Pharmacological inhibition of soluble epoxide hydrolase provides cardioprotection in hyperglycemic rats

Kathleen Guglielmino, Kaleena Jackson, Todd R. Harris, Vincent Vu, Hua Dong, Gavin Dutrow, James E. Evans, James Graham, Bethany P. Cummings, Peter J Havel, Nipavan Chiamvimonvat, Sanda Despa, Bruce D. Hammock, Florin Despa

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Glycemic regulation improves myocardial function in diabetic patients, but finding optimal therapeutic strategies remains challenging. Recent data have shown that pharmacological inhibition of soluble epoxide hydrolase (sEH), an enzyme that decreases the endogenous levels of protective epoxyeicosatrienoic acids (EETs), improves glucose homeostasis in insulin-resistant mice. Here, we tested whether the administration of sEH inhibitors preserves cardiac myocyte structure and function in hyperglycemic rats. University of California-Davis-type 2 diabetes mellitus (UCD-T2DM) rats with nonfasting blood glucose levels in the range of 150 -200 mg/dl were treated with the sEH inhibitor 1-(1-acetypiperidin-4-yl)-3-adamantanylurea (APAU) for 6 wk. Administration of APAU attenuated the progressive increase of blood glucose concentration and preserved mitochondrial structure and myofibril morphology in cardiac myocytes, as revealed by electron microscopy imaging. Fluorescence microscopy with Ca2+ indicators also showed a 40% improvement of cardiac Ca2+ transients in treated rats. Sarcoplasmic reticulum Ca2+ content was decreased in both treated and untreated rats compared with control rats. However, treatment limited this reduction by 30%, suggesting that APAU may protect the intracellular Ca2+ effector system. Using Western blot analysis on cardiac myocyte lysates, we found less downregulation of sarco(endo)plasmic reticulum Ca2+ -ATPase (SERCA), the main route of Ca2+ reuptake in the sarcoplasmic reticulum, and lower expression of hypertrophic markers in treated versus untreated UCD-T2DM rats. In conclusion, APAU enhances the therapeutic effects of EETs, resulting in slower progression of hyperglycemia, efficient protection of myocyte structure, and reduced Ca2+ dysregulation and SERCA remodeling in hyperglycemic rats. The results suggest that sEH/EETs may be an effective therapeutic target for cardioprotection in insulin resistance and diabetes.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume303
Issue number7
DOIs
StatePublished - Oct 1 2012

Keywords

  • Arachidonic acid pathway
  • Calcium
  • Diabetes
  • Hyperglycemia
  • Insulin resistance

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

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    Guglielmino, K., Jackson, K., Harris, T. R., Vu, V., Dong, H., Dutrow, G., Evans, J. E., Graham, J., Cummings, B. P., Havel, P. J., Chiamvimonvat, N., Despa, S., Hammock, B. D., & Despa, F. (2012). Pharmacological inhibition of soluble epoxide hydrolase provides cardioprotection in hyperglycemic rats. American Journal of Physiology - Heart and Circulatory Physiology, 303(7). https://doi.org/10.1152/ajpheart.00154.2012