Attractor landscape analysis of the cardiac signaling network reveals mechanism-based therapeutic strategies for heart failure

Abstract

Apoptosis and hypertrophy of cardiomyocytes are the primary causes of heart failure (HF), a global leading cause of death, and are regulated through the complicated intracellular signaling network, limiting the development of effective treatments due to its complexity. To identify effective therapeutic strategies for HF at a system level, we develop a large-scale comprehensive mathematical model of the cardiac signaling network by integrating all available experimental evidence. Attractor landscape analysis of the network model identifies distinct sets of control nodes that effectively suppress apoptosis and hypertrophy of cardiomyocytes under ischemic or pressure overload-induced HF, the two major types of HF. Intriguingly, our system-level analysis suggests that intervention of these control nodes may increase the efficacy of clinical drugs for HF and, of most importance, different combinations of control nodes are suggested as potentially effective candidate drug targets depending on the types of HF. Our study provides a systematic way of developing mechanism-based therapeutic strategies for HF.