Abstract
Rationale: Although premenopausal females have a lower risk for cardiovascular disease, the mechanism(s) are poorly understood. OBJECTIVE: We tested the hypothesis that cardioprotection in females is mediated by altered mitochondrial protein levels and/or posttranslational modifications. METHODS AND RESULTS: Using both an in vivo and an isolated heart model of ischemia and reperfusion (I/R), we found that females had less injury than males. Using proteomic methods we found that female hearts had increased phosphorylation and activity of aldehyde dehydrogenase (ALDH)2, an enzyme that detoxifies reactive oxygen species (ROS)-generated aldehyde adducts, and that an activator of ALDH2 reduced I/R injury in males but had no significant effect in females. Wortmannin, an inhibitor of phosphatidylinositol 3-kinase, blocked the protection and the increased phosphorylation of ALDH2 in females, but had no effect in males. Furthermore, we found an increase in phosphorylation of α-ketoglutarate dehydrogenase (αKGDH) in female hearts. αKGDH is a major source of ROS generation particularly with a high NADH/NAD ratio which occurs during I/R. We found decreased ROS generation in permeabilized female mitochondria given αKGDH substrates and NADH, suggesting that increased phosphorylation of αKGDH might reduce ROS generation by αKGDH. In support of this hypothesis, we found that protein kinase C-dependent phosphorylation of purified αKGDH reduced ROS generation. Additionally, myocytes from female hearts had less ROS generation following I/R than males and addition of wortmannin increased ROS generation in females to the same levels as in males. Conclusions: These data suggest that posttranslational modifications can modify ROS handling and play an important role in female cardioprotection.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1681-1691 |
| Number of pages | 11 |
| Journal | Circulation Research |
| Volume | 106 |
| Issue number | 11 |
| DOIs | |
| State | Published - Jun 11 2010 |
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Keywords
- Aldehyde dehydrogenase
- Cardioprotection
- Gender difference
- Mitochondria
- Proteomics
ASJC Scopus subject areas
- Physiology
- Cardiology and Cardiovascular Medicine
Cite this
Sex differences in the phosphorylation of mitochondrial proteins result in reduced production of reactive oxygen species and cardioprotection in females. / Lagranha, Claudia J.; Deschamps, Anne; Aponte, Angel; Steenbergen, Charles Jr; Murphy, Elizabeth.
In: Circulation Research, Vol. 106, No. 11, 11.06.2010, p. 1681-1691.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Sex differences in the phosphorylation of mitochondrial proteins result in reduced production of reactive oxygen species and cardioprotection in females
AU - Lagranha, Claudia J.
AU - Deschamps, Anne
AU - Aponte, Angel
AU - Steenbergen, Charles Jr
AU - Murphy, Elizabeth
PY - 2010/6/11
Y1 - 2010/6/11
N2 - Rationale: Although premenopausal females have a lower risk for cardiovascular disease, the mechanism(s) are poorly understood. OBJECTIVE: We tested the hypothesis that cardioprotection in females is mediated by altered mitochondrial protein levels and/or posttranslational modifications. METHODS AND RESULTS: Using both an in vivo and an isolated heart model of ischemia and reperfusion (I/R), we found that females had less injury than males. Using proteomic methods we found that female hearts had increased phosphorylation and activity of aldehyde dehydrogenase (ALDH)2, an enzyme that detoxifies reactive oxygen species (ROS)-generated aldehyde adducts, and that an activator of ALDH2 reduced I/R injury in males but had no significant effect in females. Wortmannin, an inhibitor of phosphatidylinositol 3-kinase, blocked the protection and the increased phosphorylation of ALDH2 in females, but had no effect in males. Furthermore, we found an increase in phosphorylation of α-ketoglutarate dehydrogenase (αKGDH) in female hearts. αKGDH is a major source of ROS generation particularly with a high NADH/NAD ratio which occurs during I/R. We found decreased ROS generation in permeabilized female mitochondria given αKGDH substrates and NADH, suggesting that increased phosphorylation of αKGDH might reduce ROS generation by αKGDH. In support of this hypothesis, we found that protein kinase C-dependent phosphorylation of purified αKGDH reduced ROS generation. Additionally, myocytes from female hearts had less ROS generation following I/R than males and addition of wortmannin increased ROS generation in females to the same levels as in males. Conclusions: These data suggest that posttranslational modifications can modify ROS handling and play an important role in female cardioprotection.
AB - Rationale: Although premenopausal females have a lower risk for cardiovascular disease, the mechanism(s) are poorly understood. OBJECTIVE: We tested the hypothesis that cardioprotection in females is mediated by altered mitochondrial protein levels and/or posttranslational modifications. METHODS AND RESULTS: Using both an in vivo and an isolated heart model of ischemia and reperfusion (I/R), we found that females had less injury than males. Using proteomic methods we found that female hearts had increased phosphorylation and activity of aldehyde dehydrogenase (ALDH)2, an enzyme that detoxifies reactive oxygen species (ROS)-generated aldehyde adducts, and that an activator of ALDH2 reduced I/R injury in males but had no significant effect in females. Wortmannin, an inhibitor of phosphatidylinositol 3-kinase, blocked the protection and the increased phosphorylation of ALDH2 in females, but had no effect in males. Furthermore, we found an increase in phosphorylation of α-ketoglutarate dehydrogenase (αKGDH) in female hearts. αKGDH is a major source of ROS generation particularly with a high NADH/NAD ratio which occurs during I/R. We found decreased ROS generation in permeabilized female mitochondria given αKGDH substrates and NADH, suggesting that increased phosphorylation of αKGDH might reduce ROS generation by αKGDH. In support of this hypothesis, we found that protein kinase C-dependent phosphorylation of purified αKGDH reduced ROS generation. Additionally, myocytes from female hearts had less ROS generation following I/R than males and addition of wortmannin increased ROS generation in females to the same levels as in males. Conclusions: These data suggest that posttranslational modifications can modify ROS handling and play an important role in female cardioprotection.
KW - Aldehyde dehydrogenase
KW - Cardioprotection
KW - Gender difference
KW - Mitochondria
KW - Proteomics
UR - http://www.scopus.com/inward/record.url?scp=77953811756&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77953811756&partnerID=8YFLogxK
U2 - 10.1161/CIRCRESAHA.109.213645
DO - 10.1161/CIRCRESAHA.109.213645
M3 - Article
VL - 106
SP - 1681
EP - 1691
JO - Circulation Research
JF - Circulation Research
SN - 0009-7330
IS - 11
ER -