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 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 AdipoR2. Here, we investigated whether the synthetic AdipoR1/R2 agonist AdipoRon modulates cardiac inflammation and function following application of a CPB.

Methods: A rat model of CPB with 45 minutes of deep hypothermic circulatory arrest (DHCA) was used for in vivo studies. DHCA was followed by rewarming and reperfusion of animals for 40 and 60 minutes, respectively. Thereafter, the animals were weaned from CPB over a period of 20 min and subsequently observed for a further 10 min. AdipoRon (n = 7) or vehicle (DMSO, n = 7) was applied twice 10 minutes before start of the CPB and with the beginning of rewarming, respectively. Electrolyte and blood gas analysis as well as heart rate and blood pressure were measured throughout the procedure. In vitro, neonatal cardiac myocytes were preincubated with AdipoRon or vehicle (DMSO) before stimulation with TNF-α or the TLR4 ligand lipopolysaccharide (LPS). mRNA and protein expression of inflammatory markers were analyzed by qPCR and ELISA.

Results: The application of AdipoRon significantly (p < 0.05 vs. DMSO) attenuated the CPB-induced impairments of blood pressure at different time points in the rewarming and reperfusion phases following DHCA. Moreover, after being weaned from CPB seven out of seven AdipoRon-treated animals exhibited heart rate and blood pressure values comparable to sham controls while in two out of seven of the vehicle-treated animals cardiac rhythm was lost. The AdipoRon-induced improvements of cardiocirculatory parameters following DHCA were accompanied by significantly diminished increases in plasma levels of lactate and potassium (p < 0.05 vs. DMSO, respectively). In vitro, preincubation of cardiac myocytes with AdipoRon dose-dependently attenuates the TNF-α- and LPS-induced up-regulation of TNF-α, IL-1β, IL-6, and MMP-9 (p< 0.01 vs. DMSO, respectively). Moreover, AdipoRon significantly up-regulates expression levels of ROS-detoxifying catalase in these cells (p< 0.01 vs. DMSO).

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.