Soluble epoxide hydrolase is a susceptibility factor for heart failure in a rat model of human disease

Monti, Jan; Fischer, Judith; Paskaš, Svetlana; Heinig, Matthias; Schulz, Herbert; Gösele, Claudia; Heuser, Arnd; Fischer, Robert; Schmidt, Carolin; Schirdewan, Alexander; Groß, Volkmar; Hummel, Oliver; Maatz, Henrike; Patone, Giannino; Saar, Kathrin; Vingron, Martin; Weldon, Steven M.; Lindpaintner, Klaus; Hammock, Bruce D.; Rohde, Klaus; Dietz, Rainer; Cook, Stuart A.; Schunck, Wolf Hagen; Luft, Friedrich C.; Hübner, Norbert

doi:10.1038/ng.129

Cited by 165 publications

(127 citation statements)

References 49 publications

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“…Furthermore, as NO 2 -OA did not elevate EETs or lower BP in KI mice, it was ineffective in preventing cardiac hypertrophy. These observations are consistent with several studies that show pharmacological inhibition of sEH can limit cardiac hypertrophy secondary to hypertension (6,14).…”

Section: Discussionsupporting

confidence: 93%

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Protection from hypertension in mice by the Mediterranean diet is mediated by nitro fatty acid inhibition of soluble epoxide hydrolase

Charles

Rudyk

Prysyazhna

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Soluble epoxide hydrolase (sEH) is inhibited by electrophilic lipids by their adduction to Cys521 proximal to its catalytic center. This inhibition prevents hydrolysis of the enzymes' epoxyeicosatrienoic acid (EET) substrates, so they accumulate inducing vasodilation to lower blood pressure (BP). We generated a Cys521Ser sEH redoxdead knockin (KI) mouse model that was resistant to this mode of inhibition. The electrophilic lipid 10-nitro-oleic acid (NO 2 -OA) inhibited hydrolase activity and also lowered BP in an angiotensin II-induced hypertension model in wild-type (WT) but not KI mice. Furthermore, EET/dihydroxy-epoxyeicosatrienoic acid isomer ratios were elevated in plasma from WT but not KI mice following NO 2 -OA treatment, consistent with the redox-dead mutant being resistant to inhibition by lipid electrophiles. sEH was inhibited in WT mice fed linoleic acid and nitrite, key constituents of the Mediterranean diet that elevates electrophilic nitro fatty acid levels, whereas KIs were unaffected. These observations reveal that lipid electrophiles such as NO 2 -OA mediate antihypertensive signaling actions by inhibiting sEH and suggest a mechanism accounting for protection from hypertension afforded by the Mediterranean diet.thiol | cardiovascular

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Section: Discussionsupporting

confidence: 93%

“…Consistent with the therapeutic potential of hydrolase inhibitors, sEH null mice are protected from pathological interventions (13). Conversely, genetic alterations that promote enhanced hydrolase activity are a risk factor for human heart failure (14).…”

mentioning

confidence: 81%

Protection from hypertension in mice by the Mediterranean diet is mediated by nitro fatty acid inhibition of soluble epoxide hydrolase

Charles

Rudyk

Prysyazhna

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Ephx2 is a susceptibility gene for hypertension-associated heart failure in rodents (39), and likewise, an association between single-nucleotide polymorphisms (SNPs) in Ephx2 gene and cardiovascular diseases (56). For instance, the K55R allele is associated with a higher risk of hypertension and ischemic stroke, as well as coronary heart disease (15).…”

Section: Discussionmentioning

confidence: 99%

Soluble epoxide hydrolase-dependent regulation of myogenic response and blood pressure

Sun

Cuevas

Gotlinger

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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Sun D, Cuevas AJ, Gotlinger K, Hwang SH, Hammock BD, Schwartzman ML, Huang A. Soluble epoxide hydrolase-dependent regulation of myogenic response and blood pressure. Am J Physiol Heart Circ Physiol 306: H1146-H1153, 2014. First published February 21, 2014 doi:10.1152/ajpheart.00920.2013 are metabolites of arachidonic acid via cytochrome P450 (CYP)/epoxygenases. EETs possess cardioprotective properties and are catalyzed by soluble epoxide hydrolase (sEH) to dihydroxyeicosatrienoic acids (DHETs) that lack vasoactive property. To date, the role of sEH in the regulation of myogenic response of resistant arteries, a key player in the control of blood pressure, remains unknown. To this end, experiments were conducted on sEH-knockout (KO) mice, wild-type (WT) mice, and endothelial nitric oxide synthase (eNOS)-KO mice treated with t-TUCB, a sEH inhibitor, for 4 wk. sEH-KO and t-TUCB-treated mice displayed significantly lower blood pressure, associated with significantly increased vascular EETs and ratio of EETs/DHETs. Pressure-diameter relationships were assessed in isolated and cannulated gracilis muscle arterioles. All arterioles constricted in response to increases in transmural pressure from 60 to 140 mmHg. The myogenic constriction was significantly reduced, expressed as an upward shift of pressure-diameter curve, in arterioles of sEH-KO and t-TUCB-treated eNOS-KO mice compared with their controls. Removal of the endothelium, or treatment of the vessels with PPOH, an inhibitor of EET synthase, restored the attenuated pressure-induced constriction to the levels similar to those observed in their controls but had no effects on control vessels. No difference was observed in the myogenic index, or in the vascular expression of eNOS, CYP2C29 (EET synthase), and CYP4A (20-HETE synthase) among these groups of mice. In conclusion, the increased EET bioavailability, as a function of deficiency/inhibition of sEH, potentiates vasodilator responses that counteract pressure-induced vasoconstriction to lower blood pressure. myogenic response; soluble epoxide hydrolase; epoxyeicosatrienoic acids; arterioles; endothelium THE ISSUE OF HOW THE VASCULAR system maintains basal tone and regulates blood supply and organ perfusion, as well as capillary hydrostatic pressure, has been extensively investigated. Among the above-mentioned functions, the vascular myogenic response is a key contributor. The myogenic response is characterized by the intrinsic ability of small arteries/arterioles to contract in response to increases in transmural pressure. In physiological conditions, the myogenic response functions as an autoregulator that allows the vascular bed to maintain a constant blood flow despite wide changes in arterial pressure. In certain pathological conditions, however, augmented myogenic response initiates an increase in peripheral resistance and consequently increases the risk of hypertension. On the other hand, attenuated myogenic response may exhibit beneficial properties in the regulation of blood pressure, such as an estrogen...

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“…(1) The Ephx2 haplotype and expression pattern in WKY/Bbb appeared discrepant between Corenblum et al 15 and Monti et al 16 (2) Although the expression was low, it was still significantly greater than that of the SHRSP/Bbb. 16 u, unpublished observation by Nabika et al…”

Section: Genetic Studies On Hypertension and Cerebral Stroke In Shrspmentioning

confidence: 95%

“…15 An independent study by Monti et al 16 showed that a genetic variation in the Ephx2 promoter and the resulting change in sEH expression influenced the susceptibility to heart failure in SHHF, which is a model rat for heart failure derived from SHRSP.…”

Section: Genetic Studies On Hypertension and Cerebral Stroke In Shrspmentioning

confidence: 99%

The stroke-prone spontaneously hypertensive rat: still a useful model for post-GWAS genetic studies?

et al. 2012

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The stroke-prone spontaneously hypertensive rat (SHRSP) is a unique genetic model of severe hypertension and cerebral stroke. SHRSP, as well as the spontaneously hypertensive rat, the parental strain of SHRSP, has made a tremendous contribution to cardiovascular research. However, the genetic mechanisms underlying hypertension and stroke in these rats have not yet been clarified. Recent studies using whole-genome sequencing and comprehensive gene expression analyses combined with classical quantitative trait loci analyses provided several candidate genes, such as Ephx2, Gstm1 and Slc34a1, which still need further evidence to define their pathological roles. Currently, genome-wide association studies can directly identify candidate genes for hypertension in the human genome. Thus, genetic studies in SHRSP and other rat models must be focused on the pathogenetic roles of 'networks of interacting genes' in hypertension, instead of searching for individual candidate genes. Keywords: cerebral stroke; genetics; hypertension; QTL; SHRSP INTRODUCTIONThe stroke-prone spontaneously hypertensive rat (SHRSP) is a unique genetic model of severe hypertension and cerebral stroke. Two decades have passed since the first pioneering studies on quantitative trait loci (QTLs) of blood pressure (BP) in SHRSP. 1,2 In spite of all efforts, the genetic mechanisms underlying hypertension or cerebral stroke in this rat model remain unknown. During this period, genetic analyses in humans have progressed dramatically. Technologies have made it possible to genotype a large number of samples and analyze an enormous amount of single-nucleotide polymorphism data. Genome-wide association studies (GWAS) that rely on such advanced technologies have revealed a number of loci associated with increased BP in humans. [3][4][5][6][7][8][9][10] Under such circumstance, what is the role of SHRSP and other models in genetic studies of cardiovascular diseases? In this review, we will address this issue and summarize the genetic studies performed thus far in SHRSP.

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Soluble epoxide hydrolase is a susceptibility factor for heart failure in a rat model of human disease

Cited by 165 publications

References 49 publications

Protection from hypertension in mice by the Mediterranean diet is mediated by nitro fatty acid inhibition of soluble epoxide hydrolase

Protection from hypertension in mice by the Mediterranean diet is mediated by nitro fatty acid inhibition of soluble epoxide hydrolase

Soluble epoxide hydrolase-dependent regulation of myogenic response and blood pressure

The stroke-prone spontaneously hypertensive rat: still a useful model for post-GWAS genetic studies?

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