Blockade of endothelin-1 release contributes to the anti-angiogenic effect by pro-opiomelanocortin overexpression in endothelial cells.

Pro-opiomelanocortin (POMC) is the precursor of several neuropeptides, such as corticotropin (ACTH), alpha-melanocyte-stimulating hormone (MSH), and the endogenous opioid, beta-endorphin (EP). ACTH-dependent Cushing's syndrome is characterized by ACTH overproduction and is associated with an increased risk of cardiovascular disease. Endothelial dysfunction has been recognized as an early marker of cardiovascular disease. However, the mechanism underlying endothelial dysfunction by ACTH overexpression in Cushing's patients remains elusive. Endothelial cells, the primary cells producing endothelin (ET)-1, are both the source and target of POMC-derived peptides. In the present study, we generated adenovirus vectors (Ad) encoding POMC (Ad-POMC) and green fluorescent protein (GFP; Ad-GFP) to investigate whether POMC gene transfer altered the ET-1 homeostasis and angiogenic functions in human EA.hy926 endothelial cells. Via adenovirus gene delivery, the POMC-transduced EA.hy926 cells released significantly elevated ACTH and beta-EP levels (P < 0.001). In addition, POMC gene delivery significantly decreased the ET-1 release (P < 0.001) without affecting the ET-1 messenger RNA (mRNA) level. Despite no effect on the secretion of matrix metalloproteinases (MMPs) and cell proliferation, POMC gene delivery significantly inhibited the migration (P < 0.01) and tube-forming capability (P < 0.01) of endothelial cells. Moreover, the POMC-induced inhibition of tube formation could be partially reversed by adding exogenous ET-1 (P < 0.05). In summary, the attenuated ET-1 release and angiogenic processes by POMC overexpression may contribute to endothelial dysfunction, thereby providing a link between Cushing's syndrome and cardiovascular diseases.

Hyperthyroidism is associated with higher plasma endothelin-1 concentrations.

The objective of this study was to determine the change of plasma endothelin (ET)-1 concentrations and insulin resistance index after therapy for hyperthyroidism. We studied 20 patients with hyperthyroidism (15 women and 5 men; age, 34.0 +/- 2.8 years), and 31 patients with euthyroid goiters as controls (27 women, 4 men; age, 37.0 +/- 2.4 years). All hyperthyroid patients were treated with antithyroid drugs. The patients received evaluations before and after normalization of thyroid function. The evaluations included body mass index (BMI), body fat, and measurement of circulating concentrations of thyroid hormones, glucose, insulin, and ET-1. Hyperthyroid subjects had higher plasma ET-1 concentrations than the control group (P < 0.001). No significant differences in serum glucose and insulin concentrations or insulin resistance index estimated by the R value of the homeostasis model assessment (HOMA-R) were noted between the groups. Plasma ET-1 concentrations decreased after correction of hyperthyroidism compared with pretreatment (P = 0.006). Serum glucose concentrations decreased after correction of hyperthyroidism (P = 0.005). Moreover, both body weight-adjusted insulin concentrations and the HOMA-R index were also decreased after correction of hyperthyroidism compared with pretreatment (P = 0.026 and P = 0.019, respectively). Pearson's correlation revealed that plasma ET-1 levels positively correlated with serum triiodothyronine (T3) and free thyroxine (FT4) levels. Serum insulin levels and the HOMA-R index positively correlated with BMI and body fat. The HOMA-R index also positively correlated with serum T3 and FT4 levels. Neither insulin levels nor the HOMA-R index correlated with ET-1 levels. Hyperthyroidism is associated with higher plasma ET-1 concentrations. In addition, correction of hyperthyroidism is also associated with a decrease of plasma ET-1 levels as well as the insulin resistance index calculated by HOMA-R.

The effects of different doses of atorvastatin on plasma endothelin-1 levels in type 2 diabetic patients with dyslipidemia.

We investigated the effects of three different daily doses (10 mg, 20 mg, and 40 mg) of atorvastatin, a relatively new and potent statin, on plasma endothelin (ET)-1 and highly sensitive C-reactive protein (CRP) levels in type 2 diabetic subjects. Twenty-nine type 2 diabetic patients with dyslipidemia were enrolled and randomly assigned to receive atorvastatin orally at 10 mg (A10; n = 10), 20 mg (A20; n = 10), or 40 mg (A40; n = 9) daily for 12 weeks. Levels of plasma total cholesterol and low-density lipoprotein (LDL)-cholesterol (C) in all three studied groups were significantly decreased after treatment with atorvastatin for 12 weeks (all groups, P < 0.001). However, the greatest LDL-C lowering effect and the highest percentage of subjects achieving the National Cholesterol Education Program's Adult Treatment Panel III (NCEP-ATP III) LDL-C goal were observed in the A20 group. All diabetic subjects had a higher plasma ET-1 concentration (A10, 1.02 +/- 0.37 pg/ml, mean +/- SD; A20, 1.17 +/- 0.55 pg/ml; and A40, 0.87 +/- 0.45 pg/ml) than that of age- and sex-matched normal control subjects (0.64 +/- 0.15 pg/ml; all groups, P < 0.001). Plasma ET-1 levels showed a borderline significant decrease at the end of study, by 22% in diabetic subjects treated with 10 mg atorvastatin (P = 0.05 compared with baseline), and by 30% in subjects treated with 20 mg atorvastatin (P = 0.06, compared with baseline). Paradoxically, the 40-mg dose of atorvastatin provided an increase of 2% in plasma ET-1 levels at the end of study, which is significantly different (P < 0.05) and marginally significant (P = 0.057) from the levels of the 10- and 20-mg doses, respectively. Similarly, although insignificantly, plasma concentrations of CRP also tended to decrease by 12% and 48%, and paradoxically increased by 18% in diabetic patients treated with 10 mg, 20 mg, and 40 mg atorvastatin, respectively. The clinical significance of these biphasic lipid-independent statin effects is unknown and the present study suggests that 20 mg atorvastatin may have the best benefits in treating diabetic patients with dyslipidemia.