Effect of Thyrotropin on Osteopontin, Integrin αvβ3, and VCAM-1 in the Endothelium via Activation of Akt

Abstract

Numerous epidemiological studies have shown that subclinical hypothyroidism (SCH) can impair endothelial function and cause dyslipidemia. Studies have evaluated the effects of thyroid stimulating hormone (TSH) on endothelial cells, but the mechanism underlying the proatherosclerotic effect of increased TSH levels remains unclear. In the present study, SCH rat models were established in thyroidectomized Wistar rats that were given l-T4 daily. The results showed that in vivo, the expression of osteopontin (OPN) vascular cell adhesion molecule (VCAM-1), and levels of integrin αvβ3 in the aortic tissue in SCH and Hypothyroidism (CH) groups was higher than in the control group. However, the effect in the SCH group was higher than in the CH group. In vitro, results showed that different concentration and time gradients of TSH stimulation could increase the expression of OPN, VCAM-1, and integrin αvβ3, and this was accompanied by extracellular signal regulated kinase 1/2 (Erk1/2) and Akt activation in human umbilical vein endothelial cells (HUVECs). TSH induced elevation of these proatherosclerotic factors was partially suppressed by a specific Akt inhibitor but not by a specific Erk inhibitor. Findings suggested that the endothelial dysfunction caused by SCH was related to increased proatherosclerotic factors induced by TSH via Akt activation.

Thyrotropin Regulates eNOS Expression in the Endothelium by PGRN Through Akt Pathway

“…Increased TSH and normal serum TT 4 levels in the SCH group as compared to the NC group 4 w after L-T 4 injection to 14 w indicated the successful establishment of the SCH rat model. Consecutively, increased TSH and decreased TT 4 levels were also observed in the CH group ( 22 ).…”

IMM-H004, a coumarin derivative, attenuated brain ischemia/reperfusion injuries and subsequent inflammation in spontaneously hypertensive rats through inhibition of VCAM-1

“…51 In another study using TSH as a stimulator, the enhancement of VCAM-1 was accompanied by ERK1/2 activation in HUVECs. 52 It was also observed that TNFa induced activation of JNK and p38 promoted endothelial activation resulting in enhanced VCAM-1 expression in an in vitro experiment using HUVECs, while inhibition of p38, JNK or NF-kB blocked the expression of VCAM-1. 53 In another commonly used endothelial cell type, human aortic endothelial cells (HAECs), a similar phenomenon was observed.…”

Design and Evaluation of a Polypeptide that Mimics the Integrin Binding Site for EDA Fibronectin to Block Profibrotic Cell Activity

“…This result may be explained by epidermal growth factor receptor (EGFR) and TGFβRI/II pathway-dependent activation of ERK1/2, which induced phosphorylation in a biphasic and time-dependent manner following the stimulation of fibroblasts with TGF-β1 [ 46 ]. Alternatively, the delayed ERK1/2 signaling may have been in response to FN type III, OPN or VCAM1 binding to their integrin receptor sites at distal locations [ 47 ]. However, phosphorylation of FAK protein showed significantly less activation, indicating the prolonged inhibition of the integrin/FAK signaling pathway could be achieved by the AF38Pep blocking polypeptide.…”

“…Use of the IST-9 antibody resulted in similar signaling inhibition of FAK at 12 h post-treatment ( Figure S1 ). However, IST-9 prevention of ERK1/2 phosphorylation at the 12 h timepoint suggested the blockade of additional non-EDA-FN-specific ITGA4 activation may have been implicated [ 47 ]. Matrix metalloproteinase (MMP) gelatinase release and activity has been associated with fibronectin-dependent activation of integrin α 4 β 1 and other β 1 -containing integrins [ 48 , 49 , 50 ].…”

“…We observed that early ERK1/2 signaling at 1 h post-TGF-β1 stimulation was diminished by treatment with AF38Pep, whereas ERK1/2 signaling at 12 h was not. This may be plausibly explained by previous research that showed that signaling through ERK1/2 is a temporally controlled process involving multiple receptors [ 46 ], or may involve participation from other integrin ligands, OPN and VCAM1 [ 47 ]. It remains unclear whether TGF-β1 stimulated ERK1/2 activation can be further regulated by integrin signaling in a time sensitive or cyclic manner.…”