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Liver X receptor agonist treatment attenuates cardiac dysfunction in type 2 diabetic db/db mice.

Abstract

BACKGROUND

Liver X receptor (LXR) plays a critical regulatory role in metabolism and inflammation, and has been demonstrated to be involved in cardiovascular physiology/pathology. In the present study, we investigated the effect of GW3965, a potent LXR agonist, on diabetic cardiomyopathy (DCM) in type 2 diabetic db/db mice.

METHODS AND RESULTS

Non-diabetic db/+ mice and diabetic db/db mice received either vehicle or LXR agonist GW3965 for 12 weeks. Systemic insulin resistance was evaluated by glucose tolerance test and homeostasis model assessment for insulin resistance. Endpoint cardiac function was assessed by echocardiography and catheterization. Ventricular tissue was collected for histology and gene/protein expression analysis. Untreated db/db diabetic mice exhibited diastolic dysfunction with adverse structural remodeling (including myocardial fibrosis and increased apoptosis). Treatment with GW3965 remarkably attenuated myocardial dysfunction and structural remodeling in diabetic db/db mice. Mechanistically, GW3965 restored Akt phosphorylation and inhibited MAP kinases phosphorylation, and reduced oxidative/nitrative stress and inflammation response in the diabetic myocardium.

CONCLUSIONS

Our data demonstrate that GW3965 exerts a cardioprotective effect against DCM by (at least in part) attenuating insulin resistance, modulating Akt and MAP kinases pathways, and reducing oxidative/nitrative stress and inflammatory response. These findings strongly suggest that LXR agonist may have therapeutic potential in treating DCM.

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  • Authors+Show Affiliations

    ,

    Department of Cardiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China. dr.heqing@gmail.com.

    ,

    Department of Cardiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China. pujun310@hotmail.com.

    ,

    Department of Cardiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China. yuanac@yahoo.com.cn.

    ,

    Department of Cardiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China. ytbnh@126.com.

    ,

    Department of Cardiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China. akoma78@hotmail.com.

    ,

    Department of Cardiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China. franky.superior@gmail.com.

    ,

    Department of Cardiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China. xulongwei1234321@163.com.

    ,

    Department of Cardiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China. travelh@163.com.

    Department of Cardiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China. heben1026@hotmail.com.

    Source

    Cardiovascular diabetology 13: 2014 Nov 22 pg 149

    MeSH

    Animals
    Apoptosis
    Benzoates
    Benzylamines
    Diabetes Mellitus, Experimental
    Diabetes Mellitus, Type 2
    Diabetic Cardiomyopathies
    Heart
    Insulin Resistance
    Liver X Receptors
    Male
    Mice
    Mice, Knockout
    Myocardium
    Orphan Nuclear Receptors
    Oxidative Stress

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    25416469

    Citation

    He, Qing, et al. "Liver X Receptor Agonist Treatment Attenuates Cardiac Dysfunction in Type 2 Diabetic Db/db Mice." Cardiovascular Diabetology, vol. 13, 2014, p. 149.
    He Q, Pu J, Yuan A, et al. Liver X receptor agonist treatment attenuates cardiac dysfunction in type 2 diabetic db/db mice. Cardiovasc Diabetol. 2014;13:149.
    He, Q., Pu, J., Yuan, A., Yao, T., Ying, X., Zhao, Y., ... He, B. (2014). Liver X receptor agonist treatment attenuates cardiac dysfunction in type 2 diabetic db/db mice. Cardiovascular Diabetology, 13, p. 149. doi:10.1186/s12933-014-0149-0.
    He Q, et al. Liver X Receptor Agonist Treatment Attenuates Cardiac Dysfunction in Type 2 Diabetic Db/db Mice. Cardiovasc Diabetol. 2014 Nov 22;13:149. PubMed PMID: 25416469.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Liver X receptor agonist treatment attenuates cardiac dysfunction in type 2 diabetic db/db mice. AU - He,Qing, AU - Pu,Jun, AU - Yuan,Ancai, AU - Yao,Tianbao, AU - Ying,Xiaoying, AU - Zhao,Yichao, AU - Xu,Longwei, AU - Tong,Huan, AU - He,Ben, Y1 - 2014/11/22/ PY - 2014/05/27/received PY - 2014/10/20/accepted PY - 2014/11/23/entrez PY - 2014/11/25/pubmed PY - 2015/7/28/medline SP - 149 EP - 149 JF - Cardiovascular diabetology JO - Cardiovasc Diabetol VL - 13 N2 - BACKGROUND: Liver X receptor (LXR) plays a critical regulatory role in metabolism and inflammation, and has been demonstrated to be involved in cardiovascular physiology/pathology. In the present study, we investigated the effect of GW3965, a potent LXR agonist, on diabetic cardiomyopathy (DCM) in type 2 diabetic db/db mice. METHODS AND RESULTS: Non-diabetic db/+ mice and diabetic db/db mice received either vehicle or LXR agonist GW3965 for 12 weeks. Systemic insulin resistance was evaluated by glucose tolerance test and homeostasis model assessment for insulin resistance. Endpoint cardiac function was assessed by echocardiography and catheterization. Ventricular tissue was collected for histology and gene/protein expression analysis. Untreated db/db diabetic mice exhibited diastolic dysfunction with adverse structural remodeling (including myocardial fibrosis and increased apoptosis). Treatment with GW3965 remarkably attenuated myocardial dysfunction and structural remodeling in diabetic db/db mice. Mechanistically, GW3965 restored Akt phosphorylation and inhibited MAP kinases phosphorylation, and reduced oxidative/nitrative stress and inflammation response in the diabetic myocardium. CONCLUSIONS: Our data demonstrate that GW3965 exerts a cardioprotective effect against DCM by (at least in part) attenuating insulin resistance, modulating Akt and MAP kinases pathways, and reducing oxidative/nitrative stress and inflammatory response. These findings strongly suggest that LXR agonist may have therapeutic potential in treating DCM. SN - 1475-2840 UR - https://www.unboundmedicine.com/medline/citation/25416469/Liver_X_receptor_agonist_treatment_attenuates_cardiac_dysfunction_in_type_2_diabetic_db/db_mice_ L2 - https://cardiab.biomedcentral.com/articles/10.1186/s12933-014-0149-0 DB - PRIME DP - Unbound Medicine ER -