HuR/Cx40 downregulation causes coronary microvascular dysfunction in type 2 diabetes
Patients with diabetes with coronary microvascular disease (CMD) exhibit higher cardiac mortality than patients without CMD. However, the molecular mechanism by which diabetes promotes CMD is poorly understood. RNA-binding protein human antigen R (HuR) is a key regulator of mRNA stability and transl...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2021-11-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.147982 |
| _version_ | 1811334807485939712 |
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| author | Rui Si Jody Tori O. Cabrera Atsumi Tsuji-Hosokawa Rui Guo Makiko Watanabe Lei Gao Yun Sok Lee Jae-Su Moon Brian T. Scott Jian Wang Anthony W. Ashton Jaladanki N. Rao Jian-Ying Wang Jason X.-J. Yuan Ayako Makino |
| author_facet | Rui Si Jody Tori O. Cabrera Atsumi Tsuji-Hosokawa Rui Guo Makiko Watanabe Lei Gao Yun Sok Lee Jae-Su Moon Brian T. Scott Jian Wang Anthony W. Ashton Jaladanki N. Rao Jian-Ying Wang Jason X.-J. Yuan Ayako Makino |
| author_sort | Rui Si |
| collection | DOAJ |
| description | Patients with diabetes with coronary microvascular disease (CMD) exhibit higher cardiac mortality than patients without CMD. However, the molecular mechanism by which diabetes promotes CMD is poorly understood. RNA-binding protein human antigen R (HuR) is a key regulator of mRNA stability and translation; therefore, we investigated the role of HuR in the development of CMD in mice with type 2 diabetes. Diabetic mice exhibited decreases in coronary flow velocity reserve (CFVR; a determinant of coronary microvascular function) and capillary density in the left ventricle. HuR levels in cardiac endothelial cells (CECs) were significantly lower in diabetic mice and patients with diabetes than the controls. Endothelial-specific HuR-KO mice also displayed significant reductions in CFVR and capillary density. By examining mRNA levels of 92 genes associated with endothelial function, we found that HuR, Cx40, and Nox4 levels were decreased in CECs from diabetic and HuR-KO mice compared with control mice. Cx40 expression and HuR binding to Cx40 mRNA were downregulated in CECs from diabetic mice. Cx40-KO mice exhibited decreased CFVR and capillary density, whereas endothelium-specific Cx40 overexpression increased capillary density and improved CFVR in diabetic mice. These data suggest that decreased HuR contributes to the development of CMD in diabetes through downregulation of gap junction protein Cx40 in CECs. |
| first_indexed | 2024-04-13T17:14:36Z |
| format | Article |
| id | doaj.art-6276e505da664ccaa86691d1f879b040 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-04-13T17:14:36Z |
| publishDate | 2021-11-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-6276e505da664ccaa86691d1f879b0402022-12-22T02:38:10ZengAmerican Society for Clinical investigationJCI Insight2379-37082021-11-01621HuR/Cx40 downregulation causes coronary microvascular dysfunction in type 2 diabetesRui SiJody Tori O. CabreraAtsumi Tsuji-HosokawaRui GuoMakiko WatanabeLei GaoYun Sok LeeJae-Su MoonBrian T. ScottJian WangAnthony W. AshtonJaladanki N. RaoJian-Ying WangJason X.-J. YuanAyako MakinoPatients with diabetes with coronary microvascular disease (CMD) exhibit higher cardiac mortality than patients without CMD. However, the molecular mechanism by which diabetes promotes CMD is poorly understood. RNA-binding protein human antigen R (HuR) is a key regulator of mRNA stability and translation; therefore, we investigated the role of HuR in the development of CMD in mice with type 2 diabetes. Diabetic mice exhibited decreases in coronary flow velocity reserve (CFVR; a determinant of coronary microvascular function) and capillary density in the left ventricle. HuR levels in cardiac endothelial cells (CECs) were significantly lower in diabetic mice and patients with diabetes than the controls. Endothelial-specific HuR-KO mice also displayed significant reductions in CFVR and capillary density. By examining mRNA levels of 92 genes associated with endothelial function, we found that HuR, Cx40, and Nox4 levels were decreased in CECs from diabetic and HuR-KO mice compared with control mice. Cx40 expression and HuR binding to Cx40 mRNA were downregulated in CECs from diabetic mice. Cx40-KO mice exhibited decreased CFVR and capillary density, whereas endothelium-specific Cx40 overexpression increased capillary density and improved CFVR in diabetic mice. These data suggest that decreased HuR contributes to the development of CMD in diabetes through downregulation of gap junction protein Cx40 in CECs.https://doi.org/10.1172/jci.insight.147982Vascular biology |
| spellingShingle | Rui Si Jody Tori O. Cabrera Atsumi Tsuji-Hosokawa Rui Guo Makiko Watanabe Lei Gao Yun Sok Lee Jae-Su Moon Brian T. Scott Jian Wang Anthony W. Ashton Jaladanki N. Rao Jian-Ying Wang Jason X.-J. Yuan Ayako Makino HuR/Cx40 downregulation causes coronary microvascular dysfunction in type 2 diabetes JCI Insight Vascular biology |
| title | HuR/Cx40 downregulation causes coronary microvascular dysfunction in type 2 diabetes |
| title_full | HuR/Cx40 downregulation causes coronary microvascular dysfunction in type 2 diabetes |
| title_fullStr | HuR/Cx40 downregulation causes coronary microvascular dysfunction in type 2 diabetes |
| title_full_unstemmed | HuR/Cx40 downregulation causes coronary microvascular dysfunction in type 2 diabetes |
| title_short | HuR/Cx40 downregulation causes coronary microvascular dysfunction in type 2 diabetes |
| title_sort | hur cx40 downregulation causes coronary microvascular dysfunction in type 2 diabetes |
| topic | Vascular biology |
| url | https://doi.org/10.1172/jci.insight.147982 |
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