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Despite antiatherogenic metabolic characteristics, SCD1-deficient mice have increased inflammation and atherosclerosis.

ABSTRACT: OBJECTIVE:Absence of stearoyl-CoA desaturase-1 (SCD1) in mice reduces plasma triglycerides and provides protection from obesity and insulin resistance, which would be predicted to be associated with reduced susceptibility to atherosclerosis. The aim of this study was to determine the effect of SCD1 deficiency on atherosclerosis. METHODS AND RESULTS:Despite an antiatherogenic metabolic profile, SCD1 deficiency increases atherosclerosis in hyperlipidemic low-density lipoprotein receptor (LDLR)-deficient mice challenged with a Western diet. Lesion area at the aortic root is significantly increased in males and females in two models of SCD1 deficiency. Inflammatory changes are evident in the skin of these mice, including increased intercellular adhesion molecule (ICAM)-1 and ulcerative dermatitis. Increases in ICAM-1 and interleukin-6 are also evident in plasma of SCD1-deficient mice. HDL particles demonstrate changes associated with inflammation, including decreased plasma apoA-II and apoA-I and paraoxonase-1 and increased plasma serum amyloid A. Lipopolysaccharide-induced inflammatory response and cholesterol efflux are not altered in SCD1-deficient macrophages. In addition, when SCD1 deficiency is limited to bone marrow-derived cells, lesion size is not altered in LDLR-deficient mice. CONCLUSIONS:These studies reinforce the crucial role of chronic inflammation in promoting atherosclerosis, even in the presence of antiatherogenic biochemical and metabolic characteristics.

SUBMITTER: MacDonald ML

PROVIDER: S-EPMC2873333 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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Despite antiatherogenic metabolic characteristics, SCD1-deficient mice have increased inflammation and atherosclerosis.

MacDonald Marcia L E ML van Eck Miranda M Hildebrand Reeni B RB Wong Brian W C BW Bissada Nagat N Ruddle Piers P Kontush Anatol A Hussein Hala H Pouladi Mahmoud A MA Chapman M John MJ Fievet Catherine C van Berkel Theo J C TJ Staels Bart B McManus Bruce M BM Hayden Michael R MR

Arteriosclerosis, thrombosis, and vascular biology 20081218 3

<h4>Objective</h4>Absence of stearoyl-CoA desaturase-1 (SCD1) in mice reduces plasma triglycerides and provides protection from obesity and insulin resistance, which would be predicted to be associated with reduced susceptibility to atherosclerosis. The aim of this study was to determine the effect of SCD1 deficiency on atherosclerosis.<h4>Methods and results</h4>Despite an antiatherogenic metabolic profile, SCD1 deficiency increases atherosclerosis in hyperlipidemic low-density lipoprotein rece ...[more]

PMID: 19095997

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Project description:Fat inflammation may play an important role in comorbidities associated with obesity such as atherosclerosis.To first establish feasibility of fat transplantation, epididymal fat pads were harvested from wild-type C57BL/6J mice and transplanted into leptin-deficient (Lep(ob/ob)) mice. Fat transplantation produced physiological leptin levels and prevented obesity and infertility in Lep(ob/ob) mice. However, the transplanted fat depots were associated with chronically increased macrophage infiltration with characteristics identical to those observed in fat harvested from obese animals. The inflammation in transplanted adipose depots was regulated by the same factors that have been implicated in endogenous fat inflammation such as monocyte chemoattractant protein-1. To determine whether this inflamed adipose depot could affect vascular disease in mice, epididymal fat depots were transplanted into atherosclerosis-prone apolipoprotein E-deficient ApoE(-/-) mice. Plasma from ApoE(-/-) mice receiving fat transplants contained increased leptin, resistin, and monocyte chemoattractant protein-1 compared with plasma from sham-operated ApoE(-/-) mice. Furthermore, mice transplanted with visceral fat developed significantly more atherosclerosis compared with sham-operated animals, whereas transplants with subcutaneous fat did not affect atherosclerosis despite a similar degree of fat inflammation. Treatment of transplanted ApoE(-/-) mice with pioglitazone decreased macrophage content of the transplanted visceral fat pad and reduced plasma monocyte chemoattractant protein-1. Importantly, pioglitazone also reduced atherosclerosis triggered by inflammatory visceral fat but had no protective effect on atherosclerosis in the absence of the visceral fat transplantation.Our results indicate that visceral adipose-related inflammation accelerates atherosclerosis in mice. Drugs such as thiazolidinediones might be a useful strategy to specifically attenuate the vascular disease induced by visceral inflammatory fat.

Project description:Hyperhomocysteinemia (HHcy) has been shown to promote vascular inflammation and atherosclerosis, but the underlying mechanisms remain largely unknown. The NLRP3 inflammasome has been identified as the cellular machinery responsible for activation of inflammatory processes. In this study, we hypothesized that the activation of NLRP3 inflammasomes contributes to HHcy-induced inflammation and atherosclerosis. ApoE-/- mice were fed regular chow, high-fat (HF) diet, or HF plus high methionine diet to induce HHcy. To assess the role of NLRP3 inflammasomes in HHcy-aggravated atherosclerosis, NLRP3 shRNA viral suspension was injected via tail vein to knock down the NLRP3 gene. Increased plasma levels of IL-1β and IL-18, aggravated macrophage infiltration into atherosclerotic lesions, and accelerated development of atherosclerosis were detected in HHcy mice as compared with control mice, and were associated with the activation of NLRP3 inflammasomes. Silencing the NLRP3 gene significantly suppressed NLRP3 inflammasome activation, reduced plasma levels of proinflammatory cytokines, attenuated macrophage infiltration and improved HHcy-induced atherosclerosis. We also examined the effect of homocysteine (Hcy) on NLRP3 inflammasome activation in THP-1-differentiated macrophages in the presence or absence of NLRP3 siRNA or the caspase-1 inhibitor Z-WEHD-FMK. We found that Hcy activated NLRP3 inflammasomes and promoted subsequent production of IL-1β and IL-18 in macrophages, which were blocked by NLRP3 gene silencing or Z-WEHD-FMK. As reactive oxygen species (ROS) may have a central role in NLRP3 inflammasome activation, we next investigated whether antioxidant N-acetyl-l-cysteine (NAC) prevented Hcy-induced NLRP3 inflammasome activation in macrophages. We found Hcy-induced NLRP3 inflammasome activation was abolished by NAC. Treatment with NAC in HHcy mice also suppressed NLRP3 inflammasome activation and improved HHcy-induced atherosclerosis. These data suggest that the activation of NLRP3 inflammasomes contributes to HHcy-aggravated inflammation and atherosclerosis in apoE-/- mice. Hcy activates NLRP3 inflammasomes in ROS-dependent pathway in macrophages. These results may have implication for the treatment of HHcy-associated cardiovascular diseases.

Project description:RationaleThe NLRP3 (NLR [NOD-like receptor] family, pyrin domain containing 3) inflammasome is an important driver of atherosclerosis. Our previous study shows that chaperone-mediated autophagy (CMA), one of the main lysosomal degradative process, has a regulatory role in lipid metabolism of macrophages. However, whether the NLRP3 inflammasome is regulated by CMA, and the role of CMA in atherosclerosis remains unclear.ObjectiveTo determine the role of CMA in the regulation of NLRP3 inflammasome and atherosclerosis.Methods and resultsThe expression of CMA marker, LAMP-2A (lysosome-associated membrane protein type 2A), was first analyzed in ApoE-/- mouse aortas and human coronary atherosclerotic plaques, and a significant downregulation of LAMP-2A in advanced atherosclerosis in both mice and humans was observed. To selectively block CMA, we generated macrophage-specific conditional LAMP-2A knockout mouse strains in C57BL/6 mice and ApoE-/- mice. Deletion of macrophage LAMP-2A accelerated atherosclerotic lesion formation in the aortic root and the whole aorta in ApoE-/- mice. Mechanistically, LAMP-2A deficiency promoted NLRP3 inflammasome activation and subsequent release of mature IL (interleukin)-1β in macrophages and atherosclerotic plaques. Furthermore, gain-of-function studies verified that restoration of LAMP-2A levels in LAMP-2A-deficient macrophages greatly attenuated NLRP3 inflammasome activation. Importantly, we identified the NLRP3 protein as a CMA substrate and demonstrated that LAMP-2A deficiency did not affect the NLRP3 mRNA levels but hindered degradation of the NLRP3 protein through CMA pathway.ConclusionsCMA function becomes impaired during the progression of atherosclerosis, which increases NLRP3 inflammasome activation and secretion of IL-1β, promoting vascular inflammation and atherosclerosis progression. Our study unveils a new mechanism by which NLRP3 inflammasome is regulated in macrophages and atherosclerosis, thus providing a new insight into the role of autophagy-lysosomal pathway in atherosclerosis. Pharmacological activation of CMA may provide a novel therapeutic strategy for atherosclerosis and other NLRP3 inflammasome/IL-1β-driven diseases.

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Despite antiatherogenic metabolic characteristics, SCD1-deficient mice have increased inflammation and atherosclerosis.

Publications

Despite antiatherogenic metabolic characteristics, SCD1-deficient mice have increased inflammation and atherosclerosis.

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