Abstract
Evidence suggests the existence of an intracardiac dopaminergic system that plays a pivotal role in regulating cardiac function and fibrosis through G-protein coupled receptors, particularly mediated by dopamine receptor 3 (D3R). However, the expression of dopamine receptors in cardiac tissue and their role in cardiac fibroblast function is unclear. In this brief report, first we determined expression of D1R and D3R both in left ventricle (LV) tissue and fibroblasts. Then, we explored the role of D3R in the proliferation and migration of fibroblast cell cultures using both genetic and pharmaceutical approaches; specifically, we compared cardiac fibroblasts isolated from LV of wild type (WT) and D3R knockout (D3KO) mice in response to D3R-specific pharmacological agents. Finally, we determined if loss of D3R function could significantly alter LV fibroblast expression of collagen types I (Col1a1) and III (Col3a1). Cardiac fibroblast proliferation was attenuated in D3KO cells, mimicking the behavior of WT cardiac fibroblasts treated with D3R antagonist. In response to scratch injury, WT cardiac fibroblasts treated with the D3R agonist, pramipexole, displayed enhanced migration compared to control WT and D3KO cells. Loss of function in D3R resulted in attenuation of both proliferation and migration in response to scratch injury, and significantly increased the expression of Col3a1 in LV fibroblasts. These findings suggest that D3R may mediate cardiac fibroblast function during the wound healing response. To our knowledge this is the first report of D3R's expression and functional significance directly in mouse cardiac fibroblasts.
Highlights
The catecholamine dopamine is heavily involved in a multitude of neural pathways of the brain
As indicated by co-localization of receptor specific immunofluorescence with the fibroblast marker vimentin, both D1R and D3R are expressed in mouse cardiac fibroblasts, and the absence of D3R staining in D3R knockout (D3KO) reflected the positive functional knockout for this model (Figure 2A)
We analyzed Col1a1 and Col3a1 gene expression in wild type (WT) and D3KO left ventricle (LV) cardiac fibroblasts, the results of which showed a similar trend as in the cardiac tissue (Figure 4B). This is the first study to demonstrate that the D3 receptor is present in mouse cardiac tissue and LV fibroblasts, and that it has an influence on cardiac fibroblast proliferation, migration, and collagen expression
Summary
The catecholamine dopamine is heavily involved in a multitude of neural pathways of the brain Many of these pathways involve regulating body movement, motivation, behavior, and cognitive function [1]. The class of D1-like dopamine receptors include dopamine D1 and D5 receptors (D1R and D5R), while the class of D2-like dopamine receptors include dopamine D2, D3, and D4 receptors (D2R, D3R, and D4R) These dopamine receptors are G-protein coupled, with the class of D1-like dopamine receptors typically coupled to G stimulatory sites, Gs/q/olf, to activate adenylyl cyclase, which results in increased levels of the second messenger molecule, 3’,5’cyclic-adenosine monophosphate (cAMP). The class of D2-like dopamine receptors typically couple G inhibitory sites (Gi/o) to adenylyl cyclase, resulting in decreased levels of cAMP [7, 9]
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