Heart Mitochondrial Cardiolipin Oxidation during Ischemia in the Aged Rat

1
Heart Mitochondrial Cardiolipin Oxidation during
Ischemia in the Aged Rat

• E. Lesnefsky, P. Minkler,
• Charles Hoppel Case School of Medicine
• Louis Stokes VA Medical Center

2
Edward Lesnefsky, M.D. Paul Minkler Shadi
Moghaddas, Ph.D. Bernard Tandler, Ph.D. Qun
Chen, M.D., Ph.D. Medhat Hassan, M.D. Edwin
Vazquez Alessandro Riva, M.D.,
Ph.D. Funding NIA PO1 AG15885 Aging Heart
Basis of Increased Ischemic/Reflow Injury
3
Heart Mitochondrial Cardiolipin Oxidation during
Ischemia in the Aged Rat

• Introduction
• Mitochondria in aging heart
• Mitochondrial Cardiolipin ischemia in aging
  heart
• Summary

4
Increased Injury in Aging Heart

• Aging hearts showed increased injury
• Decreased hemodynamic recovery
• Increased CPK release-increased tissue damage
• Aging myocardium has an increased intrinsic
  susceptibility to damage during ischemia and
  reperfusion

5
Heart Mitochondrial Cardiolipin Oxidation during
Ischemia in the Aged Rat

• Introduction
• Mitochondria in aging heart
• Mitochondrial Cardiolipin ischemia in aging
  heart
• Summary

6
Cardiac Mitochondria Exist in Two Populations
Subsarcolemmal Mitochondria (SSM) and
Interfibrillar Mitochondria (IFM)
Cardiomyocyte
Subsarcolemmal Mitochondria under cell membrane
contractileproteins
Interfibrillar Mitochondria in contractile regions
nucleus
Palmer et al. J Biol Chem 19772528731-8738
7
Heart Mitochondrial Cardiolipin Oxidation during
Ischemia in the Aged Rat

• Problem
• Mitochondria in aging heart
• Mitochondrial Cardiolipin ischemia in aging
  heart
• Summary

8
(No Transcript)
9
(No Transcript)
10
(No Transcript)
11
(No Transcript)
12
(No Transcript)
13
Content of Cardiolipin is Unaltered by Ischemia
and Reperfusion in Adult and Aged Hearts
pNS, ?SEM
IFM
SSM
60
50
40
nmol/mg protein
30
20
10
0
24mo n7
24mo n7
6mo n5
6mo n5
14
Ischemia-Reperfusion Increases Relative Amount
of Oxidized Cardiolipin in Aged Heart

• OD 206 peak area ratio 1496 peak /1448 peak
• Peaks identified by subsequent MS

15
Ischemia Alone Increases Relative Amount of
Oxidized Cardiolipin in Aged Heart
plt0.05vs 6mo, ?SD
0.8


0.6


0.4
Ratio Peak Area _at_OD206
0.2
0
SSM
IFM
16
(No Transcript)
17
(No Transcript)
18
MS Analysis of Oxidized Cardiolipin
MS Analysis of Oxidized Cardiolipin
Evidence of
Evidence of
Linoleic
Linoleic
Acid Oxidation
Acid Oxidation
Native
Native
4 C182 m/z 1448
4 C182 m/z 1448
19
Ischemia Increases Production of Oxidized
Cardiolipin in Aged Heart
HPLC/MS 1496 m/z RIC
20
Heart Mitochondrial Cardiolipin Oxidation during
Ischemia in the Aged Rat

• Problem
• Mitochondria in aging heart
• Mitochondrial Cardiolipin ischemia in aging
  heart
• Summary

21
Conclusions

• Oxidative damage to cardiolipin occurs in the
  ischemic-reperfused aged, but not the adult
  heart.
• Ischemia alone is sufficient to induce oxidative
  damage to cardiolipin in the aged rat heart.
• Cardiolipin modification provides evidence of
  enhanced oxidative damage to mitochondria during
  ischemia in the aged heart.