G protein‐coupled receptor (GPCR) regulation of cardiac fibrosis

One form of heart disease, cardiac fibrosis, is characterized by transformation of cardiac fibroblasts (CFs) to pro‐fibrogenic myofibroblasts, which produce excessive amounts of collagen‐rich extracellular matrix, thereby reducing cardiac function and eventually resulting in heart failure. Certain GPCRs, e.g. angiotensin receptors, can promote cardiac fibrosis but few others have been studied in this context. To identify novel therapeutic targets for cardiac fibrosis we used an unbiased approach (GPCR RT‐PCR array) to define the most abundantly expressed GPCRs that may function to regulate the fibroblast/myofibroblast transformation in rat CFs (rCFs). We identified protease‐activated receptor 1 (PAR1) as the most abundant GPCR and found that activation of PAR1 elevates the expression of numerous profibrotic markers, increases collagen synthesis, and alters cell morphology of rCFs. Additionally, since analogs of the second messenger cAMP can inhibit the phenotype induced by pro‐fibrotic agents (e.g. TGF‐β1 and angiotensin II), we have assessed rCF responses to the increase in cAMP produced by two abundantly expressed Gs‐linked GPCRs, adenosine A2A and A2B receptors. These data, which define the level of expression of GPCRs in rCFs and mechanisms for their actions, provide a proof‐of‐principle that such an approach can identify novel disease‐relevant GPCR targets. Supported by NIH.