Abstract 2948: Inhibition of the A2B Adenosine Receptor (AR) With ATL-801 Reduces Infarction-Induced Reactive Fibrosis and Cardiac Dysfunction in Mice
Adenosine has emerged as a promoter of tissue fibrosis in chronic diseases such as asthma and alcohol-induced liver fibrosis via the A2BAR. Previously, we demonstrated that reactive fibrosis and, as a result, diastolic dysfunction were less severe in A2BAR gene knock-out mice subjected to permanent coronary artery ligation (MI), suggesting adenosine also contributes to fibrotic responses in the heart. This study examined the effectiveness of the A2BAR antagonist ATL-801 (ATL) in MI-induced heart failure. C57BL/6 mice fed either a control diet or a diet containing ATL (10 mg/kg/day throughout) were subjected to MI or sham (S) surgery. Cardiac function was assessed 4 and 8 weeks after surgery by echocardiography. At the end of the study, left ventricular pressure-volume-relationships (PVR) were obtained using a conductance catheter, and the hearts were histologically assessed for infarct size and fibrosis. Control MI hearts experienced significant left ventricular dilation and reduced systolic (ejection fraction, fractional area change, and myocardial performance index) and diastolic (end-diastolic pressure [EDP, mmHg, S: 1.2±0.6; MI: 4.3±0.5], tau [ms, S: 13.6±0.7; MI: 21.8±2.8], EDPVR [mmHg/μL, S: 0.34±0.06; MI: 0.63±0.13]) function at 8 weeks. Compared to controls, there were no significant differences in post-infarction systolic dysfunction in ATL-treated mice. However, EDP (2.2±0.5), tau (15.7±0.5), and EDPVR (0.18±0.11) were markedly improved and were not worsened compared to ATL-treated shams (1.5±0.9, 12.4±0.5, 0.36±0.03, respectively). Moreover, interstitial fibrosis was elevated in the remote non-infarcted regions of control MI mice (%, S: 2.0±0.4; MI: 6.6±0.9), but not in ATL-treated mice (S: 2.0±0.3; MI: 3.0±0.5). Treating isolated cardiac fibroblasts with the A2BAR agonist BAY 60– 6583 stimulated a 2.5-fold increase in interleukin-6 release, which was antagonized by ATL. This study demonstrates that pharmacological blockade of the A2BAR attenuates post-infarction cardiac dysfunction and adverse remodeling. This study further supports the concept that adenosine signaling via the A2BAR promotes the development of fibrosis in the heart, potentially by stimulating the release of pro-fibrotic mediators from fibroblasts.
This research has received full or partial funding support from the American Heart Association, Midwest Affiliate (Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, South Dakota & Wisconsin).