Key result
A2AR antagonists suppress intracellular ROS and downregulate fibrotic and inflammatory signaling in cardiac fibroblasts.
Why the study?
To investigate the possible crosstalk between A2AR and biglycan modulation in an in vitro model of TGF-β-induced cardiac fibrosis.
Does adenosine 2A receptor antagonism with Istradefylline or ZM241385 reduce biglycan expression, oxidative stress, and fibrotic marker levels in TGF-β-stimulated human cardiac fibroblasts?
Does adenosine 2A receptor antagonism with Istradefylline or ZM241385 reduce biglycan expression, oxidative stress, and fibrotic marker levels in TGF-β-stimulated human cardiac fibroblasts?
Pharmacological blockade of the adenosine A2A receptor attenuates TGF-β-induced biglycan upregulation, oxidative stress, and fibrotic signaling in human cardiac fibroblasts, suggesting a potential preclinical target for cardiac fibrosis.
Answers are grounded in this paper and cite their sources.
A2AR antagonism attenuates fibrotic signaling in vitro; leaves open clinical translation and in vivo efficacy for cardiac fibrosis.
Cardiac fibrosis is a common pathological feature of different cardiovascular diseases, characterized by the aberrant deposition of extracellular matrix (ECM) proteins in the cardiac interstitium, myofibroblast differentiation and increased fibrillar collagen deposition stimulated by transforming growth factor (TGF)-β activation. Biglycan (BGN), a small leucine-rich proteoglycan (SLRPG) integrated within the ECM, plays a key role in matrix assembly and the phenotypic control of cardiac fibroblasts. Moreover, BGN is critically involved in pathological cardiac remodeling through TGF-β binding, thus causing myofibroblast differentiation and proliferation. Adenosine receptors (ARs), and in particular A2AR, may play a key role in stimulating fibrotic damage through collagen production/deposition, as a consequence of cyclic AMP (cAMP) and AKT activation. For this reason, A2AR modulation could be a useful tool to manage cardiac fibrosis in order to reduce fibrotic scar deposition in heart tissue. Therefore, the aim of the present study was to investigate the possible crosstalk between A2AR and BGN modulation in an in vitro model of TGF-β-induced fibrosis. Immortalized human cardiac fibroblasts (IM-HCF) were stimulated with TGF-β at the concentration of 10 ng/mL for 24 h to induce a fibrotic phenotype. After applying the TGF-β stimulus, cells were treated with two different A2AR antagonists, Istradefylline and ZM241385, for an additional 24 h, at the concentration of 10 µM and 1 µM, respectively. Both A2AR antagonists were able to regulate the oxidative stress induced by TGF-β through intracellular reactive oxygen species (ROS) reduction in IM-HCFs. Moreover, collagen1a1, MMPs 3/9, BGN, caspase-1 and IL-1β gene expression was markedly decreased following A2AR antagonist treatment in TGF-β-challenged human fibroblasts. The results obtained for collagen1a1, SMAD3, α-SMA and BGN were also confirmed when protein expression was evaluated; phospho-Akt protein levels were also reduced following Istradefylline and ZM241385 use, thus suggesting that collagen production involves AKT recruited by the A2AR. These results suggest that A2AR modulation might be an effective therapeutic option to reduce the fibrotic processes involved in heart pathological remodeling.
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Scuruchi et al. (2023) studied TGF-β-induced cardiac fibrosis (in vitro model). Istradefylline and ZM241385 (A2A receptor antagonists) vs. TGF-β-stimulated human cardiac fibroblasts without A2AR antagonist treatment, and unstimulated control cells was evaluated on Expression of biglycan (BGN) and fibrotic/inflammatory markers (collagen1a1, MMP3, MMP9, SMAD3, α-SMA, phospho-Akt, caspase-1, IL-1β) and intracellular ROS levels (p=<0.05). Istradefylline (10 µM) and ZM241385 (1 µM) significantly reduced intracellular ROS and downregulated BGN, collagen1a1, MMP3/9, SMAD3, α-SMA, p-Akt, caspase-1, and IL-1β in TGF-β-stimulated fibroblasts.
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