased CD4+ T cell and CD8+ T cell populations. Immunization with FCs significantly raised the plasma FCs-specific IgG antibodies. Of note, the FCs immune plasma could selectively recognize and bind to FC. FCs immune plasma significantly blocked the process of FCs formation, finally reduced the accumulation of FCs in plaque. Additionally, it was observed that FCs immunization down-regulated the expression level of atherosclerosis related pro-inflammatory cytokines, including IFN-γ, MCP-1, and IL-6 and enhanced the lesion stability with a significant increase in TGF-β1 level and collagen content. Conclusions: These findings demonstrate that the whole-cell vaccination using FCs significantly decreased lesion development and positively modulated lesion progression and stability by targeting FCs. The whole-cell FCs vaccine might represent a potential novel strategy for development of new antibodies and vaccines to the prevention or treatment of atherosclerosis.
| S-EPMC6335275 | biostudies-literature
Project description:Atherosclerosis is a chronic disorder of the vessel wall. One key regulator of disease progression is lipid handling in macrophages. However, the role of macrophage mitochondrial-dependent fatty acid β-oxidation (FAO) in atherosclerosis is not well defined. To address this, we focused on carnitine palmitoyltransferase (CPT) 1 and 2, which play an essential role in the transport of long chain fatty acids (FAs) into the mitochondria. Using conditional alleles of these mitochondrial enzymes, we have generated myeloid-specific Cpt1a and Cpt2 knockout mutants (CPT1a M-KO and CPT2 M-KO). In culture, macrophages derived from CPT1a and CPT2 M-KO mice have impaired FAO, enhanced expression of the CD36 scavenger receptor, increased uptake of oxidized low-density lipoprotein (oxLDL), and augmented transformation into cholesterol-rich foam cells. In line with these in vitro observations, in the atherosclerosis-susceptible apolipoprotein E (ApoE) KO background, CPT2 M-KO mice demonstrated augmented atherosclerosis, accompanied by increased accumulation of aortic macrophages with elevated CD36 expression. These data suggest that macrophage FAO is athero-protective and that augmenting FAO may potentially slow atherosclerotic progression.
| S-EPMC9124604 | biostudies-literature
Project description:Atherosclerosis is an inflammatory disease linked to elevated blood cholesterol concentrations. Despite ongoing advances in the prevention and treatment of atherosclerosis, cardiovascular disease remains the leading cause of death worldwide. Continuous retention of apolipoprotein B-containing lipoproteins in the subendothelial space causes a local overabundance of free cholesterol. Because cholesterol accumulation and deposition of cholesterol crystals (CCs) trigger a complex inflammatory response, we tested the efficacy of the cyclic oligosaccharide 2-hydroxypropyl-β-cyclodextrin (CD), a compound that increases cholesterol solubility in preventing and reversing atherosclerosis. We showed that CD treatment of murine atherosclerosis reduced atherosclerotic plaque size and CC load and promoted plaque regression even with a continued cholesterol-rich diet. Mechanistically, CD increased oxysterol production in both macrophages and human atherosclerotic plaques and promoted liver X receptor (LXR)-mediated transcriptional reprogramming to improve cholesterol efflux and exert anti-inflammatory effects. In vivo, this CD-mediated LXR agonism was required for the antiatherosclerotic and anti-inflammatory effects of CD as well as for augmented reverse cholesterol transport. Because CD treatment in humans is safe and CD beneficially affects key mechanisms of atherogenesis, it may therefore be used clinically to prevent or treat human atherosclerosis.
| S-EPMC4878149 | biostudies-literature