Pharmacological inhibition of soluble epoxide hydrolase provides cardioprotection in hyperglycemic rats

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 Ca(2+) indicators also showed a 40% improvement of cardiac Ca(2+) transients in treated rats. Sarcoplasmic reticulum Ca(2+) 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 Ca(2+) effector system. Using Western blot analysis on cardiac myocyte lysates, we found less downregulation of sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA), the main route of Ca(2+) 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 Ca(2+) 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.

Soluble epoxide hydrolase inhibition improves coronary endothelial function and prevents the development of cardiac alterations in obese insulin-resistant mice

“…These effects are probably related to the decrease in LV macrophages infiltration, inflammation, and oxidative stress, illustrated by the reduction in F4/80-positive cells and in NF-B and NOX4 protein expressions, and to the increase in pAkt, which mediate some cardiac protective effects of EETs (3,15,20). In addition, an improvement in calcium homeostasis may help to prevent diastolic dysfunction, as recently suggested from experiments performed in cardiomyocytes isolated from hyperglycemic rats treated with another sEH inhibitor (9). Accordingly, one recent study showed that the genetic modulation of EET pathway through CYP450 epoxygenase overexpression protects streptozotocin-induced diabetic mice from the development of cardiac remodeling and dysfunction (16).…”

Cardioprotection by Controlling Hyperamylinemia in a “Humanized” Diabetic Rat Model

“…In contrast, age‐ and blood glucose–matched rats expressing only wild‐type (nonamyloidogenic) rat amylin, which develop T2D associated with other pathological defects in the pancreatic β‐cells, display cardiac dysfunction after the onset of T2D . These studies suggest that myocardial accumulation of oligomerized amylin may accelerate diabetic heart dysfunction in humans.…”

“…Epoxyeicosatrienoic acids (EETs) are signaling molecules produced from arachidonic acid by cytochrome P450 epoxygenases and have several isomers with various functions . EETs are primarily degraded by soluble epoxide hydrolase (sEH), which transforms them to less lipophilic and more readily conjugated 1,2‐diols (dihydroxyeicosatrienoic acids) .…”

“…EETs are primarily degraded by soluble epoxide hydrolase (sEH), which transforms them to less lipophilic and more readily conjugated 1,2‐diols (dihydroxyeicosatrienoic acids) . Pharmacological inhibition or genetic deletion of sEH elevates EETs, which was shown to have various therapeutic effects in animal models of metabolic disorders and cardiovascular disease . For example, we showed recently that pharmacologically increased levels of EETs improve glucose homeostasis in diabetic rats .…”

“…Pharmacological inhibition or genetic deletion of sEH elevates EETs, which was shown to have various therapeutic effects in animal models of metabolic disorders and cardiovascular disease . For example, we showed recently that pharmacologically increased levels of EETs improve glucose homeostasis in diabetic rats . Because some EET isomers have antiaggregation effects and reduce proteinaceous deposition on blood vessels, we hypothesized that increasing the blood levels of EETs may also limit the infiltration of toxic amylin aggregates in the heart.…”