Identification of new G protein‐coupled receptor (GPCR) target(s) for the regulation of cardiac fibrosis

Cardiac fibrosis occurs in advanced age, after acute injury (e.g. myocardial infarction) and in disease states (e.g. diabetes mellitus). Fibrosis is characterized by the transformation of fibroblasts to myofibroblasts, which contribute to the excessive accumulation of collagen‐rich extracellular matrix resulting in reduced cardiac function. In order 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 cardiac fibroblasts (rCFs). Pharmacological analyses were then used to validate the most abundant of these receptors as a functional target. We identified protease‐activated receptor 1 (PAR1) as the most abundant GPCR in rCFs. Subsequent studies revealed that thrombin activation of PAR1 elevates (with distinct kinetics) the expression of a variety of known profibrotic markers in rCFs. Thrombin functions via at least two distinct post‐receptor mechanisms to regulate fibroblast/myofibroblast transformation, one of which is dependent on the production of the atypical second messenger sphingosine‐1‐phosphate. Ours are the first data to define the level of expression of GPCRs in rCFs; the results provide a proof‐of‐principle that such an approach can identify novel disease‐relevant GPCR targets. Supported by NIH.