Synthetic liver X receptor agonist T0901317 attenuates high glucose-induced oxidative stress, mitochondrial damage and apoptosis in cardiomyocytes

Cheng, Yi; Feng, Yukuan; Zhu, Min; Yan, Bin; Fu, Songbin; Guo, Jin; Hu, Jing; Song, Xiandong; Guo, Shu; Liu, Guibo

doi:10.1016/j.acthis.2013.07.007

Cited by 14 publications

(10 citation statements)

References 36 publications

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“…In the myocardium, the expression of LXRα was increased in streptozotocin-induced diabetic rats [ 28 ]. LXR agonist T0901317 attenuated high glucose-induced cardiomyocyte apoptosis in vitro [ 12 ] . However, the role of LXR in DCM in vivo remains unknown.…”

Section: Discussionmentioning

confidence: 99%

“…Two synthetic LXR agonists, GW3965 and T0901317, have been reported to prevent atherosclerosis, inhibit inflammation, attenuate myocardial hypertrophy, and reduce ischemia/reperfusion injury [ 7 - 11 ]. Moreover, activation of LXR by T0901317 mitigates high glucose-induced oxidative stress, and apoptosis in cardiomyocytes in vitro [ 12 ] . However, the potential of LXR activation to attenuate the structural and functional defects caused by DCM in vivo have not been investigated.…”

Section: Introductionmentioning

confidence: 99%

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

Yuan

et al. 2014

Cardiovasc Diabetol

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BackgroundLiver 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 ResultsNon-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.ConclusionsOur 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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Yuan

et al. 2014

Cardiovasc Diabetol

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“…LXRs have also been shown to regulate cell survival through inhibition of ROS production and oxidative stress [ 47 , 121 ], as well as prevent apoptosis induced by hyperglycemia [ 24 ] and diabetes [ 52 ]. Interestingly, the anti-apoptotic factor AIM, also known as apoptosis inhibitor 6 or Spα, is a direct target gene for regulation by LXRα [ 62 ], which serves to protect macrophages from the apoptotic effects of oxidized lipids.…”

Section: Local Cardiac Effects For Lxrsmentioning

confidence: 99%

Emerging role of liver X receptors in cardiac pathophysiology and heart failure

2015

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Liver X receptors (LXRs) are master regulators of metabolism and have been studied for their pharmacological potential in vascular and metabolic disease. Besides their established role in metabolic homeostasis and disease, there is mounting evidence to suggest that LXRs may exert direct beneficial effects in the heart. Here, we aim to provide a conceptual framework to explain the broad mode of action of LXRs and how LXR signaling may be an important local and systemic target for the treatment of heart failure. We discuss the potential role of LXRs in systemic conditions associated with heart failure, such as hypertension, diabetes, and renal and vascular disease. Further, we expound on recent data that implicate a direct role for LXR activation in the heart, for its impact on cardiomyocyte damage and loss due to ischemia, and effects on cardiac hypertrophy, fibrosis, and myocardial metabolism. Taken together, the accumulating evidence supports the notion that LXRs may represent a novel therapeutic target for the treatment of heart failure.

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“…LXRs have also been shown to regulate cell survival through inhibition of ROS production and oxidative stress 33, 34 , as well as prevent apoptosis induced by hyperglycemia 35 and diabetes 21 . Our study also examined ROS expression change after LXR activation, but no stable results were obtained (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Activation of LXRα improves cardiac remodeling induced by pulmonary artery hypertension in rats

Gong

Yang

et al. 2017

Sci Rep

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Inflammatory factors regulated by NF-κB play a significant role in PAH and myocardial hypertrophy. LXR activation may inhibit myocardial hypertrophy via suppressing inflammatory pathways; it is unknown whether LXR is also involved in PAH-induced myocardial hypertrophy or remodeling. To further explore the protective effect of LXR in PAH-induced cardiac hypertrophy and remodeling, a PAH model was developed, and T0901317, an agonist of LXR, was used to examine the effect of LXR activation. PAH rats demonstrated obvious cardiac hypertrophy and remodeling in the right ventricle, but significant improvement of cardiac hypertrophy and remodeling was observed in PAH rats treated with T0901317. Through RT-PCR, Western blot and ELISA examination, NF-κB, IL-6, TNF-α, and iNOS were found to be significantly reduced in PAH rats treated with T0901317 compared to PAH rats treated with DMSO. Apoptosis was also significantly reduced in PAH rats treated with T0901317. Thus, LXR activation may inhibit PAH-induced cardiac hypertrophy and remodeling by inhibiting NF-κB-mediated inflammatory pathways.

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Synthetic liver X receptor agonist T0901317 attenuates high glucose-induced oxidative stress, mitochondrial damage and apoptosis in cardiomyocytes

Cited by 14 publications

References 36 publications

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

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

Emerging role of liver X receptors in cardiac pathophysiology and heart failure

Activation of LXRα improves cardiac remodeling induced by pulmonary artery hypertension in rats

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