propylthiouracil and Atherosclerosis

Hyperthyroidism is related to vascular atherosclerosis. Propylthiouracil (PTU) and methimazole, other than their antithyroid effects, may have different mechanisms in preventing atherogenesis in Graves' disease.. This study aimed to investigate the effect of antithyroid drugs on markers of vascular atherosclerosis in Graves' hyperthyroidism.. This study was a single-blind, randomized clinical trial conducted on 36 patients with Graves' disease in Cipto Mangunkusumo General Hospital, Jakarta, Indonesia, from June 2019 until July 2020. Graves' disease was diagnosed from clinical manifestation of hyperthyroidism with diffuse goiter and then confirmed by thyroid stimulation hormone (TSH), free T4 (fT4), and TSH-receptor antibody (TRAb) measurements. Participants were randomly assigned to either a PTU or a methimazole treatment group and followed up for 3 months. Markers of vascular atherosclerosis were represented by adhesion molecules [intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin], carotid artery stiffness [pulse wave velocity (PWV)], and thickness [carotid intima media thickness (cIMT)].. By the end of the study, 24 participants reached euthyroid condition (13 from the PTU group and 11 from the methimazole group). After 3 months of follow-up, in the PTU group, we noticed an improvement of ICAM-1 [pretreatment: 204.1 (61.3) vs. posttreatment: 141.6 (58.4) ng/ml; p = 0.001], VCAM-1 [837 (707-977) vs. 510 (402-630) ng/ml; p < 0.001] and E-selectin [32.1 (24.1-42.7) vs. 28.2 (21.6-36.8) ng/ml; p = 0.045] in the PTU group. In the methimazole group, only VCAM-1 improvement [725 (565-904) vs. 472 (367-590); p = 0.001] was observed. Meanwhile, we found no significant changes in PWV or cIMT in either group.. Antithyroid treatment in Graves' disease leads to improvement in adhesion molecules, with a lesser effect on methimazole, whereas there were no significant changes in PWV or cIMT. PTU may have a better mechanism compared with methimazole in terms of improving adhesion molecules.

Topics: Adult; Antithyroid Agents; Atherosclerosis; Biomarkers; Female; Follow-Up Studies; Graves Disease; Humans; Intercellular Adhesion Molecule-1; Male; Methimazole; Middle Aged; Propylthiouracil; Pulse Wave Analysis; Single-Blind Method; Thyroid Hormones; Treatment Outcome; Vascular Cell Adhesion Molecule-1

We tested the hypothesis that arteriosclerosis-augmented aortic pulse wave velocity (PWV) and -impaired vasorelaxation were attenuated by rosuvastatin (Rosu) and propylthiouracil (PTU) therapy.. Thirty-two New Zealand rabbits were equally divided into group 1 (sham-control), group 2 [high-cholesterol-diet (HCD) for 8weeks], group 3 [HCD-Rosu (20mg/kg/day administration after 4-week HFD for 4weeks)], and group 4 [HCD-PTU (0.1% PTU in drinking water), the treatment course as group 3]. KCl-induced vasoconstriction of carotid artery (CA) was significantly higher in group 2 than in other groups (all p<0.01), but showed no differences among groups 1, 3 and 4, whereas acetylcholine-induced vasorelaxation exhibited an opposite pattern of KCl-induced vasoconstriction among the four groups (p<0.001). Basic nitric-oxide release from endothelial cells of CA was highest in group 1, lowest in group 2, but showed no difference between groups 3 and 4 (all p<0.001). PWV value was highest in group 2, lowest in group 1, and significantly higher in group 4 than in group 3 (all p<0.001). Serum levels of total-cholesterol, LDL and TG showed an identical pattern to PWV (all p<0.001), whereas the levels of free T4, sugar, and body weight did not differ among the four groups (all p>0.4). Aortic inflammatory biomarkers in cellular (CD68+/IL-1β+/CD14+) and protein (TNF-α/NF-κB/IL-1β/MMP-9/MCP-1/ICAM-1/PDGF) levels, and aortic oxidative-stress biomarkers in cellular (8-OHdG) and protein (NOX-1/NOX-2/oxidized protein) levels showed an identical pattern to PWV among the four groups (all p<0.001).. Rosu-PTU therapy ameliorated aortic stiffness and inflammation/oxidative-stress, and improved endothelial-cell function after HCD challenge in rabbit.

Topics: Animals; Anticholesteremic Agents; Aorta; Atherosclerosis; Cholesterol, Dietary; Human Umbilical Vein Endothelial Cells; Humans; Hypercholesterolemia; Propylthiouracil; Rabbits; Random Allocation; Rosuvastatin Calcium; Treatment Outcome; Vascular Stiffness

Endothelial dysfunction is an initial and vascular smooth muscle cell (VSMC) apoptosis, a later step of atherosclerosis. Hypothyroidism accelerates atherosclerosis. However, the early events responsible for this pro-atherosclerotic effect are unclear.. Rats were resistant to induction of atherosclerosis by high cholesterol diet alone, but became susceptible in hypothyroid state achieved by administration of propylthiouracil (PTU) for 6 weeks. VSMC dysfunction and apoptosis were obvious within 1 week after PTU treatment, without signs of endothelial dysfunction. This early VSMC damage was caused by hypothyroidism but not the high cholesterol diet. In ApoE knockout mice, PTU-induced hypothyroidism triggered early VSMC apoptosis, increased oxidative stress, and accelerated atherosclerosis development. Thyroid hormone supplementation (T4, 10, or 50 μg/kg) prevented atherogenic phenotypes in hypothyroid rats and mice. In rats, thyroidectomy caused severe hypothyroidism 5 days after operation, which also led to rapid VSMC dysfunction and apoptosis. In vitro studies did not show a direct toxic effect of PTU on VSMCs. In contrast, thyroid hormone (T3, 0.75 μg/L plus T4, 50 nmol/L) exerted a direct protection against VSMC apoptosis, which was reduced by knockdown of TRα1, rather than TRβ1 and TRβ2 receptors. TRα1-mediated inhibition of apoptotic signalling of JNKs and caspase-3 contributed to the anti-apoptotic action of thyroid hormone.. These findings provide an in vivo example for VSMC apoptosis as an early trigger of hypothyroidism-associated atherosclerosis, and reveal activation of TRα1 receptors to prevent VSMC apoptosis as a therapeutic strategy in this disease.

Topics: Animals; Apolipoproteins E; Apoptosis; Atherosclerosis; Cells, Cultured; Hypothyroidism; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Propylthiouracil; Rats; Rats, Sprague-Dawley; Thyroid Hormone Receptors alpha; Thyroid Hormone Receptors beta; Thyroid Hormones

The atherogenic effects of hypothyroidism on lipid metabolism could result, in part, from the reduced clearance of remnant lipoproteins. In this study, we investigated the expression of hepatic low-density lipoprotein receptor-related protein 1 (LRP1), a receptor for remnant lipoproteins, in hypothyroidism and the effect of 3,3',5-triiodo-L-thyronine (T3) treatment on hepatic LRP1 expression.. C57BL/6 mice were fed a normal diet (control group) or a low-iodine diet supplemented with 0.15% propylthiouracil (PTU/LI group) for 4 weeks. Mice in the PTU/LI group were injected intraperitoneally with T3 (0, 30, and 150 μg/kg of body weight) for 7 days. HepG2 cells were incubated in fetal bovine serum or charcoal-stripped fetal bovine serum with various concentrations of T3. The expression and function of LRP1 in liver samples and cells were analyzed.. Hypothyroidism was successfully induced in PTU/LI mice. Hepatic LRP1 protein expression was lower in the PTU/LI group than in the control group. T3 treatment upregulated hepatic LRP1 protein expression in PTU/LI mice. LRP1 expression in HepG2 cells was reduced after incubation in the medium containing charcoal-stripped fetal bovine serum, which mimics hypothyroidism in vitro, and was recovered by T3 treatment. The protein expression of LRP1 in HepG2 cells was increased by T3 treatment in a dose-dependent manner up to 2.0 nM T3. However, LRP1 mRNA transcription was not affected by hypothyroidism conditions or T3 treatment, either in liver samples or in HepG2 cells. T3 treatment on HepG2 cells increased cellular uptake of lipid-conjugated apolipoprotein E through LRP1.. Our data demonstrate that hepatic LRP1 expression and function decrease in hypothyroidism and are regulated by the thyroid hormone. These results suggest that in hypothyroidism, decreased expression of hepatic LRP1 may be associated with reduced clearance of circulating remnant lipoproteins.

Topics: Animals; Apolipoproteins E; Atherosclerosis; Disease Models, Animal; Down-Regulation; Dyslipidemias; Hep G2 Cells; Humans; Hypothyroidism; Liver; Low Density Lipoprotein Receptor-Related Protein-1; Male; Mice, Inbred C57BL; Propylthiouracil; Receptors, LDL; RNA, Messenger; Triiodothyronine; Tumor Suppressor Proteins

Propylthiouracil (PTU), in addition to its antithyroid effect, is recently found to have a potent antiatherosclerotic effect. Because collagen accumulation is the major contributor to the growth of atherosclerotic lesions and the neointimal formation after arterial injury, the aim of this study is to investigate the impact of PTU on collagen regulation. In the rat carotid injury model, PTU administration reversed the up-regulation of collagen in the neointima induced by balloon injury. In vitro, vascular smooth muscle cells (VSMCs), the main origin of arterial collagen, were treated with PTU. Propylthiouracil caused a concentration-dependent decrease in collagen I and III steady-state protein and mRNA levels, as determined by immuno-cytochemistry, Western, and/or Northern blot analyses. Transient transfection experiments using rat type I collagen promoter construct showed that PTU failed to affect collagen gene transcription in VSMCs. Actinomycin D studies demonstrated that the half-life of collagens mRNA decreased with PTU treatment, suggesting that PTU down-regulates collagen expression predominantly at the post-transcriptional level. Taken together, these data suggest that PTU inhibits VSMC collagen production via destabilization of collagen mRNA that contributes to its beneficial effect on atherogenesis and neointimal formation after arterial injury. However, whether the destabilization of collagen may induce plaque rupture in PTU-treated arteries merits further investigation.

Topics: Animals; Antithyroid Agents; Atherosclerosis; Blotting, Northern; Carotid Arteries; Collagen; Gene Expression Regulation; Immunohistochemistry; Male; Muscle, Smooth, Vascular; Propylthiouracil; Rats; Rats, Sprague-Dawley; RNA, Messenger; Transforming Growth Factor beta; Up-Regulation

It is known that there is abnormal osteopontin (OPN) expression at the sites of atherosclerotic lesions. In the Apolipoprotein E gene knockout (ApoE-KO) mouse, a model of the atherosclerotic process, altered cholesterol metabolism with associated increase in OPN expression is evident at 12-22 weeks in the aorta and at 22 weeks in the heart. In this study, we analyzed another animal model of hypothyroid mice created by ingestion of propylthiouracil (PTU). After 2 weeks of PTU ingestion, the animals had significant decreases in thyroid hormones (T3 and T4) and immediate increases in blood lipids/cholesterol. Hypothyroid mice showed 1.3-, 1.5-, 2-fold increases in blood levels of total cholesterol, triglycerides, and low density lipoprotein-cholesterol respectively. Semi-quantitative RT-PCR analysis showed that hypothyroid mice had 1.4- to 2-fold increases of OPN mRNA expression in the aorta and 1.5-fold increases in the heart. Hypothyroid animals treated with T3 (5 microg/day for 6 days) or statin (0.2 mg/30 g for 2 weeks) reduce blood lipids and aortic OPN mRNA expression. Data obtained with ELISA analyses showed 1.5- and 1.7-fold increases in OPN protein in the aorta (10 weeks) and the heart (22 weeks), respectively. This increase is close to the mRNA expression in both tissues of hypothyroid mice. In addition, western blots showed several variants of OPN protein expressed in the aorta and the heart. The decrease in the 70 kDa OPN is accompanied by an increase in 45 kDa OPN in the aorta of hypothyroid mice. In contrast, only 45 kDa OPN is found in the heart of control and hypothyroid mice. These data indicate that the increase of OPN mRNA and protein expression occurs in cardiovascular tissues of hypothyroid mice.

Topics: Animals; Aorta; Apolipoproteins E; Atherosclerosis; Blood Pressure; Blotting, Western; Body Weight; Cardiovascular System; Cholesterol; Cholesterol, LDL; Disease Models, Animal; Electrophoresis, Agar Gel; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation; Heart; Heart Rate; Hypothyroidism; Lipids; Male; Mice; Mice, Inbred ICR; Mice, Knockout; Mice, Transgenic; Models, Statistical; Myocardium; Osteopontin; Propylthiouracil; Reverse Transcriptase Polymerase Chain Reaction; RNA; RNA, Messenger; Sialoglycoproteins; Thyroxine; Time Factors; Triglycerides; Triiodothyronine

Propylthiouracil (PTU) is used to treat hyperthyroid patients by its hypothyroid effect. PTU also is found to have potent antioxidant and immunosuppressive effects. These findings suggest that PTU may play a role in the prevention of atherosclerosis.. This study evaluates the effect of PTU on atherosclerotic change in rabbits fed a high-cholesterol diet. The pronounced atherosclerotic lesions in the aortas of rabbits fed a 2% cholesterol diet for 12 weeks were significantly attenuated by the concurrent addition of 0.1% PTU to the drinking water. However, exogenous supplementation of thyroid hormone in hypothyroid PTU-treated rabbits did not abrogate the protective effect of PTU on atherogenesis. Immunohistochemical analysis showed that PTU administration apparently reduced the intimal smooth muscle cell/macrophage ratio in the atherosclerotic plaques of rabbits fed a 2% cholesterol diet. In vitro, the addition of PTU to the medium of cultured rat vascular smooth muscle cells led to a dose-dependent inhibition of cell proliferation and migration. Furthermore, this study confirmed that PTU dose-dependently increased expression of PTEN, a tumor suppressor gene known to be involved in the coordinate inhibition of VSMC proliferation and migration.. This study demonstrated that PTU inhibited the development of atherosclerosis through a thyroid-independent mechanism that may be explained, at least in part, by the ability of PTU to inhibit vascular smooth muscle cell proliferation and migration. Furthermore, PTEN induction, via disruption of the phosphatidylinsitol 3-kinase-mediated pathway, plays a crucial role in mediating the inhibitory action on vascular smooth muscle cell proliferation and migration.

Topics: Animals; Antioxidants; Aorta; Aortic Diseases; Apoptosis; Atherosclerosis; Cell Division; Cell Movement; Cells, Cultured; Cholesterol, Dietary; Diet, Atherogenic; Drug Evaluation, Preclinical; Femoral Artery; Gene Expression Regulation; Immunosuppressive Agents; Male; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phosphatidylinositol 3-Kinases; Propylthiouracil; Rabbits; Rats; Rats, Sprague-Dawley; Triiodothyronine

Topics: Arteriosclerosis; Atherosclerosis; Bile Acids and Salts; Butter; Cholesterol; Diet; Diet, Atherogenic; Infarction; Myocardial Infarction; Oils; Pathology; Propylthiouracil; Rats; Research; Salts; Thrombosis; Toxicology; Zea mays

Topics: Aortic Diseases; Arteriosclerosis; Atherosclerosis; Barium Sulfate; Blood Coagulation; Dietary Fats; Hyperlipidemias; Lipid Metabolism; Portal Vein; Propylthiouracil; Rats; Research; Thrombosis

Topics: Adrenal Glands; Animals; Arteriosclerosis; Atherosclerosis; Blood Proteins; Body Weight; Cholesterol; Heart; Hypothyroidism; Iodine Isotopes; Lipids; Liver; Pharmacology; Physiology; Pituitary Gland; Propylthiouracil; Rabbits; Research; Thyroid Gland; Thyroidectomy; Thyroxine

Topics: Animals; Atherosclerosis; Hyperlipidemias; Propylthiouracil; Rats