Role of inflammation and endothelial dysfunction of coronary arterioles in type 2 diabetes /
| Main Author: | |
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| Other Authors: | , |
| Format: | Thesis eBook |
| Language: | English |
| Published: |
[College Station, Tex.] :
[Texas A&M University],
[2010]
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| Subjects: | |
| Online Access: | Link to OAK Trust copy |
| Abstract: | We hypothesized that the interaction between tumor necrosis factor alpha(TNF[alpha])/nuclear factor-kappaB (NF[kappa]B) via activation of IKK[beta] may amplify one another resulting in the evolution of vascular disease and insulin resistance associated with diabetes. The interaction between TNF[alpha] and monocyte chemoattractant protein-1 (MCP-1) may contribute to the evolution of vascular inflammation and endothelial dysfunctionin coronary arterioles in type 2 diabetes. To test this hypothesis, endothelium-dependent(ACh) and --independent (SNP) vasodilation of isolated, pressurized coronary arterioles(40-100 [mu]m) from mLeprdb (heterozygote, normal), Leprdb (homozygote, diabetic) andLeprdb mice null for TNF[alpha] (dbTNF-/dbTNF-) were examined. Although dilation of vessels to SNP was not different between Leprdb and mLeprdb mice, dilation to ACh was reduced in Leprdb mice. The NF[kappa]B antagonist, MG-132, IKK[beta] inhibitor, sodium salicylate(NaSal), or Anti-MCP-1 partially restored endothelium-dependent coronary arteriolar dilation in Leprdb mice. Protein expression of IKK[alpha] and IKK[beta] were higher in Leprdb than in mLeprdb mice. The expression of IKK[beta], but not the expression of IKK[alpha] was increased in dbTNF-/dbTNF- mice. Leprdb mice showed increased insulin resistance, but NaSal improved insulin sensitivity. Protein expression of TNF[alpha], NF[kappa]B, phosphorylation of IKK[beta] and JNK were greater in Leprdb mice, but NaSal attenuated protein expression of them in Leprdb mice. The ratio of phosphorylated IRS-1 at Ser307 (pIRS-1)/IRS-1 protein expression was elevated in Leprdb mice; both NaSal and JNK inhibitor SP600125 reduced pIRS-1/IRS-1 in Leprdb mice. MG-132 or neutralization of TNF reduced superoxide production in Leprdb mice. Anti-MCP-1 attenuated superoxide production and protein expression of nitrotyrosine (N-Tyr), which is an indicator of peroxynitrite production, in isolated coronary arterioles of Leprdb mice. Immunostaining results showed that expression of MCP-1 and vascular cellular adhesion molecule-1 (VCAM) is co-localized with endothelial cells and macrophages. Anti-TNF[alpha] or anti-MCP-1 markedly reduced macrophage infiltration and the number of MCP-1 positive cells. Neutralization of TNF[alpha] or anti-MCP-1 reduced the expression of adhesion molecules. In conclusion, our results indicate that the interaction between NF[kappa]B and TNF[alpha] signaling induces activation of IKK[beta]. In addition, TNF[alpha] and TNF[alpha]-related signaling, including the expression of MCP-1 and adhesion molecules, further exacerbates oxidative stress leading to endothelial dysfunction in type 2 diabetes. |
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| Item Description: | "Major Subject: Biomedical Sciences" Title from author supplied metadata (automated record created 2010-03-12 12:08:51). Electronic resource. |
| Physical Description: | 1 online resource. |
| Bibliography: | Includes bibliographical references. |