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Progressive Decrease in Coronary Vascular Function Associated With Type 2 Diabetic Heart Disease
Background: The causal factors underpinning the onset and progression of diabetic heart disease (DHD) remain to be fully elucidated. Myocardial function is critically dependent on optimal coronary blood flow. Considering vascular disease occurs early in diabetes due to endothelial dysfunction, this...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5997806/ https://www.ncbi.nlm.nih.gov/pubmed/29928236 http://dx.doi.org/10.3389/fphys.2018.00696 |
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author | Katare, Rajesh Pearson, James T. Lew, Jason Kar-Sheng Wei, Melanie Tsuchimouchi, Hirotsugu Du, Cheng-Kun Zhan, Dong-Yun Umetani, Keiji Shirai, Mikiyasu Schwenke, Daryl O. |
author_facet | Katare, Rajesh Pearson, James T. Lew, Jason Kar-Sheng Wei, Melanie Tsuchimouchi, Hirotsugu Du, Cheng-Kun Zhan, Dong-Yun Umetani, Keiji Shirai, Mikiyasu Schwenke, Daryl O. |
author_sort | Katare, Rajesh |
collection | PubMed |
description | Background: The causal factors underpinning the onset and progression of diabetic heart disease (DHD) remain to be fully elucidated. Myocardial function is critically dependent on optimal coronary blood flow. Considering vascular disease occurs early in diabetes due to endothelial dysfunction, this study aimed to determine whether impaired coronary perfusion contributes to the origins of myocardial dysfunction in DHD, or whether coronary and cardiac dysfunction are independent pathologies associated with diabetes. Methods: Synchrotron radiation microangiography was used to image the coronary circulation of type-2 diabetic db/db and non-diabetic db/+ mice in vivo at 8, 16, and 24 weeks of age. We further assessed vascular function based on the vasodilatory responses to acetylcholine (ACh, 3 μg/kg/min), sodium nitroprusside (SNP, 5 μg/kg/min) and the Rho-kinase inhibitor, fasudil (20 mg/kg, i.v.). Cardiac function was assessed using echocardiography, and cardiac eNOS and ROCK expression were measured using immunohistochemistry. Results: Coronary and cardiac function were normal in 8-week-old diabetic mice. However, by 16 weeks of age, diabetic mice had advanced cardiac dysfunction. In comparison, normal coronary perfusion was preserved in diabetes until 24 weeks of age. Moreover, only the 24-week-old diabetic mice showed clear evidence of advanced coronary vascular dysfunction, based on (i) the absence of a vasodilatory response to ACh, and (ii) an exaggerated vasodilatory response to fasudil. Interestingly, fasudil also restored normal coronary perfusion in the 24-week-old diabetic heart by restoring blood flow to previously constricted vessels (diameter < 100 μm). Importantly, there was a ubiquitous decrease, and increase, in the cardiac expression of eNOS and ROCK, respectively. Conclusion: These results suggest that both cardiac and coronary dysfunction appear to have independent origins associated with diabetes and Rho-kinase pathway may be playing a role in the onset and progression of DHD. |
format | Online Article Text |
id | pubmed-5997806 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-59978062018-06-20 Progressive Decrease in Coronary Vascular Function Associated With Type 2 Diabetic Heart Disease Katare, Rajesh Pearson, James T. Lew, Jason Kar-Sheng Wei, Melanie Tsuchimouchi, Hirotsugu Du, Cheng-Kun Zhan, Dong-Yun Umetani, Keiji Shirai, Mikiyasu Schwenke, Daryl O. Front Physiol Physiology Background: The causal factors underpinning the onset and progression of diabetic heart disease (DHD) remain to be fully elucidated. Myocardial function is critically dependent on optimal coronary blood flow. Considering vascular disease occurs early in diabetes due to endothelial dysfunction, this study aimed to determine whether impaired coronary perfusion contributes to the origins of myocardial dysfunction in DHD, or whether coronary and cardiac dysfunction are independent pathologies associated with diabetes. Methods: Synchrotron radiation microangiography was used to image the coronary circulation of type-2 diabetic db/db and non-diabetic db/+ mice in vivo at 8, 16, and 24 weeks of age. We further assessed vascular function based on the vasodilatory responses to acetylcholine (ACh, 3 μg/kg/min), sodium nitroprusside (SNP, 5 μg/kg/min) and the Rho-kinase inhibitor, fasudil (20 mg/kg, i.v.). Cardiac function was assessed using echocardiography, and cardiac eNOS and ROCK expression were measured using immunohistochemistry. Results: Coronary and cardiac function were normal in 8-week-old diabetic mice. However, by 16 weeks of age, diabetic mice had advanced cardiac dysfunction. In comparison, normal coronary perfusion was preserved in diabetes until 24 weeks of age. Moreover, only the 24-week-old diabetic mice showed clear evidence of advanced coronary vascular dysfunction, based on (i) the absence of a vasodilatory response to ACh, and (ii) an exaggerated vasodilatory response to fasudil. Interestingly, fasudil also restored normal coronary perfusion in the 24-week-old diabetic heart by restoring blood flow to previously constricted vessels (diameter < 100 μm). Importantly, there was a ubiquitous decrease, and increase, in the cardiac expression of eNOS and ROCK, respectively. Conclusion: These results suggest that both cardiac and coronary dysfunction appear to have independent origins associated with diabetes and Rho-kinase pathway may be playing a role in the onset and progression of DHD. Frontiers Media S.A. 2018-06-06 /pmc/articles/PMC5997806/ /pubmed/29928236 http://dx.doi.org/10.3389/fphys.2018.00696 Text en Copyright © 2018 Katare, Pearson, Kar-Sheng Lew, Wei, Tsuchimouchi, Du, Zhan, Umetani, Shirai and Schwenke. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Physiology Katare, Rajesh Pearson, James T. Lew, Jason Kar-Sheng Wei, Melanie Tsuchimouchi, Hirotsugu Du, Cheng-Kun Zhan, Dong-Yun Umetani, Keiji Shirai, Mikiyasu Schwenke, Daryl O. Progressive Decrease in Coronary Vascular Function Associated With Type 2 Diabetic Heart Disease |
title | Progressive Decrease in Coronary Vascular Function Associated With Type 2 Diabetic Heart Disease |
title_full | Progressive Decrease in Coronary Vascular Function Associated With Type 2 Diabetic Heart Disease |
title_fullStr | Progressive Decrease in Coronary Vascular Function Associated With Type 2 Diabetic Heart Disease |
title_full_unstemmed | Progressive Decrease in Coronary Vascular Function Associated With Type 2 Diabetic Heart Disease |
title_short | Progressive Decrease in Coronary Vascular Function Associated With Type 2 Diabetic Heart Disease |
title_sort | progressive decrease in coronary vascular function associated with type 2 diabetic heart disease |
topic | Physiology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5997806/ https://www.ncbi.nlm.nih.gov/pubmed/29928236 http://dx.doi.org/10.3389/fphys.2018.00696 |
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