2-Methoxyestradiol ameliorates metabolic syndrome-induced hypertension and catechol-O-methyltransferase inhibited expression and activity in rats.

Metabolic syndrome (MetS) is a common disorder that is associated with hypertension and poses a significant cardiovascular risk. Deactivation of extra-neuronal norepinephrine is mediated by catechol-O-methyltransferase (COMT). Endogenous 2-methoxyestradiol (2ME) is a product of COMT activity. The current study investigated the impact of 2ME on MetS-induced hypertension and the possible alterations in COMT expression and activity in rats. Animals were randomly divided into 4 groups. Group 1 received drinking water and standard food pellets. Groups 2, 3 and 4 were subjected to experimental induction of MetS. Animals in groups 3 and 4 were given daily IP injection of 2ME (25 and 50 mg/kg, respectively). MetS animals showed significant increases in body weight gain and visceral fat, fasting blood glucose and serum insulin and insulin resistance. Meanwhile, MetS was associated with a significant hypertriglyceridemia. Further, MetS significantly increased systolic, diastolic and mean arterial blood pressure. These effects were associated with significant reduction in COMT expression in the liver, kidneys and aorta as well as reduced hepatic activity. 2ME inhibited the alterations in body weight gain, visceral fat accumulation, fasting blood glucose and serum insulin, insulin resistance and serum triglycerides. Elevations in blood pressure were significantly inhibited by 2ME. Also, it attenuated the decrease in liver, kidney and aorta COMT expression and hepatic COMT activity. MetS was associated with elevated epinephrine and norepinephrine levels. Only the higher dose of 2ME significantly mitigated the rise in epinephrine level. In conclusion, 2ME protects against MetS-induced hypertension and averts COMT inhibited expression and activity.

Azhar AS ，Zaher ZF ，Ashour OM ，Abdel-Naim AB ... -  《-》

Pioglitazone ameliorates high fat diet-induced hypertension and induces catechol o-methyl transferase expression in rats.

Our study aimed to investigate the effect of pioglitazone (PIO) on the obesity-associated metabolic effects and whether this effect is associated with modulation of catechol O-methyl transferase (COMT) expression in the high fat diet (HFD) induced obese rats. Male Wistar rats fed HFD were used to evaluate the effect of PIO on obesity-associated hypertension and the expression of COMT. The HFD-induced obesity was confirmed by the change in body weights, the fasting serum insulin (FSI) which assessed by ELISA, homeostasis model assessment - insulin resistance (HOMA-IR), fasting blood glucose (FBG), oral glucose tolerance test (OGTT) and lipid profile which were determined by colorimetric methods. Plasma epinephrine (EP) and norepinephrine (NE) were determined by ELISA and the systolic blood pressure (SBP) was recorded using the tail-cuff method. COMT expression was assessed by quantitative real time-polymerase chain reaction (qRT-PCR), and western blotting. The HFD-induced obesity was associated with glucose intolerance, derangement of the lipid profile, increased SBP, reduced COMT expression with a concomitant increase in plasma catecholamines. Most importantly, treatment with PIO ameliorated the HFD-induced metabolic changes, improved the lipid profile, reduced SBP, increased COMT expression, and reduced plasma catecholamines. Treatment with PIO reversed HFD-induced glucose intolerance and the associated metabolic derangement. In addition, these effects of PIO were associated with up-regulating COMT expression with a subsequent reduction in plasma catecholamines levels.

Hegazy M ，El-Shafey M ，Abulsoud AI ，Elsadek BEM ，Abd Elaziz AI ，Salama SA ... -  《-》

The potential protective effects of estradiol and 2-methoxyestradiol in ischemia reperfusion-induced kidney injury in ovariectomized female rats.

Investigating the impact of 17β estradiol (E2) and its endogenous non-hormonal metabolite 2-methoxyestradiol (2ME) on renal ischemia-reperfusion (RIR) induced kidney injury in ovariectomized (OVX) rats and the role of catechol-O-methyltransferase (COMT) in their effects. Eighty female rats were allocated into eight groups. Control group, Sham group, OVX group, OVX and RIR group, OVX + RIR + E2 group, OVX + RIR + 2ME group, OVX + RIR + E2 + Entacapone group and OVX + RIR + 2ME + Entacapone group, respectively. Twenty-four hours post RIR, creatinine (Cr) and blood urea nitrogen (BUN) were determined in serum, while malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), Glutathione (GSH), myeloperoxidase (MPO), as well as the expressions of COMT, hypoxia inducible factor-1α (HIF-1α) and tyrosine hydroxylase (TH) were assessed in the kidney tissues. Serum Cr, BUN, MPO, as well as HIF-1α and TH expressions were significantly higher with concomitant decrease in COMT expression, SOD and CAT activities and GSH content observed in OVX and RIR group compared to sham group. E2 and 2ME treatment significantly ameliorated all parameters measured in OVX and RIR rats. On the other hand, Entacapone significantly decreased the effect of E2, with no effect on 2ME treatment. E2 ameliorates RIR-induced kidney injury and this effect is mediated, at least in part, via its COMT-mediated conversion to 2ME. Thus, 2ME by the virtue of its pleiotropic pharmacological effects can be used as a safe and effective treatment of RIR injury.

Hassan E ，Allam S ，Mansour AM ，Shaheen A ，Salama SA ... -  《-》

Resistance to salt-induced hypertension in catechol-O-methyltransferase-gene-disrupted mice.

Helkamaa T ，Männistö PT ，Rauhala P ，Cheng ZJ ，Finckenberg P ，Huotari M ，Gogos JA ，Karayiorgou M ，Mervaala EM ... -  《JOURNAL OF HYPERTENSION》

Catechol-o-methyltransferase expression and 2-methoxyestradiol affect microtubule dynamics and modify steroid receptor signaling in leiomyoma cells.

Salama SA ，Kamel MW ，Botting S ，Salih SM ，Borahay MA ，Hamed AA ，Kilic GS ，Saeed M ，Williams MY ，Diaz-Arrastia CR ... -  《PLoS One》