The Role of Cyclic AMP Signaling in Cardiac Fibrosis

Abstract

Myocardial stress and injury invariably promote remodeling of the cardiac tissue, which is associated with cardiomyocyte death and development of fibrosis. The fibrotic process is initially triggered by the differentiation of resident cardiac fibroblasts into myofibroblasts. These activated fibroblasts display increased proliferative capacity and secrete large amounts of extracellular matrix. Uncontrolled myofibroblast activation can thus promote heart stiffness, cardiac dysfunction, arrhythmias, and progression to heart failure. 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. In this respect, cyclic adenosine monophosphate (cAMP) signaling acts as a major modulator of fibrotic responses activated in fibroblasts of injured or stressed hearts. 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. The current review will discuss recent advances highlighting the role of cAMP and AKAP-mediated signaling in regulating pathophysiological responses controlling cardiac fibrosis.

Therapeutic Implications for PDE2 and cGMP/cAMP Mediated Crosstalk in Cardiovascular Diseases

“…However, reduced cAMP levels may mediate alternative consequences in distinct cell types of the myocardium that may not always be favorable. In fibroblasts, diminished cAMP signalling promotes fibrotic effects, cell proliferation and collagen production [149]. In line with these publications, PDE2 overexpression in cardiac fibroblasts accelerated cAMP degradation and subsequently supported fibroblast activation and transformation into myofibroblasts.…”

Interleukin-1 receptor-induced PGE2 production controls acetylcholine-mediated cardiac dysfunction and mortality during scorpion envenomation

“…2a) and high cAMP (Fig. 2h) producers 28 , a high concentration of PGE 2 might be necessary to boost additional cAMP production by heart cells in vivo, and this could be a mechanism to prevent excessive activation of cardiac fibroblasts and interstitial fibrosis 28 . On the other hand, high concentrations of PGE 2 are apparently necessary to promote ACh release, as observed in ll1r1 −/− TsV-and PGE 2 -inoculated mice (35 μM/per animal, Fig.…”

cAMP Signaling in Pathobiology of Alcohol Associated Liver Disease

“…The anti-fibrotic effect of cAMP effector molecules PKA and EPAC has been demonstrated in various tissue fibroblasts, including HSCs (reviewed in [ 133 , 134 , 135 ]). Early studies have documented that quiescent HSCs have high levels of pCREB, which decreases upon HSC activation and could be restored with activation of PKA [ 136 , 137 , 138 , 139 ]. Our previous studies demonstrated that primary HSCs do not express cAMP-degrading PDE4 when they are quiescent; however, the expression of three PDE4 subfamilies of proteins, PDE4A, B and D, increases upon the early stage of their activation [ 80 ].…”