Dopamine receptor D1 is altered in atrial fibrillation-associated tissues and modulates Ang II-induced cardiomyocyte stress partly through PI3K/Akt signaling.

backgroundAtrial fibrillation (AF) is associated with atrial remodeling, oxidative stress, and inflammation; however, the molecular mechanisms underlying these processes remain unclear. We investigated whether dopamine receptor D1 (DRD1) is associated with AF-related cardiac phenotypes and whether DRD1 modulates cardiomyocyte responses to angiotensin II (Ang II)-induced stress.

methodsDRD1 expression was examined in the GSE135445 epicardial adipose tissue (EAT) dataset and independently in the GSE41177 myocardial transcriptomic dataset of patients with AF and sinus rhythm. DRD1 expression and AF-associated phenotypes were assessed in C57BL/6 mice subjected to chronic Ang II infusion. In HL-1 cardiomyocytes, DRD1 was overexpressed before Ang II exposure, and the contribution of PI3K/Akt signaling was evaluated using LY294002.

resultsDRD1 expression was altered in EAT and downregulated in the myocardial tissue of patients with AF compared to sinus rhythm control. DRD1 expression was also reduced in the atrial tissue of Ang II-treated mice, which exhibited increased AF inducibility and duration. In HL-1 cardiomyocytes, Ang II reduced DRD1 expression, whereas DRD1 overexpression increased PI3K/Akt phosphorylation and attenuated Ang II-induced reductions in cell viability, LDH release, hypertrophic responses, ROS generation, oxidative stress, and NLRP3 inflammasome-associated signaling. LY294002 partially attenuated these effects.

conclusionsDRD1 expression is altered in EAT and downregulated in the myocardial tissue of patients with AF and in experimental atrial remodeling. DRD1 overexpression protects cardiomyocytes against Ang II-induced stress, with PI3K/Akt signaling contributing to this effect. However, whether DRD1 causally regulates AF susceptibility in vivo remains to be established.