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Activation of κ-opioid receptor by U50,488H improves vascular dysfunction in streptozotocin-induced diabetic rats.

Zhou X, Wang D, Zhang Y, Zhang J, Xiang D, Wang H - BMC Endocr Disord (2015)

Bottom Line: U50,488H treatment resulted in reduction in ANG II, sICAM-1, IL-6 and IL-8 levels and elevation in NO levels, while these effects were abolished by nor-BNI treatment.Further more, eNOS phosphorylation was increased, and NF-κB p65 translocation was decreased after U50,488H treatment.Our study demonstrated that U50,488H may have therapeutic effects on diabetic vascular dysfunction by improving endothelial dysfunction and attenuating chronic inflammation, which may be dependent on phosphorylation of eNOS and downstream inhibition of NF-кB.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China. zhouxuanxuan2007@126.com.

ABSTRACT

Background: Evidence suggests that activation of κ-opioid receptor (KOR) by U50,488H exhibits potential cardiovascular protective properties. However, the effects of U50,488H on vascular dysfunction in diabetes mellitus (DM) are still not clear. The present study was designed to investigate the effects of U50,488H on vascular dysfunction in diabetic rats and explore the underlying mechanisms involved.

Methods: Rats were randomly divided into control, DM, DM + vehicle, DM + U50,488H and DM + nor-binaltorphimine (nor-BNI) groups. Streptozotocin injection was used to induce DM. Weight, blood glucose, blood pressure and plasma insulin for each group were measured. Arterial functions were assessed with isolated vessels mounted for isometric tension recordings. Angiotensin II (ANG II), soluble intercellular adhesion molecule-1 (sICAM-1), interleukin (IL)-6 and IL-8 levels were measured by ELISA, and endothelial nitric oxide synthase (eNOS) phosphorylation and NF-κB p65 translocation were measured by Western blot.

Results: Activation of KOR by U50,488H reduced the enhanced contractility of aortas to KCl and noradrenaline and increased acetylcholine-induced vascular relaxation, which could also protect the aortal ultrastructure in DM. U50,488H treatment resulted in reduction in ANG II, sICAM-1, IL-6 and IL-8 levels and elevation in NO levels, while these effects were abolished by nor-BNI treatment. Further more, eNOS phosphorylation was increased, and NF-κB p65 translocation was decreased after U50,488H treatment.

Conclusions: Our study demonstrated that U50,488H may have therapeutic effects on diabetic vascular dysfunction by improving endothelial dysfunction and attenuating chronic inflammation, which may be dependent on phosphorylation of eNOS and downstream inhibition of NF-кB.

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Related in: MedlinePlus

U50,488H protected thoracic aortal structure in DM rats. (A) HE staining of the aorta. The internal surfaces of thoracic aortas were smooth and well-integrated. The endothelium was falling in the DM group, while less endothelium was falling in the DM + U50,488H group. (scale bar: 25 μm). (B) Ultrastructure of the thoracic aortas under TEM (scale bar: 2 μm). In the DM group, the endothelium of the aorta was detached from the smooth muscle, the endothelial cell junctions were not integrated, smooth muscle cells migrated into the endothelium, and more collagen fibrils and irregular thickening of elastic fibers were observed. U50,488H treatment attenuated the changes. Endothelial cells are indicated with blue arrows, and internal elastic lamina is indicated with black arrows.
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Fig3: U50,488H protected thoracic aortal structure in DM rats. (A) HE staining of the aorta. The internal surfaces of thoracic aortas were smooth and well-integrated. The endothelium was falling in the DM group, while less endothelium was falling in the DM + U50,488H group. (scale bar: 25 μm). (B) Ultrastructure of the thoracic aortas under TEM (scale bar: 2 μm). In the DM group, the endothelium of the aorta was detached from the smooth muscle, the endothelial cell junctions were not integrated, smooth muscle cells migrated into the endothelium, and more collagen fibrils and irregular thickening of elastic fibers were observed. U50,488H treatment attenuated the changes. Endothelial cells are indicated with blue arrows, and internal elastic lamina is indicated with black arrows.

Mentions: Hematoxylin and eosin (HE) staining showed intact endothelium in the CON group, that the endothelium was falling in the DM group, and only part of the endothelium was falling in the DM + U50,488H group (Figure 3A). Transmission electron microscope analysis was performed to further evaluate the effects of KOR activation on the thoracic aortal ultrastructure in DM rats. In the CON group, the surface of the endothelium was smooth, well-integrated and tightly affixed to the underlying smooth muscle. However, the endothelium of aortas from the DM group showed signs of degeneration, such as swelling and necrosis, and was noticeably detached from the smooth muscle. The endothelial cell junctions were not integrated, and smooth muscle cells migrated into the endothelium. Additionally, more collagen fibrils and irregular thickening of elastic fibers were observed in the pericellular spaces of enlarged smooth muscle cells. U50,488H treatment effectively attenuated the changes, preserving the integrity of the endothelium and decreasing smooth muscle cells migration, while treatment with vehicle or nor-BNI did not show these positive effects (Figure 3B).Figure 3


Activation of κ-opioid receptor by U50,488H improves vascular dysfunction in streptozotocin-induced diabetic rats.

Zhou X, Wang D, Zhang Y, Zhang J, Xiang D, Wang H - BMC Endocr Disord (2015)

U50,488H protected thoracic aortal structure in DM rats. (A) HE staining of the aorta. The internal surfaces of thoracic aortas were smooth and well-integrated. The endothelium was falling in the DM group, while less endothelium was falling in the DM + U50,488H group. (scale bar: 25 μm). (B) Ultrastructure of the thoracic aortas under TEM (scale bar: 2 μm). In the DM group, the endothelium of the aorta was detached from the smooth muscle, the endothelial cell junctions were not integrated, smooth muscle cells migrated into the endothelium, and more collagen fibrils and irregular thickening of elastic fibers were observed. U50,488H treatment attenuated the changes. Endothelial cells are indicated with blue arrows, and internal elastic lamina is indicated with black arrows.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4355970&req=5

Fig3: U50,488H protected thoracic aortal structure in DM rats. (A) HE staining of the aorta. The internal surfaces of thoracic aortas were smooth and well-integrated. The endothelium was falling in the DM group, while less endothelium was falling in the DM + U50,488H group. (scale bar: 25 μm). (B) Ultrastructure of the thoracic aortas under TEM (scale bar: 2 μm). In the DM group, the endothelium of the aorta was detached from the smooth muscle, the endothelial cell junctions were not integrated, smooth muscle cells migrated into the endothelium, and more collagen fibrils and irregular thickening of elastic fibers were observed. U50,488H treatment attenuated the changes. Endothelial cells are indicated with blue arrows, and internal elastic lamina is indicated with black arrows.
Mentions: Hematoxylin and eosin (HE) staining showed intact endothelium in the CON group, that the endothelium was falling in the DM group, and only part of the endothelium was falling in the DM + U50,488H group (Figure 3A). Transmission electron microscope analysis was performed to further evaluate the effects of KOR activation on the thoracic aortal ultrastructure in DM rats. In the CON group, the surface of the endothelium was smooth, well-integrated and tightly affixed to the underlying smooth muscle. However, the endothelium of aortas from the DM group showed signs of degeneration, such as swelling and necrosis, and was noticeably detached from the smooth muscle. The endothelial cell junctions were not integrated, and smooth muscle cells migrated into the endothelium. Additionally, more collagen fibrils and irregular thickening of elastic fibers were observed in the pericellular spaces of enlarged smooth muscle cells. U50,488H treatment effectively attenuated the changes, preserving the integrity of the endothelium and decreasing smooth muscle cells migration, while treatment with vehicle or nor-BNI did not show these positive effects (Figure 3B).Figure 3

Bottom Line: U50,488H treatment resulted in reduction in ANG II, sICAM-1, IL-6 and IL-8 levels and elevation in NO levels, while these effects were abolished by nor-BNI treatment.Further more, eNOS phosphorylation was increased, and NF-κB p65 translocation was decreased after U50,488H treatment.Our study demonstrated that U50,488H may have therapeutic effects on diabetic vascular dysfunction by improving endothelial dysfunction and attenuating chronic inflammation, which may be dependent on phosphorylation of eNOS and downstream inhibition of NF-кB.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China. zhouxuanxuan2007@126.com.

ABSTRACT

Background: Evidence suggests that activation of κ-opioid receptor (KOR) by U50,488H exhibits potential cardiovascular protective properties. However, the effects of U50,488H on vascular dysfunction in diabetes mellitus (DM) are still not clear. The present study was designed to investigate the effects of U50,488H on vascular dysfunction in diabetic rats and explore the underlying mechanisms involved.

Methods: Rats were randomly divided into control, DM, DM + vehicle, DM + U50,488H and DM + nor-binaltorphimine (nor-BNI) groups. Streptozotocin injection was used to induce DM. Weight, blood glucose, blood pressure and plasma insulin for each group were measured. Arterial functions were assessed with isolated vessels mounted for isometric tension recordings. Angiotensin II (ANG II), soluble intercellular adhesion molecule-1 (sICAM-1), interleukin (IL)-6 and IL-8 levels were measured by ELISA, and endothelial nitric oxide synthase (eNOS) phosphorylation and NF-κB p65 translocation were measured by Western blot.

Results: Activation of KOR by U50,488H reduced the enhanced contractility of aortas to KCl and noradrenaline and increased acetylcholine-induced vascular relaxation, which could also protect the aortal ultrastructure in DM. U50,488H treatment resulted in reduction in ANG II, sICAM-1, IL-6 and IL-8 levels and elevation in NO levels, while these effects were abolished by nor-BNI treatment. Further more, eNOS phosphorylation was increased, and NF-κB p65 translocation was decreased after U50,488H treatment.

Conclusions: Our study demonstrated that U50,488H may have therapeutic effects on diabetic vascular dysfunction by improving endothelial dysfunction and attenuating chronic inflammation, which may be dependent on phosphorylation of eNOS and downstream inhibition of NF-кB.

Show MeSH
Related in: MedlinePlus