Abstract
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.
Highlights
The global incidence of diabetes mellitus is set to rise to over 550 million by 2030 [1,2]
Bed Diabetes led to enhanced phosphorylation of ErbB2 at multiple tyrosine (Y) residues (Y1221/1222, Y1248, as detected by two different antibodies indicated as Y1248a and Y1248b, and Y877) that could be attenuated by AG825 treatment (Figure 2)
Diabetes resulted in elevated levels of total ROCK I and ROCK II as well as phosphorylated levels of ROCK II at Y256 and extracellular-signal-regulated kinase 1/2 (ERK1/2) in the mesenteric vascular bed that could be significantly attenuated by chronic AG825 treatment (Figure 3a)
Summary
The global incidence of diabetes mellitus is set to rise to over 550 million by 2030 [1,2]. The exact underlying mechanisms for the development of vascular complications such as altered vascular reactivity in diabetes are poorly understood and may involve multiple signaling pathways that are affected by hyperglycemia [4,5]. ErbB2 receptor is a 175-kDa glycoprotein that lacks a known ligand and relies on heterodimerization with other EGFR family members for signaling. Transactivation of ErbBs can occur via G-protein coupled receptors (GPCRs), such as angiotensin II (Ang II), thrombin, aldosterone and endothelin [11,12,13,14,15]. Depending on the specific cellular conditions, EGFR transactivation can occur via upstream kinases such as c-src [11] or involve metalloprotease and/or ADAM(a disintegrin and metalloprotease)-dependent shedding of cell-surface bound EGFlike ligands [14]
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