الفهرس 
Introduction and aim of the workOnly 14 pages are availabe for public view
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Abstract
Diabetes mellitus is one of the most common predisposing factors for cardiovascular diseases and cardiac-related death worldwide. Endothelial dysfunction is the starting key in diabetes-associated cardiovascular complications. Several studies suggested that hyperglycemia, the hallmark in DM, is the main inducing factor of endothelial dysfunction in DM. Hyperglycemia is accompanied by activation of various staggered pathological consequences such as increased oxidative stress, endothelial cell apoptosis, and inflammation that ultimately ends with endothelial dysfunction and damage in vascular function.
Reduced nitric oxide (NO) bioavailability, increased contractile mediators, increased inflammatory mediators, and apoptotic markers are all among the contributing factors in the pathophysiology of endothelial dysfunction.
Antidiabetic drugs seek to reduce blood glucose levels and reduce diabetes-related cardiovascular complications, this aim was achieved by many of them such as Metformin and Pioglitazone through their antidiabetic effect. Also, antioxidant flavonoids such as Dihydromyricetin possess antidiabetic, anti-inflammatory activity in addition to their antioxidant effect and have an evident role in the prevention of endothelial dysfunction.
This study was conducted to investigate the possible effect of direct high glucose concentration on the function of rat aortic tissue and its alteration by different drug treatments, Metformin, Pioglitazone, and dihydromyricetin. Besides, we aimed to explore the possible signaling pathways involved in high glucose-induced endothelial dysfunction and the effect of these drugs on them.
Endothelial dysfunction was induced in the female aortic segment by incubation in high glucose (40 mM) solution for 3 hours and compare these set of experiments to other segments incubated either with low glucose (10 mM) solution or high mannitol (40 mM) solution for 3 hours to exclude the factor of time and osmolarity in this in vitro model. Also, they were compared to other segments incubated with high glucose but in presence of either Metformin, Pioglitazone, or Dihydromyricetin.
Our experiment was divided into 3 parts:
1- Incubated tissues subjected to assessment of vascular function
2- Incubated tissues stored in 10% formalin for histopathological measures and assessment of immunoreactivity of some questionable signaling pathway mediators.
3- Incubated tissues frozen in liquid nitrogen were then subjected to chemical measurement of some biochemical markers.
The results of our study can be summarized in the following points:
1- Reduced endothelial-dependent relaxation and enhanced vascular contractility were observed in aortic tissues incubated with high glucose.
2- Aortic tissues incubated with high glucose showed an increased level of total nitrite/nitrate and a compensatory increase in SOD activity and Catalase activity but not enough to overcome the observed burst of nitrosative stress level.
3- Histopathological damage and profound adventitial edema and inflammation were observed in aortic tissues incubated with high glucose.
4- The immunoreactivity of eNOS and Bcl2 was markedly attenuated in aortic tissues incubated with high glucose.
5- TNF-α, iNOS, HIF-1α, GLUT-1, ROR2, and NF-κB immunoreactivity was increased in aortic tissue incubated with high glucose.
6- Regarding the control groups, both low glucose and high mannitol groups provide an increased endothelium-dependent relaxation and reduced contractile response to PE compared to the high glucose group.
7- Incubation of aortic tissues with either low glucose or high mannitol showed a reduced level of total nitrite/nitrate, SOD, and Catalase activity compared to the high glucose group.
8- Both low glucose and high mannitol preserve the vascular integrity observed in H&E-stained aortic sections.
9- Aortic tissues incubated with low glucose revealed a reasonable increase in eNOS and Bcl2 immunoreactivity compared to the high glucose group.
10- TNF-α, iNOS, HIF-1α, GLUT-1, ROR2, and NF-κB immunoreactivity was reduced in aortic tissues incubated with low glucose compared to the high glucose group.
11- Regarding tested drugs, each causes an apparent improvement in vascular function showed in reduced vascular contractility to PE and enhanced ACh-induced relaxation compared to the high glucose group.
12- All tested drugs showed an obvious reduction in total nitrite/nitrate level, SOD, and Catalase activity compared to the high glucose group.
13- The addition of tested drugs with aortic tissues incubated in high glucose causes marked inhibition of high glucose-induced histopathological damage.
14- Compared to the high glucose group; each of Metformin, pioglitazone, and Dihydromyricetin showed a comparable and intensive increase in eNOS and Bcl2 immunoreactivity.
15- Each of the tested drugs was able to normalize inflammatory mediators (TNF-α, NF-κB, and iNOS) and downregulate their upstream mediators (HIF-1α, GLUT-1, and ROR2).
Conclusion:
This study demonstrated the protective effect of either Metformin, Pioglitazone, or Dihydromyricetin on high glucose-induced endothelial dysfunction in addition to their possible signaling pathway involved. The addition of Metformin, Pioglitazone, or Dihydromyricetin into incubation media prohibited high glucose-induced attenuated vascular responses to ACh and PE, reduced oxidative stress, and prevented high glucose-induced histopathological damage. These effects suggested being mediated through the inhibition of HIF-1α that though to be involved in the regulation of cellular glucose entrance which is subsequently involved in enhanced oxidative stress and inflammation. Also, increased glucose entrance was believed to increase hypoxic condition and overactivated HIF-1α which eventually activates Wnt5a/ROR2 and NF-κB pathways that predispose inflammation and apoptosis signaling.