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Stat3? mitigates development of atherosclerosis in apolipoprotein E-deficient mice.

ABSTRACT: The transcription factor Stat3 is an activator of systemic inflammatory genes. Two isoforms of Stat3 are generated by alternative splicing, Stat3? and Stat3?. The ? isoform lacks the transactivation domain but retains other functions, including dimerization and DNA binding. Stat3?-deficient mice exhibit elevated expression of systemic inflammatory genes and are hyperresponsive to lipopolysaccharide, suggesting that Stat3? functions predominantly as a suppressor of systemic inflammation. To test whether Stat3? deficiency would provoke pathologic effects associated with chronic inflammation, we asked whether selective removal of Stat3? would exacerbate the development of atherosclerosis in apolipoprotein E-deficient mice. In apoE(-/-)Stat3?(-/-) mice atherosclerotic plaque formation was significantly enhanced relative to apoE(-/-)Stat3?(+/+) controls. The ability of Stat3? deficiency to promote atherosclerosis was more pronounced in female mice, but could be unmasked in males by feeding a high fat diet. Infiltrating macrophages were not increased in aortas of apoE(-/-)Stat3?(-/-) mice. In contrast, the proportion of pro-inflammatory TH17 cells was significantly elevated in aortic infiltrates from apoE(-/-)Stat3?(-/-) mice, relative to paired apoE(-/-)Stat3?(+/+) littermates. These observations indicate that Stat3? can suppress pathologic sequelae associated with chronic inflammation. Our findings further suggest that in Stat3?-deficient mice the unopposed action of Stat3? may enhance atherogenesis in part by promoting differentiation of TH17 cells.

SUBMITTER: Lee J

PROVIDER: S-EPMC3739303 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Stat3β mitigates development of atherosclerosis in apolipoprotein E-deficient mice.

Lee Jihyun J Baldwin William M WM Lee Chih-Yuan CY Desiderio Stephen S

Journal of molecular medicine (Berlin, Germany) 20130426 8

The transcription factor Stat3 is an activator of systemic inflammatory genes. Two isoforms of Stat3 are generated by alternative splicing, Stat3α and Stat3β. The β isoform lacks the transactivation domain but retains other functions, including dimerization and DNA binding. Stat3β-deficient mice exhibit elevated expression of systemic inflammatory genes and are hyperresponsive to lipopolysaccharide, suggesting that Stat3β functions predominantly as a suppressor of systemic inflammation. To test ...[more]

PMID: 23619910

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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.

Dataset Information

Stat3? mitigates development of atherosclerosis in apolipoprotein E-deficient mice.

Publications

Stat3β mitigates development of atherosclerosis in apolipoprotein E-deficient mice.

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