Abstract
To investigate the expression of endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) in the aorta of subclinical hypothyroidism (SCH) rat model. The mechanisms underlying thyrotropin (TSH) affecting eNOS and PGRN expression in human umbilical vein endothelial cells (HUVECs) cultured in vitro were investigated. In the current study, SCH rat models were established by the administration of L-T4 injection after thyroidectomy in Wistar rats, as opposed to that in the normal and clinical hypothyroidism (CH) groups. The concentrations of NO (pmol/μL) in the SCH and CH groups were significantly lower than that in the normal group (40.8 ± 7.6 and 32.9 ± 10.8 vs. 51.2 ± 12.1, P < 0.05). However, the expression level of eNOS is increased significantly (P < 0.05) in both SCH and CH groups; a similar result was observed for the PGRN protein. In cultured HUVECs, TSH can also up-regulate the expression of eNOS; however, it is accompanied by a reduced concentration of NO and increased level of superoxide anion, thereby indicating uncoupled eNOS. As eNOS is increased, we found that Akt in HUVECs were upregulated by TSH, as well as PGRN expression. While inhibiting the expression of PGRN in HUVECs using siRNA, the expression of eNOS, as well as Akt were also inhibited. In conclusion, SCH can induce vascular endothelial dysfunction in rats, and PGRN participated in the process of TSH-induced expression of Akt/eNOS in the endothelium.
Highlights
Endothelial dysfunction is the early stage of many diseases, such as hypertension and atherosclerosis [1, 2]
Western blot showed that the protein expressions of aortic Endothelial nitric oxide synthase (eNOS) in the clinical hypothyroidism (CH) and Subclinical hypothyroidism (SCH) groups were significantly increased than the NC group (P < 0.05) (Figure 1)
The present study found that the expression of the aortic endothelial eNOS and PGRN increased in SCH rats; FIGURE 5 | Role of Akt in the induction by TSH of eNOS in human umbilical vein endothelial cells (HUVECs). (A) Protein expression of Akt in HUVECs stimulated by different concentrations of TSH (0, 0.1, 1, 10, and 100 mIU/ml) for 24 h; (B) Inhibition of Akt: HUVECs were pretreated with 1 μM of MK-2206 for 6 h or not, and together with or without TSH (10 mIU/ml) for 24 h
Summary
Endothelial dysfunction is the early stage of many diseases, such as hypertension and atherosclerosis [1, 2]. The vascular endothelium expressed the receptor of TSH; its function was not clear [3]. Endothelial nitric oxide synthase (eNOS) is a crucial enzyme in the production of nitric oxide (NO) generation and plays a vital role in anti-atherosclerosis [4]. Clinical hypothyroidism reduces the expression of eNOS in vascular endothelium, it is increased in the cardiac tissue [5]. Virdis et al demonstrated that eNOS was not altered in methimazole-induced hypothyroidism rat [6]. Other groups studied the endothelial function including macrovasculatures and resistance vessels in hypothyroidism induced by propylthiouracil. Subclinical hypothyroidism (SCH) is an independent risk factor of atherosclerosis; its influence on vascular endothelial function is yet controversial
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