Abstract 18616: Sirtuin 3 Ablation Exacerbates Cerebral Injury After Experimental Cardiac Surgery via Inflammasome Activation
Introduction: Neuroinflammation triggered by sterile surgical trauma, cardiopulmonary bypass and ischemia/reperfusion (I/R) is a major factor in cerebral injury and cognitive decline after cardiac surgery. NAD+-dependent sirtuins play essential roles in the control of systemic acute inflammatory processes, as well as neuroinflammation through adaptive immunometabolic reprogramming. However, the role of Sirtuin 3 (SIRT3) in regulating neuroinflammation in the context of surgical I/R remains unknown.
Hypothesis: SIRT3 ablation exacerbates neuroinflammation following experimental deep hypothermic circulatory arrest (DHCA) via cerebral NLRP3 inflammasome activation, leading to increased postoperative neuronal death and impaired neurologic function.
Methods: Using a germline SIRT3 knock-out (SIRT3-/-) rat model in a Dahl SS strain background (WT), adult male rats were subjected to DHCA (18°C) for 60 min followed by 24h reperfusion and assessment of neurologic phenotypes. Cerebral levels of NLRP3 were assessed by Western blot and immunofluorescence microscopy.
Results: SIRT3-/- rats had worse neurologic scores, neuronal necrosis and apoptosis (Fig 1), associated with increased cerebral expression of NLRP3 (in neurons, astrocytes and microglia) (Fig 2). Further, SIRT3 ablation was associated with increased expression of acetylated Mn-SOD (inactive form) and acetylated NF-kB p65 (active form).
Conclusions: Our results reveal a potential mechanism by which SIRT3 ablation exacerbates post-I/R cerebral injury and neuroinflammation, involving the NLRP3 inflammasome, activation of NF-kB and inhibition of antioxidant capacity (MnSOD) via acetylation.
- Cardiac surgery
- Cerebrovascular disorders
- Inflammation and inflammatory markers
- Gene expression
Author Disclosures: Z. Zhang: None. Q. Ma: None. M. Smith: None. M. Manning: None. Q. Quinones: None. M. Podgoreanu: None.
- © 2016 by American Heart Association, Inc.