Transdifferentiation of mouse aortic smooth muscle cells to a macrophage-like state after cholesterol loading

Rong, James X.; Shapiro, Mark S.; Trogan, Eugene; Fisher, Edward A.

doi:10.1073/pnas.1735526100

Cited by 435 publications

(461 citation statements)

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“…Regulation of progenitor cell differentiation is a complex process, dependent on numerous hormones, growth factors, and specific activation of a cascade of gene expression [42,[46][47][48][49][50][51].Critical regulators of adipocyte differentiation include C/EBPα (CCAAT/enhancer binding protein), PPARγ2 (peroxisome proliferator-activated receptor), and LPL (lipoprotein lipase) [47,48,[52][53][54][55][56][57]. Alternatively, transdifferentiation of smooth muscle cells into other phenotypes may occur [58][59][60][61]. Inhibition of 5α-reductase activity induces stromal remodeling and smooth muscle dedifferentiation in the prostate, suggesting that 5α-DHT deficiency promotes smooth muscle dedifferentiation [62].…”

Section: Testosterone Regulates Cellular Growth and Differentiationmentioning

confidence: 99%

Testosterone and Erectile Function: From Basic Research to a New Clinical Paradigm for Managing Men with Androgen Insufficiency and Erectile Dysfunction

2007

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Objectives-Androgens are essential for the development and growth of the penis, and they regulate erectile physiology by multiple mechanisms. Our goal is to provide a concise overview of the basic research and how this knowledge can be translated into a new clinical paradigm for patient management. In addition, this new paradigm may serve as a basis for stimulating constructive debate regarding the use of testosterone in men, and to promote new, innovative basic and clinical research to further understand the underlying mechanisms of androgen action in restoring erectile physiology. Methods-A literature review was performed utilizing the US National Library of Medicine's PubMed database.Results-On the basis of evidence derived from laboratory animal studies and clinical data, we postulate that androgen insufficiency disrupts cellular-signaling pathways and produces pathologic alterations in penile tissues, leading to erectile dysfunction. In this review, we discuss androgendependent cellular, molecular, and physiologic mechanisms modulating erectile function in the animal model, and the implication of this knowledge in testosterone use in the clinical setting to treat erectile dysfunction. The new clinical paradigm incorporates many of the consensed points of view discussed in traditional consensed algorithms exclusively designed for men with androgen insufficiency. There are, however, novel and innovative differences with this new clinical paradigm. This paradigm represents a fresh effort to provide mandatory and optional management strategies for men with both androgen insufficiency and erectile dysfunction. Conclusions-The new clinical paradigm is evidence-based and represents one of the first attempts to address a logical management plan for men with concomitant hormonal and sexual health concerns.

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Section: Testosterone Regulates Cellular Growth and Differentiationmentioning

confidence: 99%

Testosterone and Erectile Function: From Basic Research to a New Clinical Paradigm for Managing Men with Androgen Insufficiency and Erectile Dysfunction

2007

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“…Excessive cholesterol accumulation in cells leads to the formation of foam cells, which is one of the hallmarks of atherosclerotic plaques within the arterial wall. In a previous study [31] , we successfully established a foam cell model by using 10 μg/mL Chol:MβCD, which is "water-soluble cholesterol" containing approximately 50 mg of cholesterol per g of solid (molar ratio, 1:6 cholesterol:MβCD) that delivers cholesterol rapidly and directly to the plasma membrane [32] . Using Oil Red O staining, we determined the morphological changes in cells after incubation of VSMC with Chol:MβCD in the absence or presence of 3 μmol/L ezetimibe for 72 h. Our results showed that ezetimibe treatment dramatically reduced cellular lipid accumulation in VSMCs treated with Chol:MβCD (Figure 1).…”

Section: Resultsmentioning

confidence: 99%

Ezetimibe suppresses cholesterol accumulation in lipid-loaded vascular smooth muscle cells in vitro via MAPK signaling

Qin

Yang

et al. 2014

Acta Pharmacol Sin

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Aim: To investigate the mechanisms of anti-atherosclerotic action of ezetimibe in rat vascular smooth muscle cells (VSMCs) in vitro. Methods: VSMCs of SD rats were cultured in the presence of Chol:MβCD (10 μg/mL) for 72 h, and intracellular lipid droplets and cholesterol levels were evaluated using Oil Red O staining, HPLC and Enzymatic Fluorescence Assay, respectively. The expression of caveolin-1, sterol response element-binding protein-1 (SREBP-1) and ERK1/2 were analyzed using Western blot assays. Translocation of SREBP-1 and ERK1/2 was detected with immunofluorescence. Results: Treatment with Chol:MβCD dramatically increased the cellular levels of total cholesterol (TC), cholesterol ester (CE) and free cholesterol (FC) in VSMCs, which led to the formation of foam cells. Furthermore, Chol:MβCD treatment significantly decreased the expression of caveolin-1, and stimulated the expression and nuclear translocation of SREBP-1 in VSMCs. Co-treatment with ezetimibe (3 μmol/L) significantly decreased the cellular levels of TC, CE and FC, which was accompanied by elevation of caveolin-1 expression, and by a reduction of SREBP-1 expression and nuclear translocation. Co-treatment with ezetimibe dose-dependently decreased the expression of phosphor-ERK1/2 (p-ERK1/2) in VSMCs. The ERK1/2 inhibitor PD98059 (50 μmol/L) altered the cholesterol level and the expression of p-ERK1/2, SREBP-1 and caveolin-1 in the same manner as ezetimibe did. Conclusion: Ezetimibe suppresses cholesterol accumulation in rat VSMCs in vitro by regulating SREBP-1 and caveolin-1 expression, possibly via the MAPK signaling pathway.

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“…The cells were then loaded with FC/cyclodextrin (Sigma) (molar ratio, 1:6 cholesterol/M␤CD), 20 g/ml, in serum-free media. After 24 h of loading, cells were equilibrated for 12 h and then fixed in 4% paraformaldehyde in PBS and stained with Oil Red O (Sigma) for neutral lipids (24).…”

Section: Methodsmentioning

confidence: 99%

Rat Carboxylesterase ES-4 Enzyme Functions as a Major Hepatic Neutral Cholesteryl Ester Hydrolase

Parathath

Doğan

Joaquin

et al. 2011

Journal of Biological Chemistry

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Although esterification of free cholesterol to cholesteryl ester in the liver is known to be catalyzed by the enzyme acyl-coenzyme A:cholesterol acyltransferase, ACAT, the neutral cholesteryl ester hydrolase (nCEH) that catalyzes the reverse reaction has remained elusive. Because cholesterol undergoes continuous cycling between free and esterified forms, the steady-state concentrations in the liver of the two species and their metabolic availability for pathways, such as lipoprotein assembly and bile acid synthesis, depend upon nCEH activity. On the basis of the general characteristics of the family of rat carboxylesterases, we hypothesized that one member, ES-4, was a promising candidate as a hepatic nCEH. Using under-and overexpression approaches, we provide multiple lines of evidence that establish ES-4 as a bona fide endogenous nCEH that can account for the majority of cholesteryl ester hydrolysis in transformed rat hepatic cells and primary rat hepatocytes.Cytosolic cholesterol pools are in a dynamic state of turnover between the free (FC) 2 and esterified forms (CE) (1-3). The identification of the enzyme(s) in the liver that catalyzes the hydrolysis of CE at neutral pH has been elusive. In contrast, the CE that enters cells as part of apoB-containing lipoproteins through receptor-or heparan sulfate proteoglycan-mediated uptake is known to be hydrolyzed by lysosomal acid lipase, with the ensuing FC available to enter various cellular pools. A fraction of the FC trafficked to the endoplasmic reticulum (ER) is esterified by isoforms of acyl-coenzyme A:cholesterol acyltransferase (ACAT). When potentially cytotoxic levels of FC are reached, there is a significant increase in the formation of CE, which is then stored in cytosolic lipid droplets (4, 5).In the liver, CE is a component of very low density lipoproteins (VLDL). The source of CE can be either direct (i.e. synthesized completely in the ER membrane) or indirect through hydrolysis of cytosolic CE and re-esterification of FC by ACAT (6, 7). FC can also become part of VLDL, and, as in all cells, FC resulting from CE hydrolysis can be effluxed to HDL or used in the synthesis of other molecules. In liver, a major fate of FC is its conversion to bile acids and oxysterols. The interconversion between the non-lysosomal cellular pools of FC and CE in the liver is under metabolic regulation, with the key enzymatic components attributed to ACAT and neutral cholesteryl ester hydrolases (nCEHs) (8 -12).The explicit identification of nCEHs in the liver has been elusive. Ghosh and colleagues (13) have recently reported a human macrophage nCEH active in foam cells in atherosclerotic plaques that was related to a previously studied enzyme proposed as a rat hepatic nCEH (14). The latter was cloned from rat liver, and, when overexpressed in COS cells, the lysates exhibited nCEH activity against exogenously provided CE (14). However, whether this candidate operates as a nCEH under physiological conditions in hepatic cells has never been established. Another candidate that...

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Transdifferentiation of mouse aortic smooth muscle cells to a macrophage-like state after cholesterol loading

Cited by 435 publications

References 40 publications

Testosterone and Erectile Function: From Basic Research to a New Clinical Paradigm for Managing Men with Androgen Insufficiency and Erectile Dysfunction

Testosterone and Erectile Function: From Basic Research to a New Clinical Paradigm for Managing Men with Androgen Insufficiency and Erectile Dysfunction

Ezetimibe suppresses cholesterol accumulation in lipid-loaded vascular smooth muscle cells in vitro via MAPK signaling

Rat Carboxylesterase ES-4 Enzyme Functions as a Major Hepatic Neutral Cholesteryl Ester Hydrolase

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