Abstract 20926: Sex-Specific Cardioprotective Effects of Annexin A1 Peptide Mimetic Involve the Sirtuin 3 Signaling Pathway
Introduction: We reported cardioprotective efficacy of a novel Annexin-A1 peptide mimetic (Ac10-12, ANXA1sp) in multiple experimental models of cold myocardial ischemia-reperfusion (IR), across species, and in the presence of comorbidities, which were associated with activation of the mitochondrial deacetylase sirtuin 3 (SIRT3).
Hypothesis: SIRT3 is critical in mediating the cardioprotective effects of ANXA1sp administered upon reperfusion following warm myocardial IR by acute coronary occlusion.
Methods: Adult male and female C57Bl/6 mice (14-16 weeks) with conditional heart deletion of SIRT3 (SIRT3-/-) and wild-type (WT) controls were subjected to 1h LAD coronary occlusion and treated with ANXA1sp (1 mg/kg) or vehicle (1% DMSO in saline) at reperfusion (iv), and at 1h (ip), and 5h (ip) after reperfusion. Following 24h of reperfusion, animals underwent echocardiography (Vevo2100, VisualSonics) then sacrificed for determination of myocardial infarct size by TTC staining. A different group of WT animals were reperfused for 3h and used to assess myocardial SIRT3 expression and activity. Genotype and sex differences were tested by two-way ANOVA.
Results: ANXA1sp reduced myocardial infarct size in male but not female wild-type mice (Fig 1A), which was corroborated by improved LV systolic function (strain, strain rate). The effects were abrogated in SIRT3 deficient mice (Fig 1B). Mechanistically, this was associated with increased myocardial SIRT3 activity at 3h post-reperfusion in ANXA1sp treated male but not female mice (Fig 1C).
Conclusions: We describe a sexual dimorphic response in the cardioprotective effects of ANXA1sp, in part driven by pro-survival mechanisms involving activation of SIRT3 pathways in males. Whether constitutively higher SIRT3 activity in female hearts contributes to these observations is currently being evaluated, and may inform the biological basis of gender disparities in outcomes following myocardial IR.
Author Disclosures: Z. Zhang: None. Q. Ma: None. A. Nicoara: None. Q. Quinones: None. M. Hirschey: None. M.V. Podgoreanu: None.
- © 2016 by American Heart Association, Inc.