Activation of liver X receptors with T0901317 attenuates cardiac hypertrophy <i>in vivo</i>

Kuipers, Irma; Li, Jiang; Vreeswijk-Baudoin, Inge; Koster, J.; Harst, Pim van der; Silljé, Herman H W; Kuipers, Folkert; Veldhuisen, Dirk J. van; Gilst, Wiek H. van; Boer, Rudolf A. de

doi:10.1093/eurjhf/hfq109

Cited by 37 publications

(37 citation statements)

References 33 publications

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“…To study the potential cardiac effects of NR1H3 , we created a transgenic mouse with cardiac-specific overexpression of NR1H3 under the control of the Myh6 promoter and found a diminished susceptibility to perturbations such as transverse aortic constriction and angiotensin II infusion that provoke cardiac hypertrophy (23). This observation is in line with protective effects due to treatment with T0901317, a synthetic NR1H3 agonist, in mice challenged with aortic constriction (24). These data highlight the importance of systematic approaches to identify causal genes beyond well-known candidates.…”

Section: Resultssupporting

confidence: 73%

52 Genetic Loci Influencing Myocardial Mass

Harst

Setten

Verweij

et al. 2016

Journal of the American College of Cardiology

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BACKGROUND Myocardial mass is a key determinant of cardiac muscle function and hypertrophy. Myocardial depolarization leading to cardiac muscle contraction is reflected by the amplitude and duration of the QRS complex on the electrocardiogram (ECG). Abnormal QRS amplitude or duration reflect changes in myocardial mass and conduction, and are associated with increased risk of heart failure and death. OBJECTIVES This meta-analysis sought to gain insights into the genetic determinants of myocardial mass. METHODS We carried out a genome-wide association meta-analysis of 4 QRS traits in up to 73,518 individuals of European ancestry, followed by extensive biological and functional assessment. RESULTS We identified 52 genomic loci, of which 32 are novel, that are reliably associated with 1 or more QRS phenotypes at p < 1 × 10−8. These loci are enriched in regions of open chromatin, histone modifications, and transcription factor binding, suggesting that they represent regions of the genome that are actively transcribed in the human heart. Pathway analyses provided evidence that these loci play a role in cardiac hypertrophy. We further highlighted 67 candidate genes at the identified loci that are preferentially expressed in cardiac tissue and associated with cardiac abnormalities in Drosophila melanogaster and Mus musculus. We validated the regulatory function of a novel variant in the SCN5A/SCN10A locus in vitro and in vivo. CONCLUSIONS Taken together, our findings provide new insights into genes and biological pathways controlling myocardial mass and may help identify novel therapeutic targets.

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Section: Resultssupporting

confidence: 73%

52 Genetic Loci Influencing Myocardial Mass

Harst

Setten

Verweij

et al. 2016

Journal of the American College of Cardiology

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120

123

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“…LV fractional shortening (FS %) was calculated as FS ϭ (LVIDd Ϫ LVIDs)/LVIDd ϫ 100%. LV ejection fraction (EF %) was calculated by using the Teichholz method of estimated LV volumes (20). Hemodynamic measurement.…”

Section: Methodsmentioning

confidence: 99%

Metformin improves cardiac function in a nondiabetic rat model of post-MI heart failure

Yin

Horst²,

Melle³

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Yin M, van der Horst IC, van Melle JP, Qian C, van Gilst WH, Silljé HH, de Boer RA. Metformin improves cardiac function in a nondiabetic rat model of post-MI heart failure. Am J Physiol Heart Circ Physiol 301: H459 -H468, 2011. First published May 13, 2011 doi:10.1152/ajpheart.00054.2011Metformin is the first choice drug for the treatment of patients with diabetes, but its use is debated in patients with advanced cardiorenal disease. Epidemiological data suggest that metformin may reduce cardiac events, in patients both with and without heart failure. Experimental evidence suggests that metformin reduces cardiac ischemia-reperfusion injury. It is unknown whether metformin improves cardiac function (remodeling) in a long-term post-MI remodeling model. We therefore studied male, nondiabetic, Sprague-Dawley rats that were subjected to either myocardial infarction (MI) or sham operation. Animals were randomly allocated to treatment with normal water or metformin-containing water (250 mg·kg Ϫ1 ·day Ϫ1 ). At baseline, 6 wk, and 12 wk, metabolic parameters were analyzed and oral glucose tolerance tests (OGTT) were performed. Echocardiography and hemodynamic parameters were assessed 12 wk after MI. In the MI model, infarct size was significantly smaller after 12-wk metformin treatment (29.6 Ϯ 3.2 vs. 38.0 Ϯ 2.2%, P Ͻ 0.05). Moreover, metformin resulted in less left ventricular dilatation (6.0 Ϯ 0.4 vs. 7.6 Ϯ 0.6 mm, P Ͻ 0.05) and preservation of left ventricular ejection fraction (65.8 Ϯ 3.7% vs. 48.6 Ϯ 5.6%, P Ͻ 0.05) compared with MI control. The improved cardiac function was associated with decreased atrial natriuretic peptide mRNA levels in the metformin-treated group (50% reduction compared with MI, P Ͻ 0.05). Insulin resistance did not occur during cardiac remodeling (as indicated by normal OGTT) and fasting glucose levels and the pattern of the OGTT were not affected by metformin. Molecular analyses suggested that altered AMP kinase phosphorylation status and low insulin levels mediate the salutary effects of metformin. Altogether our results indicate that metformin may have potential to attenuate heart failure development after myocardial infarction, in the absence of diabetes and independent of systemic glucose levels.

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“…LXR agonist treatment altered expression profiles of genes involved in lipid, cholesterol and carbohydrate metabolism not only in liver, but also in adrenal, kidney, lung and heart [9]. Kuipers et al [10] showed that like in other tissues, mRNA expression of specific target genes of LXR is increased in the heart of mice treated with T0901317, which means that LXR specific pathways are activated by T0901317 treatment in the myocardium.…”

Section: Disscusionmentioning

confidence: 99%

“…LXRβ is the dominant isoform in the heart of mice [2,5,8]. Stimulation of LXRs with T0901317 in mice causes an increase in cardiac expression of genes involved in lipid and cholesterol metabolism, such as sterol response element binding protein 1c (SREBP-1c), stearoyl-CoA desaturase 1 (SCD1), ATP-binding cassette transporters A1 and G1 (ABCA1, ABCG1), known LXR target genes [9,10]. In addition the LXR agonist GW3965 increased intracellular triglyceride level in murine heart and isolated cardiomyocytes [8].…”

Section: Introductionmentioning

confidence: 99%

LXR Agonist T0901317-Induced Hyperlipidemia Does Not Lead to Lipid Accumulation in the Rat Heart

Harasiuk¹,

Baranowski²,

Zabielski³

et al. 2015

Cell Physiol Biochem

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Background/Aims: Liver X receptors (LXRα and LXRβ) are ligand-activated transcription factors that regulate expression of genes involved in lipid and cholesterol metabolism. LXR expression has been identified in human and rodent cardiac tissue, however, its role in this tissue remains unclear. The aim of this study was to investigate effects of in vivo LXR activation on lipid metabolism in the rat myocardium under the conditions of low and high lipid intake. Methods: The experiments were performed on male Wistar rats fed for 5 weeks on either low fat diet (LFD) or high fat diet (HFD). Next, the animals were randomly divided into two groups receiving either LXR agonist - T0901317 (10mg/kg/d) or vehicle for the last week of the experiment. After anesthesia samples of the left ventricle and blood were taken. Results: It was found that LXRβ is the dominant isoform in the rat myocardium and the expression of both LXR isoforms did not change after administration of T0901317. Agonist treatment induced hyperlipidemia in low fat fed rats and this effect was amplified in high fat fed rats. LXR agonist elevated content of myocardial triacylglycerols in animals fed on LFD and content of phospholipids in animals fed on HFD. Levels of the remaining examined lipid classes (nonesterified fatty acids, diacylglycerol, free cholesterol, cholesterol esters, ceramide) was decreased or unchaged after LXR activation. Conclusion: We conclude that administration of T0901317 does not lead to severe myocardial lipid accumulation in rats despite of its high plasma availability.

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Activation of liver X receptors with T0901317 attenuates cardiac hypertrophy in vivo

Cited by 37 publications

References 33 publications

52 Genetic Loci Influencing Myocardial Mass

52 Genetic Loci Influencing Myocardial Mass

Metformin improves cardiac function in a nondiabetic rat model of post-MI heart failure

LXR Agonist T0901317-Induced Hyperlipidemia Does Not Lead to Lipid Accumulation in the Rat Heart

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