A pathway and network review on beta-adrenoceptor signaling and beta blockers in cardiac remodeling

It is well established that cardiac remodeling plays a pivotal role in the development of heart failure, a leading cause of death worldwide. Meanwhile, sympathetic hyperactivity is an important factor in inducing cardiac remodeling. Therefore, an in-depth understanding of beta-adrenoceptor signaling pathways would help to find better ways to reverse the adverse remodeling. Here, we reviewed five pathways, namely mitogen-activated protein kinase signaling, Gs-AC-cAMP signaling, Ca(2+)-calcineurin-NFAT/CaMKII-HDACs signaling, PI3K signaling and beta-3 adrenergic signaling, in cardiac remodeling. Furthermore, we constructed a cardiac-remodeling-specific regulatory network including miRNA, transcription factors and target genes within the five pathways. Both experimental and clinical studies have documented beneficial effects of beta blockers in cardiac remodeling; nevertheless, different blockers show different extent of therapeutic effect. Exploration of the underlying mechanisms could help developing more effective drugs. Current evidence of treatment effect of beta blockers in remodeling was also reviewed based upon information from experimental data and clinical trials. We further discussed the mechanism of how beta blockers work and why some beta blockers are more potent than others in treating cardiac remodeling within the framework of cardiac remodeling network.