Heart failure-induced activation of phospholipase iPLA 2 γ generates hydroxyeicosatetraenoic acids opening the mitochondrial permeability transition pore

J Biol Chem. 2018 Jan 5;293(1):115-129. doi: 10.1074/jbc.RA117.000405. Epub 2017 Nov 20.

Abstract

Congestive heart failure typically arises from cardiac myocyte necrosis/apoptosis, associated with the pathological opening of the mitochondrial permeability transition pore (mPTP). mPTP opening decreases the mitochondrial membrane potential leading to the activation of Ca2+-independent phospholipase A2γ (iPLA2γ) and the production of downstream toxic metabolites. However, the array of enzymatic mediators and the exact chemical mechanisms responsible for modulating myocardial mPTP opening remain unclear. Herein, we demonstrate that human heart failure activates specific myocardial mitochondrial phospholipases that increase Ca2+-dependent production of toxic hydroxyeicosatetraenoic acids (HETEs) and attenuate the activity of phospholipases that promote the synthesis of protective epoxyeicosatrienoic acids (EETs). Mechanistically, HETEs activated the Ca2+-induced opening of the mPTP in failing human myocardium, and the highly selective pharmacological blockade of either iPLA2γ or lipoxygenases attenuated mPTP opening in failing hearts. In contrast, pharmacological inhibition of cytochrome P450 epoxygenases opened the myocardial mPTP in human heart mitochondria. Remarkably, the major mitochondrial phospholipase responsible for Ca2+-activated release of arachidonic acid (AA) in mitochondria from non-failing hearts was calcium-dependent phospholipase A2ζ (cPLA2ζ) identified by sequential column chromatographies and activity-based protein profiling. In contrast, iPLA2γ predominated in failing human myocardium. Stable isotope kinetics revealed that in non-failing human hearts, cPLA2ζ metabolically channels arachidonic acid into EETs, whereas in failing hearts, increased iPLA2γ activity channels AA into toxic HETEs. These results mechanistically identify the sequelae of pathological remodeling of human mitochondrial phospholipases in failing myocardium. This remodeling metabolically channels AA into toxic HETEs promoting mPTP opening, which induces necrosis/apoptosis leading to further progression of heart failure.

Keywords: cytochrome P-450; eicosanoid; heart failure; lipoxygenase; mitochondrial permeability transition pore (mPTP); phospholipase.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Calcium / metabolism
  • Calcium Channels / metabolism
  • Group VI Phospholipases A2 / metabolism*
  • Heart Failure / enzymology
  • Heart Failure / metabolism*
  • Heart Failure / pathology
  • Humans
  • Hydroxyeicosatetraenoic Acids / biosynthesis*
  • Hydroxyeicosatetraenoic Acids / metabolism
  • Membrane Potential, Mitochondrial
  • Mitochondria, Heart / enzymology
  • Mitochondria, Heart / metabolism*
  • Mitochondrial Membrane Transport Proteins / metabolism*
  • Mitochondrial Membranes / enzymology
  • Mitochondrial Membranes / metabolism
  • Mitochondrial Permeability Transition Pore
  • Myocardium / enzymology
  • Myocardium / metabolism
  • Myocardium / pathology
  • Permeability
  • Phospholipases A2 / metabolism

Substances

  • Calcium Channels
  • Hydroxyeicosatetraenoic Acids
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Permeability Transition Pore
  • Group VI Phospholipases A2
  • PLA2G6 protein, human
  • Phospholipases A2
  • Calcium