Role of Dopamine Receptor 3 in Cardiac Fibrosis

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)

Shannon Elizabeth Byrne (Creator)

Institution

East Carolina University (ECU )

Web Site: http://www.ecu.edu/lib/

Abstract: Dopamine receptors are known to exist primarily in the central nervous system and have been extensively studied there. However, other organ systems in the periphery, such as the kidney, have been shown to express these receptors as well. Studies on dopamine receptors in the cardiovascular system are both lacking and contradictory. Dopamine receptor agonists are prescribed to patients with neurological diseases and some medications have been removed from the market due to fibrosis and heart valve regurgitation. We hypothesized that there is an intrinsic cardiac dopaminergic system and changes to that system can lead to left ventricular (LV) remodeling and particularly, cardiac fibrosis. The first aim focused on determining the relative gene expression of all five dopamine receptors in both wild type (WT) mouse heart tissue and LV cardiac fibroblasts. Then, the expression and relationship between excitatory dopamine receptor 1 (D1R) and inhibitory dopamine receptor 3 (D3R) was examined through a dopamine receptor 3 global knock out (D3KO) mouse model. Both receptors were confirmed to express in WT cardiac fibroblast cells and heart tissues through a comprehensive analysis via immunofluorescence, RT-qPCR, and western blot. We found that in the D3KO fibroblasts, D1R expression is significantly increased around 8-fold compared to WT. In addition, regardless of pharmacological treatment with agonists and antagonists, the increase in D1R expression was seen in the D3KO fibroblasts. The second aim focused on the relative expression of known profibrotic markers in order to determine if dysfunctional D3R can lead to a profibrotic phenotype. Relative gene expression of type I collagen decreased, while relative gene expression of type III collagen increased in the D3KO heart tissue samples. Both matrix metalloproteinases (MMP's), MMP2 and MMP9 were significantly decreased in the D3KO LV cardiac fibroblasts. Finally, known profibrotic marker, transforming growth factor [beta]1 (TGF-[beta]1), and the angiotensin II receptor type I were examined. In the D3KO LV cardiac fibroblasts, angiotensin II receptor type I was significantly increased many folds. TGF-[beta]1 was also increased in D3KO fibroblasts and myocardial tissue. Thus, we determined that there is an intrinsic cardiac dopaminergic system in WT mice, and that the loss of function of D3R in the cardiac system contributes to a profibrotic phenotype. This data provides positive proof for the existence of an intracardiac dopaminergic system as well as highlighting the possibility that dysfunctional D3R can contribute to cardiac fibrosis.

Additional Information

Publication

Thesis

Language: English

Date: 2023

Subjects

Dopamine Receptor 3;Dopamine Receptor 1;Cardiac Fibrosis;Heart

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