Dataset Information

Transforming Growth Factor-? Protects against Inflammation-Related Atherosclerosis in South African CKD Patients.

ABSTRACT: Background:Transforming growth factor-? (TGF-?) may inhibit the development of atherosclerosis. We evaluated serum levels of TGF-? isoforms concurrently with serum levels of endotoxin and various inflammatory markers. In addition, we determined if any association exists between polymorphisms in the TGF-?1 gene and atherosclerosis in South African CKD patients. Methods:We studied 120 CKD patients and 40 healthy controls. Serum TGF-?1, TGF-?2, TGF-?3, endotoxin, and inflammatory markers were measured. Functional polymorphisms in the TGF-?1 genes were genotyped using a polymerase chain reaction-sequence specific primer method and carotid intima media thickness (CIMT) was assessed by B-mode ultrasonography. Results:TGF-? isoforms levels were significantly lower in the patients with atherosclerosis compared to patients without atherosclerosis (p<0.001). Overall, TGF-? isoforms had inverse relationships with CIMT. TGF-?1 and TGF-?2 levels were significantly lower in patients with carotid plaque compared to those without carotid plaque [TGF-?1: 31.9 (17.2 - 42.2) versus 45.9 (35.4 - 58.1) ng/ml, p=0.016; and TGF-?2: 1.46 (1.30 - 1.57) versus 1.70 (1.50 - 1.87) ng/ml, p=0.013]. In multiple logistic regression, age, TGF-?2, and TGF-?3 were the only independent predictors of subclinical atherosclerosis in CKD patients [age: odds ratio (OR), 1.054; 95% confidence interval (CI): 1.003 - 1.109, p=0.039; TGF-?2: OR, 0.996; 95% CI: 0.994-0.999, p=0.018; TGF-?3: OR, 0.992; 95% CI: 0.985-0.999, p=0.029). TGF-?1 genotypes did not influence serum levels of TGF-?1 and no association was found between the TGF-?1 gene polymorphisms and atherosclerosis risk. Conclusion:TGF-? isoforms seem to offer protection against the development of atherosclerosis among South African CKD patients.

SUBMITTER: Hassan MO

PROVIDER: S-EPMC6011064 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Transforming Growth Factor-<i>β</i> Protects against Inflammation-Related Atherosclerosis in South African CKD Patients.

Hassan Muzamil Olamide MO Duarte Raquel R Dix-Peek Therese T Dickens Caroline C Naidoo Sagren S Vachiat Ahmed A Grinter Sacha S Manga Pravin P Naicker Saraladevi S

International journal of nephrology 20180606

<h4>Background</h4>Transforming growth factor-<i>β</i> (TGF-<i>β</i>) may inhibit the development of atherosclerosis. We evaluated serum levels of TGF-<i>β</i> isoforms concurrently with serum levels of endotoxin and various inflammatory markers. In addition, we determined if any association exists between polymorphisms in the <i>TGF-β1</i> gene and atherosclerosis in South African CKD patients.<h4>Methods</h4>We studied 120 CKD patients and 40 healthy controls. Serum TGF-<i>β</i>1, TGF-<i>β</i> ...[more]

PMID: 29977619

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Project description:Cholesterol biosynthetic intermediates, such as lanosterol and desmosterol, are emergent immune regulators of macrophages in response to inflammatory stimuli or lipid overloading, respectively. However, the participation of these sterols in regulating macrophage functions in the physiological context of atherosclerosis, an inflammatory disease driven by the accumulation of cholesterol-laden macrophages in the artery wall, has remained elusive. Here, we report that desmosterol, the most abundant cholesterol biosynthetic intermediate in human coronary artery lesions, plays an essential role during atherogenesis, serving as a key molecule integrating cholesterol homeostasis and immune responses in macrophages. Depletion of desmosterol in myeloid cells by overexpression of 3β-hydroxysterol Δ24-reductase (DHCR24), the enzyme that catalyzes conversion of desmosterol to cholesterol, promotes the progression of atherosclerosis. Single-cell transcriptomics in isolated CD45+CD11b+ cells from atherosclerotic plaques demonstrate that depletion of desmosterol increases interferon responses and attenuates the expression of antiinflammatory macrophage markers. Lipidomic and transcriptomic analysis of in vivo macrophage foam cells demonstrate that desmosterol is a major endogenous liver X receptor (LXR) ligand involved in LXR/retinoid X receptor (RXR) activation and thus macrophage foam cell formation. Decreased desmosterol accumulation in mitochondria promotes macrophage mitochondrial reactive oxygen species production and NLR family pyrin domain containing 3 (NLRP3)-dependent inflammasome activation. Deficiency of NLRP3 or apoptosis-associated speck-like protein containing a CARD (ASC) rescues the increased inflammasome activity and atherogenesis observed in desmosterol-depleted macrophages. Altogether, these findings underscore the critical function of desmosterol in the atherosclerotic plaque to dampen inflammation by integrating with macrophage cholesterol metabolism and inflammatory activation and protecting from disease progression.

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Dataset Information

Transforming Growth Factor-? Protects against Inflammation-Related Atherosclerosis in South African CKD Patients.

Publications

Transforming Growth Factor-<i>β</i> Protects against Inflammation-Related Atherosclerosis in South African CKD Patients.

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