Thyroid hormone stimulates nitric oxide production via activation of the phosphatidylinositol-3-Kinase/Akt pathway in vascular myocytes

anonnn1 · May 25, 2018, 6:20am

Abstract:

CONTEXT: Low-T(3) syndrome is a predictor of poor outcome in patients with cardiac dysfunction. The study aimed to assess the short-term effects of synthetic L-T(3) replacement therapy in patients with low-T(3) syndrome and ischemic or nonischemic dilated cardiomyopathy (DC). DESIGN: A total of 20 clinically stable patients with ischemic (n = 12) or nonischemic (n = 8) DC were enrolled. There were 10 patients (average age 72 yr, range 66-77; median, 25-75th percentile) who underwent 3-d synthetic L-T(3) infusion (study group); the other 10 patients (average age 68 yr, range 64-71) underwent placebo infusion (control group). Clinical examination, electrocardiography, cardiac magnetic resonance, and bio-humoral profile (free thyroid hormones, TSH, plasma renin activity, aldosterone, noradrenaline, N-terminal-pro-B-Type natriuretic peptide, and IL-6) were assessed at baseline and after 3-d synthetic L-T(3) (initial dose: 20 microg/m(2) body surface.d) or placebo infusion. RESULTS: After T(3) administration, free T(3) concentrations increased until reaching a plateau at 24-48 h (3.43, 3.20-3.84 vs. 1.74, 1.62-1.93 pg/ml; P = 0.03) without side effects. Heart rate decreased significantly after T(3) infusion (63, 60-66 vs. 69, 60-76 beats per minute; P = 0.008). Plasma noradrenaline (347; 270-740 vs. 717, 413-808 pg/ml; P = 0.009), N-terminal pro-B-Type natriuretic peptide (3000, 438-4005 vs. 3940, 528-5628 pg/ml; P = 0.02), and aldosterone (175, 152-229 vs. 231, 154-324 pg/ml; P = 0.047) significantly decreased after T(3) administration. Neurohormonal profile did not change after placebo infusion in the control group. After synthetic L-T(3) administration, left-ventricular end-diastolic volume (142, 132-161 vs. 133, 114-158 ml/m(2) body surface; P = 0.02) and stroke volume (40, 34-44 vs. 35, 28-39 ml/m(2) body surface; P = 0.01) increased, whereas external and intracardiac workload did not change. CONCLUSIONS: In DC patients, short-term synthetic L-T(3) replacement therapy significantly improved neuroendocrine profile and ventricular performance. These data encourage further controlled trials with more patients and longer periods of synthetic L-T(3) administration.

anonnn1 · May 25, 2018, 6:20am

LINK: eje-online.org/cgi/content/a … /147/1/117

Nitric oxide synthase activity in hyperthyroid and hypothyroid rats
A Quesada, J Sainz, R Wangensteen, I Rodriguez-Gomez, F Vargas, and A Osuna
Departamento de Fisiologia de la Facultad de Medicina de Granada, Granada, Spain.

OBJECTIVE: Thyroid disorders are accompanied by important changes in haemodynamic and cardiac functions and renal sodium handling. Since nitric oxide (NO) plays a crucial role in regulating vascular tone and renal sodium excretion, the present paper was designed to determine whether changes in the activity of NO synthase (NOS) participate in the cardiovascular and renal manifestations of thyroid disorders. METHODS: We measured NOS activity in the heart (left and right ventricles), vessels (aorta and cava) and kidney (cortex and medulla) of euthyroid, hyperthyroid and hypothyroid rats after 6 weeks of treatment. NOS activity was determined by measuring the conversion of L-[(3)H]-arginine to L-[(3)H]-citruline. RESULTS: NOS activity was higher in all tissues from hyperthyroid rats when compared with controls, except in the right ventricle. In the hypothyroid group, NOS activity showed a more heterogeneous pattern, with significant increases in both ventricles but significant reduction in the aorta, while in the vena cava, renal cortex and medulla the enzyme activity also tended to be higher, but significance was not reached. CONCLUSIONS: These data indicated that NOS activity was upregulated in tissues primarily related to blood pressure control in hyperthyroid rats, suggesting that an increased NO production may contribute to the hyperdynamic circulation in hyperthyroidism and may have a protective homeostatic effect in the target organs of the hypertension that accompanies this endocrine disease. The aortic and renal findings in hypothyroid rats suggested a possible role for NOS in the increased peripheral resistance and the normal pressure-diuresis-natriuresis response of these hypotensive animals, although hypothyroidism produced a heterogeneous tissue response in NOS activity.

anonnn1 · May 25, 2018, 6:20am

Thyroid status and nitric oxide in rat arterial vessels

LINK: joe.endocrinology-journals.org/c … /185/1/111

Thyroid disease has profound effects on cardiovascular function. Hypo- and hyperthyroidism, for example, are associated with reduced and increased maximal endothelium-dependent vasodilation respectively. We therefore hypothesized that the capacity for vascular nitric oxide (NO) formation is decreased in hypothyroidism and increased in hyperthyroidism. To test this hypothesis, rats were made hypothyroid (HYPO) with propylthiouracil or hyperthyroid (HYPER) with triiodothyronine over 3–4 months. Compared with euthyroid control rats (EUT), HYPO exhibited blunted growth and lower citrate synthase activity in the soleus muscle; HYPER exhibited left ventricular hypertrophy and higher citrate synthase activity in the soleus muscle (P<0.05 for all effects). The capacity for NO formation was determined in aortic extracts by formation of [3H]L-citrulline from [3H]L-arginine, i.e. NO synthase (NOS) activity. Thyroid status modulated NOS activity (EUT, 36.8 ± 5.5 fmol/h per mg protein; HYPO, 26.0 ± 7.9; HYPER, 64.6 ± 12.7; P<0.05, HYPER vs HYPO). Expression of endothelial and neural isoforms of NOS was modulated by thyroid status in a parallel fashion. Capacity for responding to NO was also determined via measuring cGMP concentration in aortae incubated with sodium nitroprusside. Stimulated cGMP formation was also modulated by thyroid status (EUT, 73.0 ± 20.2 pmol/mg protein; HYPO, 152.4 ± 48.7; HYPER, 10.4 ± 2.6; P<0.05, HYPER vs HYPO). These data indicate that thyroid status alters capacities for both formation of and responding to NO. The former finding may contribute to previous findings concerning vascular function in thyroid disease states.

anonnn1 · May 25, 2018, 6:20am

LINK: cardiovascres.oxfordjournals.org … cvr.cvp304

Aims Thyroid hormone (TH) rapidly relaxes vascular smooth muscle cells (VSMCs). However, the mechanisms involved in this effect remain unclear. We hypothesize that TH- induced rapid vascular relaxation is mediated by VSMCs-derived nitric oxide (NO) production and is associated with the phosphatidylinositol 3-kinase/ B Kinase Protein (PI3K/Akt) signaling pathway.
Methods and Results NO levels were determined using the NO-specific fluorescent dye (DAF-2) and nitrite (NO2-) levels. Expression of nitric oxide synthase (NOS) isoforms and proteins of the PI3K/Akt pathways was determined by both western blotting and immunocytochemistry. Myosin light chain (MLC) phosphorylation levels were also investigated by western blotting. Exposure of cultured VSMCs from rat thoracic aortas to triiodothyronine (T3) resulted in a significant decrease of MLC phosphorylation levels. T3 also induced a rapid increase in Akt phosphorylation and increased NO production in a dose-dependent manner (0.001µm-1µM). VSMCs stimulated with T3 for 30 minutes showed increase on the expression of all three NOS isoforms and augmented NO production, which were prevented by inhibitors of the PI3K. Vascular reactivity studies showed that vessels treated with T3 displayed decreased response to phenylephrine (PE), which was reversed by NOS inhibition. These data suggest that T3-treatment induces greater generation of NO both in aorta and VSMCs and this phenomenon is endothelium-independent. In addition, these findings show for the first time that PI3K/Akt signaling pathway is involved to T3-induced NO production by VSMCs, which occurs with expressive participation of inducible and neuronal NOS. Conclusion Our data strongly indicate that T3 causes NO-dependent rapid relaxation of VSMC and that this effect is mediated by PI3K/Akt signaling pathways.

anonnn1 · May 25, 2018, 6:20am

LINK: stroke.ahajournals.org/cgi/conte … 36/10/2302

Thyroid Diseases and Cerebrovascular Disease
A. Squizzato, MD; V.E.A. Gerdes, MD, PhD; D.P.M. Brandjes, MD, PhD; H.R. Büller, MD, PhD J. Stam, MD, PhD

From the Department of Vascular Medicine (A.S., V.E.A.G., H.R.B.), Academical Medical Center, Amsterdam, The Netherlands; the Department of Internal Medicine (V.E.A.G., D.P.M.B.), Slotervaart Hospital, Amsterdam, The Netherlands; the Department of Neurology (J.S.), Academical Medical Center, Amsterdam, The Netherlands; and the Department of Internal Medicine (A.S.), University of Insubria, Varese, Italy.

Correspondence to Alessandro Squizzato, Department of Internal Medicine, University of Insubria, Ospedale di Circolo, Viale Borri, 57, 21100 Varese, Italy. E-mail alexsquizzo@libero.it

Background and Purpose— Acute cerebral ischemia has been described in different diseases of the thyroid gland, and not only as a result of thyrotoxic atrial fibrillation and cardioembolic stroke. The purpose of this review is to summarize the studies on the relationship between thyroid diseases and cerebrovascular diseases, discussing the main findings for overt hyperthyroidism and hypothyroidism, as well as for subclinical thyroid dysfunction.

Summary of Review— In overt hyperthyroidism, cardioembolic stroke is clearly associated to thyrotoxic atrial fibrillation, and in subclinical hyperthyroidism with serum thyroid-stimulating hormone levels <0.1 mU/L, the incidence of atrial fibrillation is increased. Although in vitro and in vivo studies indicate a hypercoagulability state in hyperthyroidism, there is insufficient evidence to prove that this state leads to an increased risk of cardiac emboli. However, the hypothesis that overt hyperthyroidism may cause acute cerebral venous thrombosis is intriguing. Possible associations between hyperthyroidism and Moyamoya or Giant cell arteritis have only been described in case reports. There is enough evidence that overt hypothyroidism is associated with several traditional and newer atherosclerotic risk factors, especially hypertension, hyperlipidemia, and hyperhomocysteinemia. For subclinical hypothyroidism, these associations are less certain. Hypothyroidism has been associated with signs of aortic or coronary atherosclerosis, but no case-control or cohort studies have ever investigated hypothyroidism as a possible risk factor for atherothrombotic stroke.

Conclusions— Hyperthyroidism is associated with atrial fibrillation and cardioembolic stroke. Hypothyroidism is associated with a worse cardiovascular risk factor profile and leads to progression of atherosclerosis. Associations between hyperthyroidism and acute cerebral venous thrombosis, Moyamoya, and Giant cell arteritis have been suggested, but sound evidence is lacking. Additional studies are needed to clarify these issues.