The thyroid receptor β modulator GC-1 reduces atherosclerosis in ApoE deficient mice

Kannisto, Kristina; Rehnmark, Stefan; Slätis, Katharina; Webb, Paul; Larsson, Lars-Olof; Gåfvels, Mats; Eggertsen, Gösta; Parini, Paolo

doi:10.1016/j.atherosclerosis.2014.09.035

Cited by 17 publications

(14 citation statements)

References 37 publications

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“…Nevertheless, impaired relaxation has been observed previously in mice expressing a mutant TRβ (Owen et al 2007), and blocking TRβ in mesenteric arteries inhibited the T3-induced nongenomic vasodilation (Zloh et al 2016). Taken together, these findings suggest that activation of TRβ might be beneficial for aortic stiffness, a notion that is supported by reports that the TRβ-selective agonist GC-1 delays the onset of atherosclerosis in ApoE-deficient mice (Kannisto et al 2014). Interestingly, however, the transporter SLC10A1, which seems to be required for GC-1 uptake (Kersseboom et al 2017), was below the expression level threshold in our microarray study.…”

Section: Role Of Th Receptor βsupporting

confidence: 79%

Aortic effects of thyroid hormone in male mice

Gachkar

Nock

Geißler

et al. 2019

Journal of Molecular Endocrinology

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It is well established that thyroid hormones are required for cardiovascular functions; however, the molecular mechanisms remain incompletely understood, especially the individual contributions of genomic and non-genomic signalling pathways. In this study, we dissected how thyroid hormones modulate aortic contractility. To test the immediate effects of thyroid hormones on vasocontractility, we used a wire myograph to record the contractile response of dissected mouse aortas to the adrenergic agonist phenylephrine in the presence of different doses of T3 (3,3′,5-triiodothyronine). Interestingly, we observed reduced vasoconstriction under low and high T3 concentrations, indicating an inversed U-shaped curve with maximal constrictive capacity at euthyroid conditions. We then tested for possible genomic actions of thyroid hormones on vasocontractility by treating mice for 4 days with 1 mg/L thyroxine in drinking water. The study revealed that in contrast to the non-genomic actions the aortas of these animals were hyperresponsive to the contractile stimulus, an effect not observed in endogenously hyperthyroid TRβ knockout mice. To identify targets of genomic thyroid hormone action, we analysed aortic gene expression by microarray, revealing several altered genes including the well-known thyroid hormone target gene hairless. Taken together, the findings demonstrate that thyroid hormones regulate aortic tone through genomic and non-genomic actions, although genomic actions seem to prevail in vivo. Moreover, we identified several novel thyroid hormone target genes that could provide a better understanding of the molecular changes occurring in the hyperthyroid aorta.

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Section: Role Of Th Receptor βsupporting

confidence: 79%

Aortic effects of thyroid hormone in male mice

Gachkar

Nock

Geißler

et al. 2019

Journal of Molecular Endocrinology

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“…The selective TRβ modulator GC-1 enhances several steps in reverse cholesterol transport and reduces serum cholesterol independently of LDL-R. In a study aiming to determine whether GC-1 reduces atherosclerosis and the mechanisms that are involved, apoE-deficient mice were fed an atherogenic diet ± GC-1 ( 87 ). GC-1 reduced cholesteryl esters in the aorta after 20 weeks.…”

Section: Thyromimetics and Lipidsmentioning

confidence: 99%

A Renewed Focus on the Association Between Thyroid Hormones and Lipid Metabolism

2018

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Thyroid dysfunction, manifesting as either overt or subclinical hypothyroidism, negatively affects lipid metabolism: this leads to hypercholesterolemia which progressively increases the risk for cardiovascular disease and, potentially, mortality. Hypercholesterolemia in hypothyroidism is mainly due to a reduction in low-density lipoprotein (LDL) receptor activity, this accompanied by concomitant diminishing control by triiodothyronine (T3) of sterol regulatory element-binding protein 2 (SREBP-2), which modulates cholesterol biosynthesis by regulating rate-limit degrading enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA) activity. Recently, 3,5-diiodothyronine (T2), a natural thyroid hormone derivative, was found to repress the transcription factor carbohydrate-response element-binding protein (ChREBP) and also to be involved in lipid catabolism and lipogenesis, though via a different pathway than that of T3. While thyroid hormone could therapeutically reverse the dyslipidemic profile commonly occurring in hypothyroidism, it should be borne in mind that the potency of the effects may be age-and sex-dependent. Thyroid hormone administration possibly also sustains and enhances the efficacy of hypolipidemic drugs, such as statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9), in patients with dyslipidemia and hypothyroidism.

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“…Obviously, an important substrate for oxidative processes with ionizing radiation is lipids (Dostert et al, 1991), and the lipid profile is closely related to the thyroid status of the organism (Mustafina et al, 2010;Kannisto et al, 2014;Lindemann et al, 2014;Sinha et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Interdependence of oxidative/antioxidant system indicators and thyroid status under conditions of prolonged exposure to small doses of radiation

Sokolenko¹,

Sokolenko²

2019

Regul. Mech. Biosyst.

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We have studied the interdependence of the intensity of oxidative processes/antioxidant level and the thyroid status parameters in a group of students aged 18–24 who lived for a long time in the territory of enhanced radioecological control (density of soil contamination by isotopes (137Cs 3.7 ∙ 104 – 18.5 ∙ 104 Bq/m2). We examined 50 people from relatively environmentally friendly areas (control group) and 50 people from IV radiation zone (experimental group). In the experimental group, there were no individuals with clinical manifestations of thyroid pathology. However, subgroups with signs of hyperthyroidism and hypothyroidism were identified. We evaluated the level of cortisol, thyrotrophic hormone (TSH), triiodothyronine (T3), thyroxine (T4), malonic dialdehyde (MDA), ceruloplasmin (CP), transferrin (Tf), sulfhydryl groups (SH); we calculated the oxidative stress index (OSI). The research was conducted one month before the examination time and also during the exams as a factor in increased emotional stress. A lowered CP level was found in the subgroup with signs of hypothyroidism; SH groups – in all subgroups, separated by thyroid status. The oxidative stress index was higher in all students examined of the experimental group, compared with the control. The growth of MDA level is marked in the experimental group – it is the most strongly pronounced in conditions of additional emotional load in people with signs of hyperthyroidism and hypothyroidism. CP level significantly decreased in the subgroup of hyperthyroidism on the background of T3 decrease. OSI increased in all students examined from the experimental group. In the subgroup of hypothyroidism it became significantly higher than in the subgroup of euthyroidism. A positive correlation between the levels of CP and T3 was found. The highest values of the correlation coefficients were noted for subgroups with signs of hyperthyroidism and hypothyroidism, with the coefficient significance increasing under conditions of emotional stress. The index of oxidative stress in the experimental group positively correlated with the level of TSH – in terms of emotional stress, the statistical significance of the coefficients disappeared. In the subgroups divided by thyroid status, variability of interactions between OSI and T3 was observed but it was not statistically significant. It was found that the participation of thyroid status in supporting redox homeostasis in people aged 18–24 who suffered from chronic small-doze radiation exposure was realized mainly by the influence on the antioxidant system. The ability of thyroid hormones to maintain a proper antioxidant state was suppressed in this group. The unbalanced relationship between thyroid hormones and oxidative stress indicators is strongly manifested under conditions of additional emotional stress.

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The thyroid receptor β modulator GC-1 reduces atherosclerosis in ApoE deficient mice

Cited by 17 publications

References 37 publications

Aortic effects of thyroid hormone in male mice

Aortic effects of thyroid hormone in male mice

A Renewed Focus on the Association Between Thyroid Hormones and Lipid Metabolism

Interdependence of oxidative/antioxidant system indicators and thyroid status under conditions of prolonged exposure to small doses of radiation

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