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Biology of the heart is meticulously orchestrated by various mechanisms, including receptor-mediated signal transduction, post-translational modification, protein degradation, and transcriptional regulation. To maintain the hemodynamic homeostasis, the heart uses these processes in a chronologically regulated manner. Because the time between heart beats is usually less than one second, instant changes in the body blood demand must be rapidly adapted. This is achieved by modifying β-adrenergic signaling and subsequent phosphorylation/dephosphorylation of proteins related to excitation–contraction coupling. In contrast, chronically altered hemodynamic status, such as hypertension, is adapted via network of signal transductions leading to reprogramming of the gene expression. Emerging evidence indicates that microRNAs, long noncoding RNAs, or circular RNAs are also critically involved in these transcriptional regulations. Sustained activation of certain pathways initially induces adaptive responses but eventually become maladaptive, causing pathological hypertrophy, contractile dysfunction, cell loss, and extracellular remodeling. These changes are clinically represented as heart failure and predispose patients to increased morbidity and mortality. With the rapid advances in the development of small molecule inhibitors and gene therapy approaches that can possibly target key pathological pathways in vivo, we are approaching the point of being able to readily manipulate these pathways in patients. Noncoding RNAs not only play crucial roles in orchestrating the genome and cellular pathways but also can be used as novel therapeutic targets and diagnostic markers. Therefore, understanding the molecular mechanisms governing cardiac pathophysiology is essential to understanding the signaling networks that regulate heart failure development. In this chapter, we will highlight the role of important regulators and biological molecular principles in cardiac homeostasis and disease.


Activation of cardiac β-adrenergic receptors (ARs) represents a powerful system to increase cardiac contractility and heart rate. ARs are a family of G protein–coupled receptors, and agonist binding to β-ARs induces dissociation of heterotrimeric G protein αβγ into active Gα and free heterodimer Gβγ. These subunits activate their respective downstream signal transductions.1 Switching off the activated β-adrenergic signaling is mediated by phosphorylation of β-ARs through G protein–coupled receptor kinases (GRKs)1 (Fig. 6–1).


G protein–coupled receptor activation and G protein-coupled receptor kinase (GRK)-mediated desensitization. A. At rest, G protein–coupled receptors and Gαβγ are not associated. B. Agonist (catecholamine) binding leads to receptor-Gαβγ association, followed by GDP release and subsequent binding of GTP on Gα. C. Gα and Gβγ become dissociated and mediate respective downstream signaling. Active eceptors are soon phosphorylated by GRKs, which induce conformational changes and subsequent recruitment of β-arrestins. Arrestin binding to the receptor inhibits G-protein coupling and terminates signaling, a process termed desensitization. D. β-arrestin bound receptors are then endocytosed and processed for degradation or recycling. GTP on the Gα is hydrolyzed and Gα become available for next coupling event. Reproduced with permission from Sato PY, Chuprun JK, Schwartz M, et al: The evolving impact of Gg protein-coupled receptor kinases in cardiac health and disease. Physiol Rev. 2015 Apr;95(2):377-404.1

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