Heart failure-induced activation of phospholipase iPLA2γ generates hydroxyeicosatetraenoic acids opening the mitochondrial permeability transition pore

Sung Ho Moon, Xinping Liu, Ari M. Cedars, Kui Yang, Michael A. Kiebish, Susan M. Joseph, John Kelley, Christopher M. Jenkins, Richard W. Gross

Research output: Contribution to journalReview article

8 Citations (Scopus)

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 A2γ (cPLA2γ) 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, cPLA2γ 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.

Original languageEnglish (US)
Pages (from-to)115-129
Number of pages15
JournalJournal of Biological Chemistry
Volume293
Issue number1
DOIs
StatePublished - Jan 1 2018
Externally publishedYes

Fingerprint

Hydroxyeicosatetraenoic Acids
Phospholipases
Phospholipases A2
Heart Failure
Chemical activation
Poisons
Arachidonic Acid
Myocardium
Mitochondria
Necrosis
Lipoxygenases
Pharmacology
Apoptosis
Calcium
Heart Mitochondria
Mitochondrial Membrane Potential
Column chromatography
mitochondrial permeability transition pore
Cardiac Myocytes
Isotopes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Heart failure-induced activation of phospholipase iPLA2γ generates hydroxyeicosatetraenoic acids opening the mitochondrial permeability transition pore. / Moon, Sung Ho; Liu, Xinping; Cedars, Ari M.; Yang, Kui; Kiebish, Michael A.; Joseph, Susan M.; Kelley, John; Jenkins, Christopher M.; Gross, Richard W.

In: Journal of Biological Chemistry, Vol. 293, No. 1, 01.01.2018, p. 115-129.

Research output: Contribution to journalReview article

Moon, Sung Ho ; Liu, Xinping ; Cedars, Ari M. ; Yang, Kui ; Kiebish, Michael A. ; Joseph, Susan M. ; Kelley, John ; Jenkins, Christopher M. ; Gross, Richard W. / Heart failure-induced activation of phospholipase iPLA2γ generates hydroxyeicosatetraenoic acids opening the mitochondrial permeability transition pore. In: Journal of Biological Chemistry. 2018 ; Vol. 293, No. 1. pp. 115-129.
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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 A2γ (cPLA2γ) 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, cPLA2γ 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.",
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T1 - Heart failure-induced activation of phospholipase iPLA2γ generates hydroxyeicosatetraenoic acids opening the mitochondrial permeability transition pore

AU - Moon, Sung Ho

AU - Liu, Xinping

AU - Cedars, Ari M.

AU - Yang, Kui

AU - Kiebish, Michael A.

AU - Joseph, Susan M.

AU - Kelley, John

AU - Jenkins, Christopher M.

AU - Gross, Richard W.

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