Protective actions of epoxyeicosatrienoic acid: Dual targeting of cardiovascular PI3K and KATP channels

Sreedhar Bodiga, Rong Zhang, Dexter E. Jacobs, Brandon T. Larsen, Akihito Tampo, Vijay L. Manthati, Wai Meng Kwok, Darryl C. Zeldin, John R. Falck, David D. Gutterman, Elizabeth R. Jacobs, Meetha M. Medhora

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Epoxyeicosatrienoic acid(s) (EETs) have been shown to protect cardiovascular tissue against apoptosis dependent on activation of targets such as ATP-sensitive K+ (KATP) channels (sarcolemmal and mitochondrial), calcium-activated K+ channels, extracellular signal-regulated kinase or phosphoinositide 3-kinase (PI3K). We tested if EETs protect human atrial tissue ex vivo from hypoxia/reoxygenation (H/R) injury, and compared our results with myocardium from two rodent species, rats and mice. EETs reduced myocardial caspase 3 activity in all three species and protected against loss of mitochondrial membrane potential in primary cultures of neonatal rat ventricular myocytes submitted to H/R. In addition, EETs protected mouse pulmonary arteries ex vivo exposed to H/R. Myocardium and pulmonary arteries from genetically engineered mice having elevated plasma levels of EETs (Ephx2-/-) exhibited protection from H/R-induced injury over that of wild type controls, suggesting that endogenously produced EETs may have pro-survival effects. Electrophysiological studies in myocytes demonstrated that EETs can stimulate KATP currents even when PI3K is inhibited. Similarly, activation of PI3K/Akt occurred in the presence of the KATP channel blocker glibenclamide. Based upon loss of protection with EETs in the presence of either wortmannin (a PI3K inhibitor) or glibenclamide, simultaneous activation of at least 2 pathways, PI3K and KATP channels respectively, appears to be required for protection. In conclusion, we demonstrate that exogenous and endogenous EETs have powerful pro-survival effects in cardiovascular tissues including diseased human myocardium, mediated by activation of not only one but at least two pathways, PI3K and KATP channels.

Original languageEnglish (US)
Pages (from-to)978-988
Number of pages11
JournalJournal of Molecular and Cellular Cardiology
Volume46
Issue number6
DOIs
StatePublished - Jun 2009

Fingerprint

KATP Channels
1-Phosphatidylinositol 4-Kinase
Acids
Myocardium
Glyburide
Muscle Cells
Pulmonary Artery
Calcium-Activated Potassium Channels
Survival
Mitochondrial Membrane Potential
Extracellular Signal-Regulated MAP Kinases
Wounds and Injuries
Caspase 3
Rodentia
Adenosine Triphosphate
Apoptosis

Keywords

  • Epoxide hydrolase
  • Human myocardium
  • Hypoxia/reoxygenation
  • Lactate dehydrogenase release
  • Mitochondrial membrane potential
  • Pulmonary artery

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

Bodiga, S., Zhang, R., Jacobs, D. E., Larsen, B. T., Tampo, A., Manthati, V. L., ... Medhora, M. M. (2009). Protective actions of epoxyeicosatrienoic acid: Dual targeting of cardiovascular PI3K and KATP channels. Journal of Molecular and Cellular Cardiology, 46(6), 978-988. https://doi.org/10.1016/j.yjmcc.2009.01.009

Protective actions of epoxyeicosatrienoic acid : Dual targeting of cardiovascular PI3K and KATP channels. / Bodiga, Sreedhar; Zhang, Rong; Jacobs, Dexter E.; Larsen, Brandon T.; Tampo, Akihito; Manthati, Vijay L.; Kwok, Wai Meng; Zeldin, Darryl C.; Falck, John R.; Gutterman, David D.; Jacobs, Elizabeth R.; Medhora, Meetha M.

In: Journal of Molecular and Cellular Cardiology, Vol. 46, No. 6, 06.2009, p. 978-988.

Research output: Contribution to journalArticle

Bodiga, S, Zhang, R, Jacobs, DE, Larsen, BT, Tampo, A, Manthati, VL, Kwok, WM, Zeldin, DC, Falck, JR, Gutterman, DD, Jacobs, ER & Medhora, MM 2009, 'Protective actions of epoxyeicosatrienoic acid: Dual targeting of cardiovascular PI3K and KATP channels', Journal of Molecular and Cellular Cardiology, vol. 46, no. 6, pp. 978-988. https://doi.org/10.1016/j.yjmcc.2009.01.009
Bodiga, Sreedhar ; Zhang, Rong ; Jacobs, Dexter E. ; Larsen, Brandon T. ; Tampo, Akihito ; Manthati, Vijay L. ; Kwok, Wai Meng ; Zeldin, Darryl C. ; Falck, John R. ; Gutterman, David D. ; Jacobs, Elizabeth R. ; Medhora, Meetha M. / Protective actions of epoxyeicosatrienoic acid : Dual targeting of cardiovascular PI3K and KATP channels. In: Journal of Molecular and Cellular Cardiology. 2009 ; Vol. 46, No. 6. pp. 978-988.
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AU - Larsen, Brandon T.

AU - Tampo, Akihito

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