In:
Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 125, No. Suppl_1 ( 2019-08-02)
Abstract:
Objectives: ATGL is a key enzyme that regulates triglyceride lipolysis in most cells, including the adipocyte and the cardiomyocyte. Recent studies indicate that accelerated adipose tissue lipolysis contributes to worsening heart failure (HF), suggesting that ATGL inhibition specifically in the adipocyte may prevent worsening HF. Indeed, we have shown that the ATGL inhibitor, Atglistatin, which appears to be largely adipocyte-specific, ameliorates cardiac dysfunction and hypertrophy in HF induced by transverse aortic constriction (TAC). However, the mechanisms by which Atglistatin treatment prevents worsening HF in mice remains unknown. Methods: Eight week-old C57BL/6N mice underwent TAC or sham surgery. After 1 week, mice with HF were assigned into 4 groups: 1) vehicle (standard chow)-sham, 2) Atglistain-sham, 3) vehicle-TAC and 4) Atglistatin-TAC. Atglistain was administered in food pellets containing 2mmol Atglistatin/kg for 2 weeks. Thereafter, mice were euthanized and hearts were used for subsequent histological and quantitative PCR analysis. Results: Picro-sirius red staining demonstrated that hearts from the Atglistatin TAC mice had significantly less cardiac fibrosis than the vehicle TAC mice (1.6±0.4 vs 5.3±1.1%, in Atglistatin TAC vs vehicle TAC; p 〈 0.01). Consistent with this finding, Atglistatin treatment of the TAC group reduced transcript levels of fibrosis-related genes, including Col1a1 (-58.7%, p=0.03) and Postn (-54.7%, p 〈 0.01), compared to vehicle-treated hearts. Furthermore, Atglistatin decreased the transcript levels of the macrophage polarization-related genes, including Lgals3 (-55.3%, p 〈 0.01) and Spp1 (-38.7%, p=0.03) , in the hearts from TAC mice compared to controls. Moreover, immunofluorescent analysis showed that Atglistatin reduced infiltration of Galectin-3 positive macrophages in the heart compared to vehicle-TAC mice, suggesting reduced macrophage infiltration and activation and less cardiac fibrosis. Conclusion: Our data indicate that reducing triglyceride lipolysis in the adipose tissue via ATGL inhibition may ameliorate HF via modulation of HF-induced macrophage and fibroblast activation in the heart.
Type of Medium:
Online Resource
ISSN:
0009-7330
,
1524-4571
DOI:
10.1161/res.125.suppl_1.847
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2019
detail.hit.zdb_id:
1467838-X
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