Losartan inhibits EGFR transactivation in vascular smooth muscle cells

Mustafa Kirça,Akın Yeşi̇lkaya

doi:10.3906/sag-1802-113

Abstract

Angiotensin II (Ang II)-induced molecular signaling pathways play a significant role in the progression of cardiovascular diseases, including hypertension and atherosclerosis. In addition to the well-known effects of Ang II, it may activate epidermal growth factor receptor (EGFR) in a process known as transactivation, which contributes to vascular pathologies. The aim of this study was to determine whether losartan could reduce EGFR transactivation induced by Ang II. Additionally, we evaluated the roles of heparin-binding epidermal-like growth factor (HB-EGF) and matrix metalloproteinases (MMPs) in Ang II-induced EGFR transactivation. Vascular smooth muscle cells were isolated from a rat aorta and grown in primary culture. Ang II-induced EGFR phosphorylation (tyrosine 1068) and ERK1/2 MAPK phosphorylation (threonine 202 and tyrosine 204) were evaluated by western blotting. Ang II induced EGFR phosphorylation through the Ang II type I receptor (P < 0.05). The transactivation process was inhibited by losartan and mediated by HB-EGF and MMPs. Ang II transactivates EGFR in an AT1R-dependent manner. The results of this study show that losartan, a widely used antihypertensive agent, can suppress EGFR phosphorylation (Y1068) upon Ang II stimulation in vascular smooth muscle cells. EGFR inhibition is a candidate therapy for combating cardiovascular diseases such as hypertension and atherosclerosis.

Highlights

Cardiovascular diseases (CVDs) are the most common cause of death in developing and developed countries
The balance between vascular smooth muscle cell (VSMC) proliferation and apoptosis is crucial in the progression of atherosclerosis, because excess proliferation of VSMCs contributes to the thickening of the arterial wall at the initial phase of atherosclerotic plaque formation [2]
Angiotensin II (Ang II)-induced ERK1/2 MAPK phosphorylation is not EGFR transactivation-dependent We examined proliferative ERK1/2 MAPK phosphorylation (Thr202/Tyr204), which is an intracellular target of Ang II

Summary

Introduction

Cardiovascular diseases (CVDs) are the most common cause of death in developing and developed countries (www.who.int). CVDs include atherosclerosis, which is becoming more prevalent in the world [1]. The balance between vascular smooth muscle cell (VSMC) proliferation and apoptosis is crucial in the progression of atherosclerosis, because excess proliferation of VSMCs contributes to the thickening of the arterial wall at the initial phase of atherosclerotic plaque formation [2]. Angiotensin II (Ang II) can act as a growth factor to stimulate the migration and proliferation of VSMCs [3]. Ang II mainly shows its effects on VSMCs in the vascular wall [4]. The discovery of an intracellular reninangiotensin system (RAS) [5] has made understanding the cellular effects and related signaling pathways of Ang II more important

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