![]() ![]() (Left side) Stimulation of AT1-Rs by Ang-II enhances AKAP13 Rho-guanine nucleotide exchange factor (GEF) activity through a signaling pathway that involves Gα 12. ( A) AKAP13-dependent modulation of fibrotic responses in ventricular fibroblasts. Regulation of fibrotic signaling pathways by PKA and AKAPs. Both Epac1 and PKA/AKAP complexes modulate, positively or negatively, multiple fibrotic responses including myofibroblast differentiation, collagen production, proliferation, migration, and invasion, which contribute to the development of myocardial fibrosis. The anchoring sites for PKA and other signaling enzymes (E) as well as the AKAP targeting domains are indicated. Epac1 catalyzes the GDP to GTP exchange on Rap1, whereas PKA, which are anchored at specific subcellular sites by A-kinase anchoring protein (AKAPs), promotes the phosphorylation of cellular substrates on serine and threonine residues. cAMP activates two main effectors, Epac1 and protein kinase A (PKA). Two adenylyl cyclases, AC5 and AC6, as well as well as several phosphodiesterases families have been show to modulate cardiac fibrosis. Phosphodiesterases (PDEs), which promote degradation of cAMP to AMP, are also involved in shaping intracellular cAMP microdomains. Stimulation of different membrane GPCRs is believed to induce the activation of distinct pool of ACs and the generation of separate cAMP microdomains. Cardiac fibroblasts express several Gs-coupled G protein-coupled receptors (GPCRs) including β 1- and β 2- adrenergic receptors (ARs), A 2B adenosine receptors (A 2BRs), prostaglandin E 2 receptor 4 (EP4), prostacyclin receptors (IP), calcitonin receptor-like receptors (CLRs), and relaxin receptors (LGR7), which activate cAMP signaling cascades involved in the regulation of fibrotic responses. The current review will discuss recent advances highlighting the role of cAMP and AKAP-mediated signaling in regulating pathophysiological responses controlling cardiac fibrosis.Ī-kinase anchoring protein (AKAP), adenylyl cyclase cardiac fibrosis cardiac remodeling cyclic AMP phosphodiesterase protein kinase A.Ĭyclic adenosine monophosphate (cAMP) signaling modulators involved in the regulation fibrotic responses in cardiac fibroblasts. In particular, accumulating evidence now suggests that upstream cAMP modulators including G protein-coupled receptors, adenylyl cyclases (ACs), and phosphodiesterases (PDEs) downstream cAMP effectors such as protein kinase A (PKA) and the guanine nucleotide exchange factor Epac and cAMP signaling organizers such as A-kinase anchoring proteins (AKAPs) modulate a variety of fundamental cellular processes involved in myocardial fibrosis including myofibroblast differentiation, proliferation, collagen secretion, and invasiveness. In this respect, cyclic adenosine monophosphate (cAMP) signaling acts as a major modulator of fibrotic responses activated in fibroblasts of injured or stressed hearts. Despite the well-established role of myofibroblasts in mediating cardiac disease, our current knowledge on how signaling pathways promoting fibrosis are regulated and coordinated in this cell type is largely incomplete. Uncontrolled myofibroblast activation can thus promote heart stiffness, cardiac dysfunction, arrhythmias, and progression to heart failure. These activated fibroblasts display increased proliferative capacity and secrete large amounts of extracellular matrix. The fibrotic process is initially triggered by the differentiation of resident cardiac fibroblasts into myofibroblasts. Myocardial stress and injury invariably promote remodeling of the cardiac tissue, which is associated with cardiomyocyte death and development of fibrosis. ![]()
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