Activation of ErbB2 and Downstream Signalling via Rho Kinases and ERK1/2 Contributes to Diabetes-Induced Vascular Dysfunction.
Diabetes mellitus leads to vascular complications but the underlying signalling mechanisms are not fully understood. Here, we examined the role of ErbB2 (HER2/Neu), a transmembrane receptor tyrosine kinase of the ErbB/EGFR (epidermal growth factor receptor) family, in mediating diabetes-induced vasc...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2013-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3694874?pdf=render |
| _version_ | 1818910798052851712 |
|---|---|
| author | Saghir Akhtar Mariam H M Yousif Gursev S Dhaunsi Fatma Sarkhouh Bindu Chandrasekhar Sreeja Attur Ibrahim F Benter |
| author_facet | Saghir Akhtar Mariam H M Yousif Gursev S Dhaunsi Fatma Sarkhouh Bindu Chandrasekhar Sreeja Attur Ibrahim F Benter |
| author_sort | Saghir Akhtar |
| collection | DOAJ |
| description | Diabetes mellitus leads to vascular complications but the underlying signalling mechanisms are not fully understood. Here, we examined the role of ErbB2 (HER2/Neu), a transmembrane receptor tyrosine kinase of the ErbB/EGFR (epidermal growth factor receptor) family, in mediating diabetes-induced vascular dysfunction in an experimental model of type 1 diabetes. Chronic treatment of streptozotocin-induced diabetic rats (1 mg/kg/alt diem) or acute, ex-vivo (10(-6), 10(-5) M) administration of AG825, a specific inhibitor of ErbB2, significantly corrected the diabetes-induced hyper-reactivity of the perfused mesenteric vascular bed (MVB) to the vasoconstrictor, norephinephrine (NE) and the attenuated responsiveness to the vasodilator, carbachol. Diabetes led to enhanced phosphorylation of ErbB2 at multiple tyrosine (Y) residues (Y1221/1222, Y1248 and Y877) in the MVB that could be attenuated by chronic AG825 treatment. Diabetes- or high glucose-mediated upregulation of ErbB2 phosphorylation was coupled with activation of Rho kinases (ROCKs) and ERK1/2 in MVB and in cultured vascular smooth muscle cells (VSMC) that were attenuated upon treatment with either chronic or acute AG825 or with anti-ErbB2 siRNA. ErbB2 likley heterodimerizes with EGFR, as evidenced by increased co-association in diabetic MVB, and further supported by our finding that ERK1/2 and ROCKs are common downstream effectors since their activation could also be blocked by AG1478. Our results show for the first time that ErbB2 is an upstream effector of ROCKs and ERK1/2 in mediating diabetes-induced vascular dysfunction. Thus, potential strategies aimed at modifying actions of signal transduction pathways involving ErbB2 pathway may prove to be beneficial in treatment of diabetes-induced vascular complications. |
| first_indexed | 2024-12-19T22:48:31Z |
| format | Article |
| id | doaj.art-9828ec605115477086f99b23630bf5c1 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-19T22:48:31Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-9828ec605115477086f99b23630bf5c12022-12-21T20:02:54ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0186e6781310.1371/journal.pone.0067813Activation of ErbB2 and Downstream Signalling via Rho Kinases and ERK1/2 Contributes to Diabetes-Induced Vascular Dysfunction.Saghir AkhtarMariam H M YousifGursev S DhaunsiFatma SarkhouhBindu ChandrasekharSreeja AtturIbrahim F BenterDiabetes mellitus leads to vascular complications but the underlying signalling mechanisms are not fully understood. Here, we examined the role of ErbB2 (HER2/Neu), a transmembrane receptor tyrosine kinase of the ErbB/EGFR (epidermal growth factor receptor) family, in mediating diabetes-induced vascular dysfunction in an experimental model of type 1 diabetes. Chronic treatment of streptozotocin-induced diabetic rats (1 mg/kg/alt diem) or acute, ex-vivo (10(-6), 10(-5) M) administration of AG825, a specific inhibitor of ErbB2, significantly corrected the diabetes-induced hyper-reactivity of the perfused mesenteric vascular bed (MVB) to the vasoconstrictor, norephinephrine (NE) and the attenuated responsiveness to the vasodilator, carbachol. Diabetes led to enhanced phosphorylation of ErbB2 at multiple tyrosine (Y) residues (Y1221/1222, Y1248 and Y877) in the MVB that could be attenuated by chronic AG825 treatment. Diabetes- or high glucose-mediated upregulation of ErbB2 phosphorylation was coupled with activation of Rho kinases (ROCKs) and ERK1/2 in MVB and in cultured vascular smooth muscle cells (VSMC) that were attenuated upon treatment with either chronic or acute AG825 or with anti-ErbB2 siRNA. ErbB2 likley heterodimerizes with EGFR, as evidenced by increased co-association in diabetic MVB, and further supported by our finding that ERK1/2 and ROCKs are common downstream effectors since their activation could also be blocked by AG1478. Our results show for the first time that ErbB2 is an upstream effector of ROCKs and ERK1/2 in mediating diabetes-induced vascular dysfunction. Thus, potential strategies aimed at modifying actions of signal transduction pathways involving ErbB2 pathway may prove to be beneficial in treatment of diabetes-induced vascular complications.http://europepmc.org/articles/PMC3694874?pdf=render |
| spellingShingle | Saghir Akhtar Mariam H M Yousif Gursev S Dhaunsi Fatma Sarkhouh Bindu Chandrasekhar Sreeja Attur Ibrahim F Benter Activation of ErbB2 and Downstream Signalling via Rho Kinases and ERK1/2 Contributes to Diabetes-Induced Vascular Dysfunction. PLoS ONE |
| title | Activation of ErbB2 and Downstream Signalling via Rho Kinases and ERK1/2 Contributes to Diabetes-Induced Vascular Dysfunction. |
| title_full | Activation of ErbB2 and Downstream Signalling via Rho Kinases and ERK1/2 Contributes to Diabetes-Induced Vascular Dysfunction. |
| title_fullStr | Activation of ErbB2 and Downstream Signalling via Rho Kinases and ERK1/2 Contributes to Diabetes-Induced Vascular Dysfunction. |
| title_full_unstemmed | Activation of ErbB2 and Downstream Signalling via Rho Kinases and ERK1/2 Contributes to Diabetes-Induced Vascular Dysfunction. |
| title_short | Activation of ErbB2 and Downstream Signalling via Rho Kinases and ERK1/2 Contributes to Diabetes-Induced Vascular Dysfunction. |
| title_sort | activation of erbb2 and downstream signalling via rho kinases and erk1 2 contributes to diabetes induced vascular dysfunction |
| url | http://europepmc.org/articles/PMC3694874?pdf=render |
| work_keys_str_mv | AT saghirakhtar activationoferbb2anddownstreamsignallingviarhokinasesanderk12contributestodiabetesinducedvasculardysfunction AT mariamhmyousif activationoferbb2anddownstreamsignallingviarhokinasesanderk12contributestodiabetesinducedvasculardysfunction AT gursevsdhaunsi activationoferbb2anddownstreamsignallingviarhokinasesanderk12contributestodiabetesinducedvasculardysfunction AT fatmasarkhouh activationoferbb2anddownstreamsignallingviarhokinasesanderk12contributestodiabetesinducedvasculardysfunction AT binduchandrasekhar activationoferbb2anddownstreamsignallingviarhokinasesanderk12contributestodiabetesinducedvasculardysfunction AT sreejaattur activationoferbb2anddownstreamsignallingviarhokinasesanderk12contributestodiabetesinducedvasculardysfunction AT ibrahimfbenter activationoferbb2anddownstreamsignallingviarhokinasesanderk12contributestodiabetesinducedvasculardysfunction |