Fibrosis, the result of excess deposition of extracellular matrix (ECM), in particular collagen, leads to scarring and loss of function in tissues that include the heart, lung, kidney and liver. The second messenger cAMP can inhibit the formation and extent of ECM during this late phase of inflammation, but the mechanisms for these actions of cAMP and of agents that elevate tissue cAMP levels are not well understood. In this article, we review the fibrotic process and focus on two recently recognized aspects of actions of cAMP and its effector Epac (Exchange protein activated by cAMP): (a) blunting of epithelial-mesenchymal transformation (EMT) and (b) down-regulation of Epac expression by profibrotic agents (e.g. TGF-b, angiotensin II), which may promote tissue fibrosis by decreasing Epac-mediated antifibrotic actions. Pharmacological approaches that raise cAMP or blunt the decrease in Epac expression by profibrotic agents may thus be strategies to block or perhaps reverse tissue fibrosis. LINKED ARTICLESThis article is part of a themed section on Novel cAMP Signalling Paradigms. To view the other articles in this section visit http://dx.doi. org/10.1111/bph.2012.166.issue-2 Abbreviations CF, cardiac fibroblast; ECM, extracellular matrix; Epac, Exchange protein activated by cyclic AMP; 8-Me-cAMP, 8-CPT-2′-O-Me-cAMP; N6-cAMP, N6-Benzoyl-cAMP; NSAIDs, non-steroidal anti-inflammatory drugs; a-SMA, a-smooth muscle actin Introduction to tissue fibrosis and cAMP signalling Tissue fibrosisTissue fibrosis (scarring) results from the excess deposition of extracellular matrix (ECM) and occurs as part of normal physiology (e.g. aging) and following injury, in particular, with recurrent or persistent stimulation of the inflammatory process. Tissue fibrosis often alters tissue function. For example, cardiac fibrosis contributes to diastolic dysfunction and a decrease in cardiac output that accompany advanced age (Lakatta, 2003;Chen and Frangogiannis, 2010). Inflammation that follows tissue injury produces a series of acute and late-phase responses. In its acute phase, inflammation is characterized by several cardinal features [calor, rubor, dolor and tumour (heat, redness, pain and swelling)], which can be treated by pharmacological agents, in particular nonsteroidal anti-inflammatory drugs (NSAIDs), whose major action is inhibition of COXs and thus the synthesis of prostaglandins.Much less is known regarding the mechanisms that mediate the late phase of inflammation during which resolution of the tissue infiltration of acute inflammatory cells occurs, but tissue fibrosis can be initiated. Recent efforts have helped identify mechanisms of the resolution of inflammation (Serhan, 2010;Maskrey et al., 2011;Wynn, 2011;Yates et al., 2011). Glucocorticoids, the principal class of drugs used to treat this phase of the inflammatory process, block protein synthesis, thereby decreasing the accumulation of collagens and other ECM proteins. However, the use of glucocorticoids is associated with numerous side effects. Pirfenidone is ...

Brown adipose tissue (BAT) dissipates nutritional energy as heat via the uncoupling protein-1 (UCP1) and BAT activity correlates with leanness in human adults. Here we profile G protein-coupled receptors (GPCRs) in brown adipocytes to identify druggable regulators of BAT. Twenty-one per cent of the GPCRs link to the Gq family, and inhibition of Gq signalling enhances differentiation of human and murine brown adipocytes. In contrast, activation of Gq signalling abrogates brown adipogenesis. We further identify the endothelin/Ednra pathway as an autocrine activator of Gq signalling in brown adipocytes. Expression of a constitutively active Gq protein in mice reduces UCP1 expression in BAT, whole-body energy expenditure and the number of brown-like/beige cells in white adipose tissue (WAT). Furthermore, expression of Gq in human WAT inversely correlates with UCP1 expression. Thus, our data indicate that Gq signalling regulates brown/beige adipocytes and inhibition of Gq signalling may be a novel therapeutic approach to combat obesity.

In cardiac myocytes activation of an exchange factor activated by cAMP (Epac) leads to activation of phospholipase Cε (PLCε)-dependent hydrolysis of phosphatidylinositol 4-phosphate (PI4P) in the Golgi apparatus a process critical for development of cardiac hypertrophy. Here we show that β-adrenergic receptor (βAR) stimulation does not stimulate this pathway in the presence of the broad spectrum phosphodiesterase (PDE) inhibitor IBMX, but selective PDE3 inhibition revealed βAR-dependent PI4P depletion. On the other hand, selective inhibition of PDE2 or PDE9A blocked endothelin-1 (ET-1) and cAMP-dependent PI4P hydrolysis by PLCε. Direct activation of protein kinase A (PKA), protein kinase G (PKG), or the atrial natriuretic factor (ANF) receptor abolished PI4P hydrolysis in response to multiple upstream stimuli. These results reveal distinct pools of cyclic nucleotides that either inhibit PLCε at the Golgi through PKA/PKG, or activate PLCε at the Golgi through Epac. These data together reveal a new mechanism by which ANF and selective PDE inhibitors can protect against cardiac hypertrophy.