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Liver X receptor agonist treatment attenuates cardiac dysfunction in type 2 diabetic db/db mice
Qing He1, Jun Pu2, Ancai Yuan3
1Department of Cardiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China. dr.heqing@gmail.com.
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.
Insights
This study shows that the Liver X receptor (LXR) agonist GW3965 protects against diabetic cardiomyopathy (DCM) by improving insulin resistance and reducing heart inflammation and stress.
Area of Science:
- Cardiovascular Biology
- Metabolic Disease Research
- Pharmacology
Background:
- Liver X receptor (LXR) is crucial in regulating metabolism and inflammation, impacting cardiovascular health.
- Diabetic cardiomyopathy (DCM) is a significant complication of type 2 diabetes.
- Investigating LXR's role in DCM is vital for therapeutic development.
Purpose of the Study:
- To determine the therapeutic effect of the LXR agonist GW3965 on diabetic cardiomyopathy (DCM).
- To evaluate GW3965's impact on cardiac function and structure in a type 2 diabetes mouse model.
Main Methods:
- Type 2 diabetic db/db mice and non-diabetic db/+ mice were treated with GW3965 or vehicle for 12 weeks.
- Cardiac function assessed via echocardiography and catheterization; insulin resistance evaluated using glucose tolerance tests.
- Myocardial tissue analyzed for structural remodeling, apoptosis, and molecular pathways (Akt, MAP kinases, oxidative stress, inflammation).
Main Results:
- Diabetic db/db mice showed diastolic dysfunction, fibrosis, and apoptosis.
- GW3965 treatment significantly improved cardiac function and reduced structural damage in diabetic mice.
- GW3965 normalized Akt phosphorylation, reduced MAP kinase activity, and decreased oxidative stress and inflammation in the diabetic heart.
Conclusions:
- GW3965 demonstrates significant cardioprotective effects against DCM.
- The protective mechanism involves improved insulin resistance, modulation of Akt/MAPK pathways, and reduced oxidative stress and inflammation.
- LXR agonists like GW3965 hold therapeutic promise for treating diabetic cardiomyopathy.
