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THE DIFFERENTIAL EFFECTS OF SIRTUIN-3 IN CARDIO-PROTECTION
  1. Andrew R Hall,
  2. Sanjeev Kumar,
  3. Rachel K Dongworth,
  4. Niall Burke,
  5. Derek M Yellon,
  6. Derek J Hausenloy
  1. The Hatter Cardiovascular Institute, University College London, UK

Abstract

Background The mitochondrial specific deacetylase, Sirtuin-3 has been reported to regulate oxidative phosphorylation, the activity of Cyclophilin D (a key component of the mitochondrial permeability transition pore, MPTP), and the ROS scavenger MnSOD. We hypothesise Sirtuin-3 to be a potential therapeutic target for cardio-protection based its ability to prevent MPTP formation and inhibit ROS generation.

Methods and Results In HL-1 cells (a murine cardiac cell line), Sirtuin-3 over-expression reduced cell death following simulated ischemia-reperfusion injury. Futhermore, Sirtuin-3 over-expression reduced MPTP formation, and induced mitochondrial fusion. To investigate the role of endogenous Sirtuin-3 in the adult heart, Sirtuin-3 (whole body) KO mice and WT littermates were subjected to in vivo cardiac ischemia (30 min) followed by 24 hrs reperfusion. Myocardial infarct (MI) size was determined as a percentage of area at risk. Interestingly, no differences in MI size were observed between WT and KO mice under fed conditions. However, overnight fasting (to induce Sirtuin-3 expression and activity) resulted in a smaller MI size in the Sirtuin-3 KO when compared to WT mice.

Conclusions We report that the role of Sirtuin-3 in cardio-protection differs between the HL-1 cardiac cell line and the adult heart. In HL-1 cells, Sirtuin-3 over-expression protects against acute IRI, suggesting that activating Sirtuin-3 in this cell-line may be cardio-protective. In contrast, fasted mice deficient in Sirtuin-3 had smaller MI following IRI, suggesting that inhibiting Sirtuin-3 in the fasted adult heart may be cardio-protective. This finding may have clinical implications in patients who are fasted before surgery.

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