Abstract 18224: Mitochondrial Morphology, Dynamics and Function in Humans With Severe Aortic Stenosis and Preserved or Reduced Ejection Fraction

    loading  Checking for direct PDF access through Ovid

Abstract

Introduction: Activation of the FOXO3a-BNIP3 pathway mediates mitochondrial fragmentation and dysfunction in rodents with aortic banding induced contractile dysfunction.

Hypothesis: In human myocardium, the FOXO3a-BNIP3 pathway is activated in severe aortic stenosis with reduced (ASrEF) but not preserved (ASpEF) ejection fraction.

Methods and Results: Epicardial LV biopsies (10x1x1 mm3) were obtained at aortic valve replacement in ASpEF (n=5), ASrEF (n=4) and in Controls (n=2, aortic root replacement or atrial myxoma resection, normal LV). Additional control biopsies (n=3) were obtained from donor hearts immediately post-mortem. Surgical (not donor) biopsies were suitable for electron microscopy. All biopsies were used to assess protein expression of FOXO3a, BNIP3, lysosomal (LAMP-2), mitochondrial biogenesis (PGC-1α), mitochondrial dynamics (DRP-1, OPA-1 and MFN 2) and mitochondrial oxidative phosphorylation (citrate synthase and electron transport chain complexes I, II, III, IV and V) markers by immunoblotting and cytochrome C oxidase (COX IV) activity. There were mitochondrial fragmentation and cristae destruction in ASpEF versus Control (P<0.05), which were more pronounced in ASrEF(P<0.05 vs ASpEF). Total BNIP3 expression (monomer and dimer) was increased in AS (P<0.05 vs Control). In ASpEF, BNIP3 dimer and dimer/monomer ratio were increased (P<0.05 vs Control) without changes in markers of mitochondrial biogenesis, dynamics, oxidative phosphorylation or COX IV activity. In ASrEF, BNIP3 monomer was increased with decreased mitochondrial biogenesis (PGC-1α), increased mitochondrial fission (DRP-1) and reduced oxidative capacity (COX IV activity)(P<0.05 vs Control for all).

Conclusions: These findings in human myocardium confirm studies in rodent pressure overload, where transition to contractile dysfunction is associated with activation of the FOXO3-BNIP3 pathway and altered mitochondrial dynamics, biogenesis and function.

Related Topics

    loading  Loading Related Articles