The Synthetic Adiponectin Receptor Agonist AdipoRon Attenuates Impairment of Cardiac Function Associated with Cardiopulmonary Bypass-induced Systemic Inflammatory Response Syndrome

Objectives: Cardiac surgery using a cardiopulmonary bypass (CPB) frequently provokes a deleterious systemic inflammatory response syndrome (SIRS) that is triggered by Toll-like receptor (TLR)4 and tumor necrosis factor (TNF)-α signaling. The adipokine Adiponectin mediates anti-inflammatory and cytoprotective effects via its ubiquitously expressed receptors AdipoR1 and R2. Here, we investigated whether the synthetic AdipoR1/R2 agonist AdipoRon modulates cardiac inflammation and function following CPB.

Methods: A rat model of CPB with 45 minute of deep hypothermic circulatory arrest (DHCA) resulting in global ischemia was used for in vivo-studies. DHCA was followed by rewarming and reperfusion of animals for 40 and 60 minute, respectively. AdipoRon (n = 8) or vehicle (DMSO, n = 8) was injected i.p. 10 minute before initiation of CPB. Electrolyte and blood gas analysis as well as heart rate and blood pressure were measured throughout the procedure. In vitro, neonatal cardiac myocytes were pre-incubated with AdipoRon or vehicle (DMSO) before stimulation with TNF-α (10 ng/mL) or lipopolysaccharide (LPS, 1 µg/mL). mRNA and protein expression of inflammatory markers were measured by qRT-PCR and ELISA, respectively.

Results: A single AdipoRon application significantly attenuated the CPB-induced impairment of LV function as assessed by increased heart rate and blood pressure following circulatory arrest (p < 0.05 versus DMSO, respectively). Moreover, following reperfusion all AdipoRon-treated animals exhibited heart rate and blood pressure values comparable to sham controls while in 50% of the vehicle-treated animals hearts had discontinued to beat (AdipoRon: 8 out of 8 versus DMSO: 4 out of 8, p < 0.05). The AdipoRon-induced improvements of cardiocirculatory parameters following DHCA were accompanied by in trend diminished increases in plasma levels of lactate and potassium. In vitro, pre-incubation of cardiac myocytes with AdipoRon significantly and dose-dependently attenuates the TNF-α- and LPS-induced up-regulation of TNF-α, interleukin (IL)-1b, IL-6 and matrix metalloproteinase (MMP)-9 (p < 0.01 versus DMSO, respectively). Moreover, AdipoRon up-regulates expression levels of anti-inflammatory IL-10 and ROS-detoxifying catalase in cardiac myocytes (p < 0.01 versus DMSO, respectively).

Conclusion: Our observations indicate that AdipoRon attenuates impairment of cardiac function following CPB with DHCA by inhibiting TLR4 and TNF-α signaling in cardiac myocytes.