Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 166, Issue 2, Pages 447-456Publisher
WILEY
DOI: 10.1111/j.1476-5381.2012.01847.x
Keywords
cyclic AMP; Epac; fibrosis; G protein-coupled receptors; protein kinase A; MDCK cell; myofibroblast; protein kinase A; TGF-ss
Categories
Funding
- National Institutes of Health
- Ellison Medical Foundation
- Grants-in-Aid for Scientific Research [24659100, 21590936] Funding Source: KAKEN
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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 epithelialmesenchymal transformation (EMT) and (b) down-regulation of Epac expression by profibrotic agents (e.g. TGF-beta, 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.
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