Atorvastatin Protects Vascular Smooth Muscle Cells From TGF-�1-Stimulated Calcification by Inducing Autophagy via Suppression of the �-Catenin Pathway

Liu, Demin; Cui, Wei; Liu, Bin; Hu, Haijuan; Liu, Jing; Xie, Ruiqin; Yang, Xiaohong; Gu, Guoqiang; Zhang, Jidong; Zheng, Hongmei

doi:10.1159/000356656

Cited by 97 publications

(72 citation statements)

References 42 publications

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“…HE indicates hematoxylin and eosin; and mTOR, mammalian target of rapamycin. Downloaded from http://ahajournals.org by on September 3, 2018 February 2, 2018 Also, Liu et al 35 demonstrated that atorvastatin attenuates vascular smooth muscle cell calcification by inducing autophagy, which is in good correspondence with our own results on the effects of miR-100 on endothelial autophagy.…”

Section: Discussionsupporting

confidence: 89%

MicroRNA-100 Suppresses Chronic Vascular Inflammation by Stimulation of Endothelial Autophagy

Pankratz

Hohnloser

Bemtgen

et al. 2018

Circulation Research

101

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Many attempts to modulate leukocyte-endothelial interaction to prevent or reduce excessive inflammatory reactions were made in the past. However, the basic regulatory principles of the endothelial inflammatory process remain unclear. It seems that the inhibition of individual components of the inflammatory cascade, for example, by a single antibody against an adhesion molecule, may not be enough to achieve a sustained effect on vascular inflammation.In the past years, microRNAs have been identified as important regulators of gene expression in a wide range of Molecular Medicine© 2017 American Heart Association, Inc. Rationale:The interaction of circulating cells within the vascular wall is a critical event in chronic inflammatory processes, such as atherosclerosis, but the control of the vascular inflammatory state is still largely unclear.Objective: This study was undertaken to characterize the function of the endothelial-enriched microRNA miR-100 during vascular inflammation and atherogenesis. Methods and Results:Based on a transcriptome analysis of endothelial cells after miR-100 overexpression, we identified miR-100 as a potent suppressor of endothelial adhesion molecule expression, resulting in attenuated leukocyte-endothelial interaction in vitro and in vivo as shown by flow cytometry and intravital imaging. Mechanistically, miR-100 directly repressed several components of mammalian target of rapamycin complex 1-signaling, including mammalian target of rapamycin and raptor, which resulted in a stimulation of endothelial autophagy and attenuated nuclear factor κB signaling in vitro and in vivo. In a low-density lipoprotein receptordeficient atherosclerotic mouse model, pharmacological inhibition of miR-100 resulted in enhanced plaque lesion formation and a higher macrophage content of the plaque, whereas a systemic miR-100 replacement therapy had protective effects and attenuated atherogenesis, resulting in a decrease of plaque area by 45%. Finally, analysis of miR-100 expression in >70 samples obtained during carotid endarterectomy revealed that local miR-100 expression was inversely correlated with inflammatory cell content in patients. Conclusions: In summary, we describe an anti-inflammatory function of miR-100 in the vascular response to injury and inflammation and identify an important novel modulator of mammalian target of rapamycin signaling and autophagy

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Section: Discussionsupporting

confidence: 89%

MicroRNA-100 Suppresses Chronic Vascular Inflammation by Stimulation of Endothelial Autophagy

Pankratz

Hohnloser

Bemtgen

et al. 2018

Circulation Research

101

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“…Atorvastatin, initially used as a modulator of hypercholesterolemia, has been recently associated with different functions, such as protection against microvascular damage, antifibrotic and anticalcifying effects; in addition, it exhibits antioxidant properties if administered in high doses for the pretreatment of lesions of the myocardium in heart failure, renal disease and abdominal surgery (35)(36)(37). These functions are due to the effect of this drug on populations of mononuclear cells, for example the subpopulations of TCD4 + lymphocytes in reciprocity with or independent from the population of cells of the mononuclear system, such as tissue macrophages, Kupffer cells in the liver, microglial cells in the central nervous system and mucosal dendritic cells (38)(39)(40).…”

Section: Discussionmentioning

confidence: 99%

Atorvastatin and trans-caryophyllene for the prevention of leukopenia in an experimental chemotherapy model in Wistar rats

Campos

Vieira

Campos

et al. 2015

Molecular and Clinical Oncology

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Abstract. Malignant neoplasia represents the second cause of disease-related mortality and, among all patients diagnosed with cancer, 70% will receive chemotherapy during the course of treatment. As a consequence, an increasing number of researchers have focused their attention on the search for more specific anticancer therapies associated with fewer side effects. Leukopenia is an important adverse effect associated with chemotherapy. Secondary infection is very common among leukopenic patients, directly affecting the continuity of the chemotherapeutic treatment and leading to possible complications in tumor immune defense. Atorvastatin, a type of statin, is a known agent used to control hypercholesterolemia. Trans-caryophyllene, isolated from a resinous oil extracted from the Copaiba tree, possesses anti-inflammatory and analgesic properties. The aim of the present study was to evaluate, through a complete leukocyte count, the systemic immunomodulation potential of pentoxifylline (PTX), atorvastatin and trans-caryophyllene, as well as the possible prophylactic role of these drugs against secondary leukopenia, in an experimental chemotherapy model induced by 5-fluorouracil (5-FU) in Wistar rats. A total of 32 male Wistar rats were used, 24 of which were submitted to treatment with atorvastatin, PTX and trans-caryophyllene prior to the administration of chemotherapy. The Shapiro-Wilk test was used to verify normality and the Kruskal-Wallis test was used for negative data in the normality test. Among the drugs selected, atorvastatin exhibited the best preventive potential in regards to leukopenia secondary to experimental chemotherapy induced by 5-FU, in comparison to the group receiving saline solution, while PTX amplified such alterations in the leukograms of the animals in this trial.

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“…Finally, it worthwhile to mention that statins, such as simvastatin and atorvastatin, have pleiotropic effects, including the induction of autophagy, that are well beyond their lipid-lowering properties. 110,111 For other autophagy-inducing drugs, a link between autophagy induction and the prevention (or amelioration) of vascular disease is less obvious. For example, resveratrol is a polyphenol present in red wine that attenuates endothelial inflammation by inducing autophagy in an mTOR-independent way via several key molecules, including cAMP, AMPK, and sirtuin 1.…”

Section: Systemic Administration Of Rapamycin and Rapalogsmentioning

confidence: 99%

Autophagy in Vascular Disease

Meyer

Grootaert

Michiels

et al. 2015

Circulation Research

253

179

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A utophagy is a complex intracellular process that delivers cytoplasmic constituents for degradation into lysosomes.1,2 Three main types of autophagy have been described: (1) microautophagy, comprising direct engulfment of cytoplasmic material by lysosomes via inward invaginations of the lysosomal membrane, (2) macroautophagy, characterized by formation of double-membrane sequestering compartments termed autophagosomes that fuse with lysosomes for delivery of cytoplasmic cargo, and (3) chaperone-mediated autophagy, mediated by a chaperone complex and lysosomal-associated membrane protein type 2A to degrade cytosolic proteins with a specific targeting motif. The term autophagy usually refers to macroautophagy, which is the most prevalent and beststudied form of autophagy. Also in this review, we will focus exclusively on macroautophagy, further cited as autophagy.Autophagy occurs at basal levels in most tissues to allow constitutive turnover of cytosolic components but is stimulated by environmental stress-related signals (eg, nutrient deprivation and oxidative injury) to recycle nutrients and to generate energy for maintenance of cell viability in unfavorable conditions.1 In addition to cellular stress, basal autophagy can be intensified by specific drugs, 3 indicating that the autophagic machinery is a potential therapeutic target for diverse diseases. Indeed, given that autophagy is involved in the prevention

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Atorvastatin Protects Vascular Smooth Muscle Cells From TGF-�1-Stimulated Calcification by Inducing Autophagy via Suppression of the �-Catenin Pathway

Cited by 97 publications

References 42 publications

MicroRNA-100 Suppresses Chronic Vascular Inflammation by Stimulation of Endothelial Autophagy

MicroRNA-100 Suppresses Chronic Vascular Inflammation by Stimulation of Endothelial Autophagy

Atorvastatin and trans-caryophyllene for the prevention of leukopenia in an experimental chemotherapy model in Wistar rats

Autophagy in Vascular Disease

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