Synergism in hyperhomocysteinemia and diabetes: role of PPAR gamma and tempol
<p>Abstract</p> <p>Background</p> <p>Hyperhomocysteinemia (HHcy) and hyperglycemia cause diabetic cardiomyopathy by inducing oxidative stress and attenuating peroxisome proliferator- activated receptor (PPAR) gamma. However, their synergistic contribution is not clear.&...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2010-09-01
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| Series: | Cardiovascular Diabetology |
| Online Access: | http://www.cardiab.com/content/9/1/49 |
| _version_ | 1818177948344123392 |
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| author | Mishra Paras K Tyagi Neetu Sen Utpal Joshua Irving G Tyagi Suresh C |
| author_facet | Mishra Paras K Tyagi Neetu Sen Utpal Joshua Irving G Tyagi Suresh C |
| author_sort | Mishra Paras K |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Hyperhomocysteinemia (HHcy) and hyperglycemia cause diabetic cardiomyopathy by inducing oxidative stress and attenuating peroxisome proliferator- activated receptor (PPAR) gamma. However, their synergistic contribution is not clear.</p> <p>Methods</p> <p>Diabetic Akita (Ins2+/-) and hyperhomocysteinemic cystathionine beta synthase mutant (CBS+/-) were used for M-mode echocardiography at the age of four and twenty four weeks. The cardiac rings from WT, Akita and hybrid (Ins2+/-/CBS+/-) of Akita and CBS+/- were treated with different doses of acetylcholine (an endothelial dependent vasodilator). High performance liquid chromatography (HPLC) was performed for determining plasma homocysteine (Hcy) level in the above groups. Akita was treated with ciglitazone (CZ) - a PPAR gamma agonist and tempol-an anti-oxidant, separately and their effects on cardiac remodeling were assessed.</p> <p>Results</p> <p>At twenty four week, Akita mice were hyperglycemic and HHcy. They have increased end diastolic diameter (EDD). In their heart PPAR gamma, tissue inhibitor of metalloproteinase-4 (TIMP-4) and anti-oxidant thioredoxin were attenuated whereas matrix metalloproteinase (MMP)-9, TIMP-3 and NADPH oxidase 4 (NOX4) were induced. Interestingly, they showed synergism between HHcy and hyperglycemia for endothelial-myocyte (E-M) uncoupling. Additionally, treatment with CZ alleviated MMP-9 activity and fibrosis, and improved EDD. On the other hand, treatment with tempol reversed cardiac remodeling in part by restoring the expressions of TIMP-3,-4, thioredoxin and MMP-9.</p> <p>Conclusions</p> <p>Endogenous homocysteine exacerbates diabetic cardiomyopathy by attenuating PPAR gamma and inducing E-M uncoupling leading to diastolic dysfunction. PPAR gamma agonist and tempol mitigates oxidative stress and ameliorates diastolic dysfunction in diabetes.</p> |
| first_indexed | 2024-12-11T20:40:11Z |
| format | Article |
| id | doaj.art-9dd1c34920d7464882848b6a7de2aa73 |
| institution | Directory Open Access Journal |
| issn | 1475-2840 |
| language | English |
| last_indexed | 2024-12-11T20:40:11Z |
| publishDate | 2010-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Cardiovascular Diabetology |
| spelling | doaj.art-9dd1c34920d7464882848b6a7de2aa732022-12-22T00:51:32ZengBMCCardiovascular Diabetology1475-28402010-09-01914910.1186/1475-2840-9-49Synergism in hyperhomocysteinemia and diabetes: role of PPAR gamma and tempolMishra Paras KTyagi NeetuSen UtpalJoshua Irving GTyagi Suresh C<p>Abstract</p> <p>Background</p> <p>Hyperhomocysteinemia (HHcy) and hyperglycemia cause diabetic cardiomyopathy by inducing oxidative stress and attenuating peroxisome proliferator- activated receptor (PPAR) gamma. However, their synergistic contribution is not clear.</p> <p>Methods</p> <p>Diabetic Akita (Ins2+/-) and hyperhomocysteinemic cystathionine beta synthase mutant (CBS+/-) were used for M-mode echocardiography at the age of four and twenty four weeks. The cardiac rings from WT, Akita and hybrid (Ins2+/-/CBS+/-) of Akita and CBS+/- were treated with different doses of acetylcholine (an endothelial dependent vasodilator). High performance liquid chromatography (HPLC) was performed for determining plasma homocysteine (Hcy) level in the above groups. Akita was treated with ciglitazone (CZ) - a PPAR gamma agonist and tempol-an anti-oxidant, separately and their effects on cardiac remodeling were assessed.</p> <p>Results</p> <p>At twenty four week, Akita mice were hyperglycemic and HHcy. They have increased end diastolic diameter (EDD). In their heart PPAR gamma, tissue inhibitor of metalloproteinase-4 (TIMP-4) and anti-oxidant thioredoxin were attenuated whereas matrix metalloproteinase (MMP)-9, TIMP-3 and NADPH oxidase 4 (NOX4) were induced. Interestingly, they showed synergism between HHcy and hyperglycemia for endothelial-myocyte (E-M) uncoupling. Additionally, treatment with CZ alleviated MMP-9 activity and fibrosis, and improved EDD. On the other hand, treatment with tempol reversed cardiac remodeling in part by restoring the expressions of TIMP-3,-4, thioredoxin and MMP-9.</p> <p>Conclusions</p> <p>Endogenous homocysteine exacerbates diabetic cardiomyopathy by attenuating PPAR gamma and inducing E-M uncoupling leading to diastolic dysfunction. PPAR gamma agonist and tempol mitigates oxidative stress and ameliorates diastolic dysfunction in diabetes.</p>http://www.cardiab.com/content/9/1/49 |
| spellingShingle | Mishra Paras K Tyagi Neetu Sen Utpal Joshua Irving G Tyagi Suresh C Synergism in hyperhomocysteinemia and diabetes: role of PPAR gamma and tempol Cardiovascular Diabetology |
| title | Synergism in hyperhomocysteinemia and diabetes: role of PPAR gamma and tempol |
| title_full | Synergism in hyperhomocysteinemia and diabetes: role of PPAR gamma and tempol |
| title_fullStr | Synergism in hyperhomocysteinemia and diabetes: role of PPAR gamma and tempol |
| title_full_unstemmed | Synergism in hyperhomocysteinemia and diabetes: role of PPAR gamma and tempol |
| title_short | Synergism in hyperhomocysteinemia and diabetes: role of PPAR gamma and tempol |
| title_sort | synergism in hyperhomocysteinemia and diabetes role of ppar gamma and tempol |
| url | http://www.cardiab.com/content/9/1/49 |
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