Soluble epoxide hydrolase: sex differences and role in endothelial cell survival.

OBJECTIVE: Sex differences in cerebral ischemic injury are, in part, attributable to the differences in cerebrovascular perfusion. We determined whether the brain microvascular endothelial cells (ECs) isolated from the female brain are more resistant to ischemic injury compared with male ECs, and whether the difference is attributable to lower expression of soluble epoxide hydrolase and higher levels of vasoprotective epoxyeicosatrienoic acids (EETs). We also determined whether protection by EETs is linked to the inhibition of rho-kinase (ROCK). METHODS AND RESULTS: EC ischemic damage was measured after oxygen-glucose deprivation (OGD) using propidium iodide (PI) and cleaved caspase-3 labeling. Expression of soluble epoxide hydrolase was determined by quantitative polymerase chain reaction and immunocytochemistry, EETs levels by liquid chromatography-tandem mass spectrometry, and ROCK activity by ELISA. EC damage was higher in males compared with females, which correlated with higher soluble epoxide hydrolase mRNA, stronger immunoreactivity, and lower EETs compared with female ECs. Inhibition of soluble epoxide hydrolase abolished the sex difference in EC damage. ROCK activity was higher in male versus female ECs after OGD, and sex differences in EC damage and ROCK activity were abolished by 14,15-EET and ROCK inhibition. CONCLUSIONS: Sex differences in ischemic brain injury are, in part, attributable to differences in EET-mediated inhibition of EC ROCK activation after ischemia.

Coronary autoregulation is abnormal in syndrome X: insights using myocardial contrast echocardiography.

BACKGROUND: Syndrome X in women is thought to be caused by coronary microvascular dysfunction, the exact site of which is unknown. The aim of this study was to characterize the microvascular site of dysfunction in these patients using myocardial contrast echocardiography. METHODS: Women with exertional angina, positive test results on stress imaging, but no coronary artery disease (the study group, n = 18) and age-matched control women also with no coronary artery disease (n = 17) were enrolled. Myocardial contrast echocardiography was performed at rest and during dipyridamole-induced hyperemia. Mean microbubble velocity (ß) and myocardial blood volume (A) were measured, and myocardial blood flow (A · ß) was computed. In addition, plasma concentrations of eicosanoids, female sex hormones, and C-reactive protein were measured. RESULTS: Rest ß and myocardial blood flow (A · ß) were higher in the study compared with the control women (1.61 ± 0.68 vs. 0.74 ± 0.44, P = .0001, and 157 ± 121 vs. 54 ± 54, P = 0.0001, respectively) despite similar heart rates and systolic blood pressures. After the administration of dipyridamole, whereas the changes in A and A · ß were not significantly different between the two groups, ß reserve (the ratio of stress ß to rest ß) was markedly lower in the study group (1.48 ± 0.62 vs. 2.78 ± 0.94, P = .0001). Blood hematocrit, eicosanoids, female sex hormones, glucose, and C-reactive protein were not different between the two groups. CONCLUSIONS: Coronary autoregulation is abnormal in patients with syndrome X (higher resting ß and myocardial blood flow and lower ß reserve), which suggests that the coronary resistance vessels are the site of microvascular abnormality.