Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

2022

DOI: 10.1016/j.bbadis.2022.166450

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BMAL1 modulates smooth muscle cells phenotypic switch towards fibroblast-like cells and stabilizes atherosclerotic plaques by upregulating YAP1

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Cardiovascular Diseases Associated With Vsmcs Phenotypic Swi...1

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Circadian Rhythms Of Nonhematopoietic Cells Of the Cardiovas...1

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Cited by 17 publications

(12 citation statements)

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“…75 Gain-of-function studies in mouse endothelial cells and observations in human carotid plaques show that Bmal1 can inhibit atherosclerosis and promote plaque stability by suppressing oxLDL (oxidized-LDL) and ROS accumulation, 76 and in one study, treatment with recombinant Bmal1 decreased total cholesterol in PPARγ Deacetylation Inhibits Atherosclerosis in Aging mice. 77 In humans, Bmal1 is higher in stable plaques than in plaques more vulnerable to rupture, 78,79 and in our findings, plaque necrosis is significantly reduced. Necrotic tissue contributes to plaque instability in humans, and although plaque rupture does not occur in mice, 80 it is a notable observation that holds relevance to human atherosclerosis.…”

Section: Discussionsupporting

confidence: 65%

PPARγ (Peroxisome Proliferator-Activated Receptor γ) Deacetylation Suppresses Aging-Associated Atherosclerosis and Hypercholesterolemia

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Background: Atherosclerosis is a medical urgency manifesting at the onset of hypercholesterolemia and is associated with aging. Activation of PPARγ (peroxisome proliferator-activated receptor γ) counteracts metabolic dysfunction influenced by aging, and its deacetylation displays an atheroprotective property. Despite the marked increase of PPARγ acetylation during aging, it is unknown whether PPARγ acetylation is a pathogenic contributor to aging-associated atherosclerosis. Methods: Mice with constitutive deacetylation-mimetic PPARγ mutations on lysine residues K268 and K293 (2KR) in an LDL (low-density lipoprotein)-receptor knockout ( Ldlr −/− ) background ( 2KR:Ldlr −/− ) were aged for 18 months on a standard laboratory diet to examine the cardiometabolic phenotype, which was confirmed in Western-type diet–fed 2KR:Ldlr +/− mice. Whole-liver RNA-sequencing and in vitro studies in bone marrow–derived macrophages were conducted to decipher the mechanism. Results: In contrast to severe atherosclerosis in WT:Ldlr −/− mice, aged 2KR:Ldlr −/− mice developed little to no plaque, which was underlain by a significantly improved plasma lipid profile, with particular reductions in circulating LDL. The protection from hypercholesterolemia was recapitulated in Western-type diet–fed 2KR:Ldlr +/− mice. Liver RNA-sequencing analysis revealed suppression of liver inflammation rather than changes in cholesterol metabolism. This anti-inflammatory effect of 2KR was attributed to polarized M2 activation of macrophages. Additionally, the upregulation of core circadian component Bmal1, perceived to be involved in anti-inflammatory immunity, was observed in the liver and bone marrow–derived macrophages. Conclusions: PPARγ deacetylation in mice prevents the development of aging-associated atherosclerosis and hypercholesterolemia, in association with the anti-inflammatory phenotype of 2KR macrophages.

“…75 Gain-of-function studies in mouse endothelial cells and observations in human carotid plaques show that Bmal1 can inhibit atherosclerosis and promote plaque stability by suppressing oxLDL (oxidized-LDL) and ROS accumulation, 76 and in one study, treatment with recombinant Bmal1 decreased total cholesterol in PPARγ Deacetylation Inhibits Atherosclerosis in Aging mice. 77 In humans, Bmal1 is higher in stable plaques than in plaques more vulnerable to rupture, 78,79 and in our findings, plaque necrosis is significantly reduced. Necrotic tissue contributes to plaque instability in humans, and although plaque rupture does not occur in mice, 80 it is a notable observation that holds relevance to human atherosclerosis.…”

Section: Discussionsupporting

confidence: 65%

PPARγ (Peroxisome Proliferator-Activated Receptor γ) Deacetylation Suppresses Aging-Associated Atherosclerosis and Hypercholesterolemia

¹

,

²

,

³

et al. 2023

View full text Add to dashboard Cite

Background: Atherosclerosis is a medical urgency manifesting at the onset of hypercholesterolemia and is associated with aging. Activation of PPARγ (peroxisome proliferator-activated receptor γ) counteracts metabolic dysfunction influenced by aging, and its deacetylation displays an atheroprotective property. Despite the marked increase of PPARγ acetylation during aging, it is unknown whether PPARγ acetylation is a pathogenic contributor to aging-associated atherosclerosis. Methods: Mice with constitutive deacetylation-mimetic PPARγ mutations on lysine residues K268 and K293 (2KR) in an LDL (low-density lipoprotein)-receptor knockout ( Ldlr −/− ) background ( 2KR:Ldlr −/− ) were aged for 18 months on a standard laboratory diet to examine the cardiometabolic phenotype, which was confirmed in Western-type diet–fed 2KR:Ldlr +/− mice. Whole-liver RNA-sequencing and in vitro studies in bone marrow–derived macrophages were conducted to decipher the mechanism. Results: In contrast to severe atherosclerosis in WT:Ldlr −/− mice, aged 2KR:Ldlr −/− mice developed little to no plaque, which was underlain by a significantly improved plasma lipid profile, with particular reductions in circulating LDL. The protection from hypercholesterolemia was recapitulated in Western-type diet–fed 2KR:Ldlr +/− mice. Liver RNA-sequencing analysis revealed suppression of liver inflammation rather than changes in cholesterol metabolism. This anti-inflammatory effect of 2KR was attributed to polarized M2 activation of macrophages. Additionally, the upregulation of core circadian component Bmal1, perceived to be involved in anti-inflammatory immunity, was observed in the liver and bone marrow–derived macrophages. Conclusions: PPARγ deacetylation in mice prevents the development of aging-associated atherosclerosis and hypercholesterolemia, in association with the anti-inflammatory phenotype of 2KR macrophages.

“…BMAL1 is found at higher levels in unstable plaques in humans, accompanied by elevated YAP1 and the fibroblast marker FSP1. BMAL1 overexpression promotes the conversion of VSMCs to fibroblast-like cells by transcriptionally upregulating the expression of YAP1 [ 41 ]. A traditional Chinese medicine previously used to treat itchy skin, vertigo, and certain cardiovascular diseases, Furostanol saponins enriched extract (FSEE) of T. terrestris L., has been shown to inhibit the development of atherosclerosis and suppress the proliferation of VSMCs by inhibiting Akt/MEK/ERK signaling [ 42 ].…”

Section: Cardiovascular Diseases Associated With Vsmcs Phenotypic Swi...mentioning

confidence: 99%

Vascular Smooth Muscle Cells Phenotypic Switching in Cardiovascular Diseases

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Vascular smooth muscle cells (VSMCs), the major cell type in the arterial vessel wall, have a contractile phenotype that maintains the normal vessel structure and function under physiological conditions. In response to stress or vascular injury, contractile VSMCs can switch to a less differentiated state (synthetic phenotype) to acquire the proliferative, migratory, and synthetic capabilities for tissue reparation. Imbalances in VSMCs phenotypic switching can result in a variety of cardiovascular diseases, including atherosclerosis, in-stent restenosis, aortic aneurysms, and vascular calcification. It is very important to identify the molecular mechanisms regulating VSMCs phenotypic switching to prevent and treat cardiovascular diseases with high morbidity and mortality. However, the key molecular mechanisms and signaling pathways participating in VSMCs phenotypic switching have still not been fully elucidated despite long-term efforts by cardiovascular researchers. In this review, we provide an updated summary of the recent studies and systematic knowledge of VSMCs phenotypic switching in atherosclerosis, in-stent restenosis, aortic aneurysms, and vascular calcification, which may help guide future research and provide novel insights into the prevention and treatment of related diseases.

“…Interestingly, the circadian clock transcription factor BMAL1, which is essential for normal circadian variations in SMC contraction, was described to promote a phenotypic switch of SMCs towards fibroblast-like cells and to stabilize atherosclerotic plaques [ 90 ]. As shown in Figure S2 SPN, KLF4 and PKR are both under BMAL1 control [ 91 ].…”

Section: Resultsmentioning

confidence: 99%

Smooth Muscle Cell Phenotypic Switch Induced by Traditional Cigarette Smoke Condensate: A Holistic Overview

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Cigarette smoke (CS) is a risk factor for inflammatory diseases, such as atherosclerosis. CS condensate (CSC) contains lipophilic components that may represent a systemic cardiac risk factor. To better understand CSC effects, we incubated mouse and human aortic smooth muscle cells (SMCs) with CSC. We evaluated specific markers for contractile [i.e., actin, aortic smooth muscle (ACTA2), calponin-1 (CNN1), the Kruppel-like factor 4 (KLF4), and myocardin (MYOCD) genes] and inflammatory [i.e., IL-1β, and IL-6, IL-8, and galectin-3 (LGALS-3) genes] phenotypes. CSC increased the expression of inflammatory markers and reduced the contractile ones in both cell types, with KLF4 modulating the SMC phenotypic switch. Next, we performed a mass spectrometry-based differential proteomic approach on human SMCs and could show 11 proteins were significantly affected by exposition to CSC (FC ≥ 2.7, p ≤ 0.05). These proteins are active in signaling pathways related to expression of pro-inflammatory cytokines and IFN, inflammasome assembly and activation, cytoskeleton regulation and SMC contraction, mitochondrial integrity and cellular response to oxidative stress, proteostasis control via ubiquitination, and cell proliferation and epithelial-to-mesenchymal transition. Through specific bioinformatics resources, we showed their tight functional correlation in a close interaction niche mainly orchestrated by the interferon-induced double-stranded RNA-activated protein kinase (alternative name: protein kinase RNA-activated; PKR) (EIF2AK2/PKR). Finally, by combining gene expression and protein abundance data we obtained a hybrid network showing reciprocal integration of the CSC-deregulated factors and indicating KLF4 and PKR as the most relevant factors.

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