Vascular effects of glycoprotein130 ligands — Part II: Biomarkers and therapeutic targets

Abstract

Glycoprotein130 (gp130) ligands are defined by the use of the common receptor subunit gp130 and comprise interleukin (IL)-6, oncostatin M (OSM), IL-11, leukemia inhibitory factor (LIF), cardiotrophin-1 (CT-1), cardiotrophin-like cytokine (CLC), ciliary neurotrophic factor (CNTF), IL-27 and neuropoietin (NP). In part I of this review we addressed the pathophysiological functions of gp130 ligands with respect to the vascular wall. In part II of this review on the vascular effects of gp130 ligands we will discuss data about possible use of these molecules as biomarkers to predict development or progression of cardiovascular diseases. Furthermore, the possibility to modulate circulating levels of gp130 ligands or their tissue expression by specific antibodies, soluble gp130 protein, renin–angiotensin–aldosterone system (RASS) inhibitors, statins, agonists of peroxisome proliferator-activated receptors (PPAR), hormone replacement therapy, nonsteroidal anti-inflammatory drugs (NSAID) or lifestyle modulating strategies are presented. Recent knowledge about the application of recombinant cytokines from the gp130 cytokine family as therapeutic agents in obesity or atherosclerosis is also summarized. Thus the purpose of this review is to cover a possible usefulness of gp130 ligands as biomarkers and targets for therapy in cardiovascular pathologies.

Introduction

Despite substantial progress in diagnosis and therapy regimes atherosclerosis and related diseases, such as myocardial infarction (MI), stroke, hypertension, aneurysms, peripheral artery disease and heart failure (HF), are still major causes of death and hospitalization (Roger et al., 2011). Therefore, the prognostic evaluation and risk stratification of patients with the above-mentioned vascular disorders continues to increase in importance. A biomarker, or biological marker, is a term often used to refer to a substance, mostly a protein, measured in the blood, the concentration of which reflects the severity or presence of a particular disease state, correlates with the risk or progression of disease, or with the susceptibility of the disease to a given treatment (Herder et al., 2011, Wang, 2011). There is substantial interest in the discovery and use of newer biomarkers in order to complement the best existing ones and to identify persons who are at risk for the development of cardiovascular disease and who could be targeted for preventive measures (Barderas et al., 2011). Definition of novel biomarkers for inflammatory events may also be used for the development of novel therapeutic treatment options.

Glycoprotein 130 (gp130) is a transmembrane protein that can transduce signals from many different ligands that have diverse biological functions. These include the cytokines interleukin (IL)-6, oncostatin M (OSM), leukemia inhibitory factor (LIF), IL-11, cardiotrophin-1 (CT-1), ciliary neurotrophic factor (CNTF), cardiotrophin-like cytokine (CLC), IL-27 and neuropoietin (NP) (Derouet et al., 2004, Fischer and Hilfiker-Kleiner, 2007, Heinrich et al., 2003, Pflanz et al., 2002). The current challenge is to identify which cytokine represents the most appropriate intervention target for a particular group of patients (Jones et al., 2011). Several strategies have been developed to block gp130-receptor-mediated signaling, and will be discussed in this review together with the potential use of gp130 ligands and its soluble receptors as biomarkers in vascular diseases.