Development of Epoxyeicosatrienoic Acid Analogs with in Vivo Anti-Hypertensive Actions

Epoxyeicosatrienoic acids (EETs) contribute importantly to the regulation of vascular tone and blood pressure control. The purpose of this study was to develop stable EET analogs and test their in vivo blood pressure lowering effects in hypertensive rats. Using the pharmacophoric moiety of EETs, ether EET analogs were designed with improved solubility and resistance to auto-oxidation and metabolism by soluble epoxide hydrolase. Ether EET analogs were chosen based on their ability to dilate afferent arterioles and subsequently tested for blood pressure lowering effects in rodent models of hypertension. Initially, 11,12-ether-EET-8-ZE failed to lower blood pressure in angiotensin hypertension or spontaneously hypertensive rats (SHR). Esterification of the carboxylic group of 11,12-ether-EET-8-ZE prevented blood pressure increase in SHR when injected at 2 mg/day for 12 days (MAP Δ change at day 8 of injection was −0.3 ± 2 for treated and 12 ± 1 mmHg for control SHR). Amidation of the carboxylic group with aspartic acid produced another EET analog (NUDSA) with a blood pressure lowering effect when injected at 3 mg/day in SHR for 5 days. Amidation of the carboxylic group with lysine amino acid produced another analog with minimal blood pressure lowering effect. These data suggest that esterification of the carboxylic group of 11,12-ether-EET-8-ZE produced the most effective ether-EET analog in lowering blood pressure in SHR and provide the first evidence to support the use of EET analogs in treatment of cardiovascular diseases

Multivariable logistic regression model for acute kidney injury (AKI) in whites with baseline eGFR > 60 mL/min/1.73m² in the replication cohort adjusted for age, sex, body mass index, baseline estimated glomerular filtration rate, history of diabetes, and cardiopulmonary bypass graft use.

<p>Multivariable logistic regression model for acute kidney injury (AKI) in whites with baseline eGFR > 60 mL/min/1.73m² in the replication cohort adjusted for age, sex, body mass index, baseline estimated glomerular filtration rate, history of diabetes, and cardiopulmonary bypass graft use.</p

Baseline characteristics of whites from the replication cohort with a baseline eGFR ≥ 60 mL/min/1.73m².

<p>Baseline characteristics of whites from the replication cohort with a baseline eGFR ≥ 60 mL/min/1.73m².</p

Multivariable logistic regression model for acute kidney injury (AKI) in the discovery cohort adjusted for age, sex, race, body mass index, baseline estimated glomerular filtration rate, history of diabetes, and cardiopulmonary bypass graft use.

<p>Multivariable logistic regression model for acute kidney injury (AKI) in the discovery cohort adjusted for age, sex, race, body mass index, baseline estimated glomerular filtration rate, history of diabetes, and cardiopulmonary bypass graft use.</p

Baseline characteristics of whites from the discovery cohort stratified by perioperative baseline eGFR.

<p>Baseline characteristics of whites from the discovery cohort stratified by perioperative baseline eGFR.</p

Multivariable logistic regression model for acute kidney injury (AKI) in whites with baseline eGFR ≥ 60 mL/min/1.73m² in the discovery cohort adjusted for age, sex, body mass index, baseline estimated glomerular filtration rate, history of diabetes, and cardiopulmonary bypass graft use.

<p>Multivariable logistic regression model for acute kidney injury (AKI) in whites with baseline eGFR ≥ 60 mL/min/1.73m² in the discovery cohort adjusted for age, sex, body mass index, baseline estimated glomerular filtration rate, history of diabetes, and cardiopulmonary bypass graft use.</p

Association of gain-of-function <i>EPHX2</i> polymorphism Lys55Arg with acute kidney injury following cardiac surgery

<div><p>Twenty to thirty percent of patients undergoing cardiac surgery develop acute kidney injury (AKI). In mice, inhibition of soluble epoxide hydrolase (sEH) attenuates renal injury following ischemia-reperfusion. We tested the hypothesis that functional variants of <i>EPHX2</i>, encoding sEH, are associated with AKI after cardiac surgery. We genotyped patients in two independent cardiac surgery cohorts for functional <i>EPHX2</i> polymorphisms, Lys55Arg and Arg287Gln, and determined AKI using Acute Kidney Injury Network criteria. The 287Gln variant was not associated with AKI. In the discovery cohort, the gain-of-function 55Arg variant was associated with an increased incidence of AKI in univariate (p = 0.03) and multivariable (p = 0.04) analyses. In white patients without chronic kidney disease (CKD), the 55Arg variant was independently associated with AKI with an OR of 2.04 (95% CI 0.95–4.42) for 55Arg heterozygotes and 31.53 (1.57–633.19) for homozygotes (p = 0.02), after controlling for age, sex, body mass index, baseline estimated glomerular filtration rate, and use of cardiopulmonary bypass. These findings were replicated in the second cardiac surgery cohort. 12,13- and total- dihydroxyoctadecanoic acids (DiHOME): epoxyoctadecanoic acids (EpOME) ratios were increased in <i>EPHX2</i> 55Arg variant carriers, consistent with increased hydrolase activity. The <i>EPHX2</i> Lys55Arg polymorphism is associated with AKI following cardiac surgery in patients without preexisting CKD. Pharmacological strategies to decrease sEH activity might decrease postoperative AKI.</p></div

Dihydroxy-12Z-octadecenoic acids:epoxy-12Z-octadecenoic acids (DiHOME:EpOME) ratios in plasma from 33 patients collected before surgery, following surgery and on post-operative day one according to Lys55Arg genotype.

<p>By analysis of repeated measures, carriers of the 55Arg variant G allele had higher sEH activity over time than homozygous AA. *p<0.05 for post hoc comparison.</p