Elements of Computational Systems Biology

3

IN SILICO ANALYSIS OF COMBINED THERAPEUTICS STRATEGY FOR HEART FAILURE

Sung-Young Shin, Tae-Hwan Kim, and Kwang-Hyun Cho^*

Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea

Sang-Mok Choo

School of Electrical Engineering, University of Ulsan, Ulsan, Korea

3.1 INTRODUCTION

In failing cardiac myocytes, chronic stimulation of β-adrenergic receptor (β-AR) due to the high level of circulating catecholamine secreted by activation of the sympathetic nervous system leads to desensitization and impaired β-AR responsiveness [1]. Furthermore, chronic activation of β-adrenergic signaling pathway may result in altered expression and functional activity of β-AR, G-protein, adenylyl cyclase (AC), and G-protein receptor kinase [2]. The alteration of this pathway makes the β-ARmediated cardiac response substantially blunt and ultimately delivers adverse biological signals [3]. These molecular and biochemical alterations of the β-AR signaling pathway are common to the failing hearts despite the varying etiologies [4]. Therefore, restoring the altered signaling pathway is a generally accepted notion to treat heart failure (HF), and actually, new therapeutic strategies have been developed based on this notion [5]. Among those new therapeutic strategies, β-AR-blocking agent (β-blocker) is conceived as a standard therapy for patients with mild-to-moderate HF [6]. The diastolic function of such patients gets worsened with decreasing cardiac ...