Oxidant‐induced Endothelial Dysfunction is a failure of the Mitochondria to Process Cytosolic ROS
Introduction Increased ROS is associated with vascular pathology. Recent reports showed that whereas short‐term (4 weeks) increase in NADPH oxidase‐derived endothelium (EC)‐specific ROS improved coronary endothelial function, long‐term (16+ weeks) increase in ROS had adverse effects. Hypothesis We tested the hypothesis that short‐term (4‐8 weeks) ROS increase induces AMPK‐FOXO1‐mediated expression of SOD2 and thus exert protective effects on EC mitochondria; in contrast, long‐term (16‐20 weeks) ROS increase results in nitrotyration and inactivation of MnSOD, mitochondrial membrane potential loss, and mitophagy in EC. Results: Our binary (Tet‐ON/OFF) conditional transgenic mouse (Tet‐Nox2:VE‐Cad‐tTA) induces 1.8±0.42‐fold increase in ROS in endothelium. Using these animals, we have examined the effects of short‐term vs. the long‐term effects of ROS on EC signaling, mitochondrial activity, and coronary endothelial function (microvessel reactivity). Isolated ECs from mouse heart showed that both short‐term and long‐term increase in ROS induced AMPK and eNOS, and nitric oxide (NO) synthesis, however, long‐term increase in ROS abrogated these positive effects due to increased peroxynitrite levels and nitrotyration of MnSOD. Long‐term ROS increase also results in mitochondrial membrane potential loss, reduction in mitochondrial content and EC function. Conclusion We report that whereas short‐term increase in ROS is beneficial for EC function, long‐term increase results in mitochondrial damage and inhibition of endothelial function..
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2015 |
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| Erschienen: |
2015 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:29 |
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| Enthalten in: |
The FASEB Journal - 29(2015) |
| Beteiligte Personen: |
Shafique, Ehtesham [VerfasserIn] |
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| BKL: |
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| Anmerkungen: |
© Federation of American Societies for Experimental Biology |
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| Umfang: |
1 |
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| doi: |
10.1096/fasebj.29.1_supplement.797.3 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
WLY006303145 |
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| 520 | |a Introduction Increased ROS is associated with vascular pathology. Recent reports showed that whereas short‐term (4 weeks) increase in NADPH oxidase‐derived endothelium (EC)‐specific ROS improved coronary endothelial function, long‐term (16+ weeks) increase in ROS had adverse effects. Hypothesis We tested the hypothesis that short‐term (4‐8 weeks) ROS increase induces AMPK‐FOXO1‐mediated expression of SOD2 and thus exert protective effects on EC mitochondria; in contrast, long‐term (16‐20 weeks) ROS increase results in nitrotyration and inactivation of MnSOD, mitochondrial membrane potential loss, and mitophagy in EC. Results: Our binary (Tet‐ON/OFF) conditional transgenic mouse (Tet‐Nox2:VE‐Cad‐tTA) induces 1.8±0.42‐fold increase in ROS in endothelium. Using these animals, we have examined the effects of short‐term vs. the long‐term effects of ROS on EC signaling, mitochondrial activity, and coronary endothelial function (microvessel reactivity). Isolated ECs from mouse heart showed that both short‐term and long‐term increase in ROS induced AMPK and eNOS, and nitric oxide (NO) synthesis, however, long‐term increase in ROS abrogated these positive effects due to increased peroxynitrite levels and nitrotyration of MnSOD. Long‐term ROS increase also results in mitochondrial membrane potential loss, reduction in mitochondrial content and EC function. Conclusion We report that whereas short‐term increase in ROS is beneficial for EC function, long‐term increase results in mitochondrial damage and inhibition of endothelial function. | ||
| 700 | 1 | |a Torina, Anali |4 aut | |
| 700 | 1 | |a Liu, Youhong |4 aut | |
| 700 | 1 | |a Feng, Jun |4 aut | |
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| 700 | 1 | |a Harrington, Elizabeth |4 aut | |
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| 700 | 1 | |a Abid, Ruhul |4 aut | |
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