Synergism between AT1 receptor and hyperhomocysteinemia during vascular remodeling

Utpal Sen; Markus Herrmann; Wolfgang Herrmann; Suresh C. Tyagi

doi:10.1515/CCLM.2007.354

Article

Synergism between AT1 receptor and hyperhomocysteinemia during vascular remodeling

Utpal Sen , Markus Herrmann , Wolfgang Herrmann and Suresh C. Tyagi

Published/Copyright: December 8, 2007

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Clinical Chemistry and Laboratory Medicine (CCLM)

From the journal Volume 45 Issue 12

Abstract

Background: Hyperhomocysteinemia (HHcy) is an independent risk factor of cardiovascular diseases. Extracellular signal-regulated kinase-1/2 (ERK-1/2) and the JAK/STAT pathway kinase, signal transducer and activator of transcription 3 (STAT3), are involved in matrix metalloproteinase-9 (MMP-9) induction and matrix remodeling. However, their role in homocysteine (Hcy)-mediated MMP-9 induction and matrix remodeling is unclear. Clinical and experimental evidence indicates that HHcy and activation of the renin-angiotensin system, mediated by angiotensin II type 1 (AT1) receptor, are involved in a variety of vascular pathologies. Despite this fact, the relationship between HHcy and activation of the renin-angiotensin system has not been comprehensively characterized. Therefore, we hypothesized that Hcy activates AT1 receptor that potentiates STAT3 via ERK-1/2 phosphorylation. STAT3 modulates target MMP-9 and collagen, resulting in vascular remodeling.

Methods: Mouse aortic endothelial cells (MAEC) were treated with various doses of Hcy for different time periods. The levels of AT1 receptor, ERK-1/2, STAT3, MMP-9 and collagen type-1 were measured by immunoblot analyses. The activation of ERK-1/2 and STAT3 were determined by measuring ERK-1/2 phosphorylation and phosphoserine (727) STAT3.

Results: Although Hcy dose-dependently induced AT1 receptor expression in the endothelial cells, a significant induction was observed at 100 μM at 48 h. We investigated Hcy-induced ERK-1/2 and STAT3 phosphorylation through AT1 receptor induction, and our results suggest that Hcy activated AT1 receptor which led to ERK-1/2 and STAT3 phosphorylation. In addition, findings of this study suggest that Hcy-mediated STAT3 activation regulated MMP-9 and collagen type-1. However, AT1 receptor blocker, valsartan, and the specific STAT3 inhibitor peptide attenuated MMP-9 and collagen type-1 induction.

Conclusions: These findings demonstrate for the first time the contribution of AT1 receptor in HHcy-induced atherosclerotic diseases; Hcy-induced activation of AT1 receptor involves MMP-9 and collagen type-1 modulation using ERK-1/2 and STAT3 signaling cascades.

Clin Chem Lab Med 2007;45:1771–6.

Keywords: angiotensin II type 1 (AT1) receptor; collagen type-1; extracellular matrix; extracellular signal-regulated kinase-1/2 (ERK-1/2); matrix metalloproteinase-9 (MMP-9); signal transducer and activator of transcription-3 (STAT3)

Corresponding author: Suresh C. Tyagi, Department of Physiology and Biophysics, University of Louisville School of Medicine, A-1215, 500 South Preston Street, Louisville, KY 40202, USA Phone: +1-502-852-3381, Fax: +1-502-852-6239, suresh.tyagi@louisville.edu

Received: 2007-7-17

Accepted: 2007-9-28

Published Online: 2007-12-08

Published in Print: 2007-12-01

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https://doi.org/10.1515/CCLM.2007.354

Keywords for this article

angiotensin II type 1 (AT1) receptor; collagen type-1; extracellular matrix; extracellular signal-regulated kinase-1/2 (ERK-1/2); matrix metalloproteinase-9 (MMP-9); signal transducer and activator of transcription-3 (STAT3)