Long-term modifications of blood pressure in normotensive and spontaneously hypertensive rats by gene delivery of rAAV-mediated cytochrome P450 arachidonic acid hydroxylase

Zhang, Fan; Chen, Chun Lian; Qian, Jia; Yan, Jun; Cianflone, Katherine; Xiao, Xiao; Wang, Dao Wen

doi:10.1038/sj.cr.7290341

Cited by 22 publications

(15 citation statements)

References 38 publications

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“…In the present study, animals were pretreated with HET0016 for 5 min before MCAO to determine the contribution of 20-HETE to ischemic stroke outcomes in normotensive and hypertensive rats. Administration of HET0016 also reduced MAP in SHR and SHRSP by about 30 mmHg, which is consistent with previous suggestions that elevated vascular production of 20-HETE may contribute to increased peripheral vascular tone and the maintenance of hypertension in the SHR (17,30,52,63,64,67). This reduction in MAP in SHR and SHRSP may also contribute to the reduction in infarct size with HET0016 treatment by reducing the driving force for edema formation.…”

Section: Discussionsupporting

confidence: 78%

Elevated production of 20-HETE in the cerebral vasculature contributes to severity of ischemic stroke and oxidative stress in spontaneously hypertensive rats

Dunn¹,

Renić²,

Flasch³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

127

132

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Dunn KM, Renic M, Flasch AK, Harder DR, Falck J, Roman RJ. Elevated production of 20-HETE in the cerebral vasculature contributes to severity of ischemic stroke and oxidative stress in spontaneously hypertensive rats. Am J Physiol Heart Circ Physiol 295: H2455-H2465, 2008. First published October 17, 2008 doi:10.1152/ajpheart.00512.2008.-Hypertension is a major risk factor for stroke, but the factors that contribute to the increased incidence and severity of ischemic stroke in hypertension remain to be determined. 20-hydroxyeicosatetraenoic acid (20-HETE) has been reported to be a potent constrictor of cerebral arteries, and inhibitors of 20-HETE formation reduce infarct size following cerebral ischemia. The present study examined whether elevated production of 20-HETE in the cerebral vasculature could contribute to the larger infarct size previously reported after transient middle cerebral artery occlusion (MCAO) in hypertensive strains of rat [spontaneously hypertensive rat (SHR) and spontaneously hypertensive stroke-prone rat (SHRSP)]. The synthesis of 20-HETE in the cerebral vasculature of SHRSP measured by liquid chromatography-tandem mass spectrometry was about twice that seen in Wistar-Kyoto (WKY) rats. This was associated with the elevated expression of cytochrome P-450 (CYP)4A protein and CYP4A1 and CYP4A8 mRNA. Infarct volume after transient MCAO was greater in SHRSP (36 Ϯ 4% of hemisphere volume) than in SHR (19 Ϯ 5%) or WKY rats (5 Ϯ 2%). This was associated with a significantly greater reduction in regional cerebral blood flow (rCBF) in SHR and SHRSP than in WKY rats during the ischemic period (78% vs. 62%). In WKY rats, rCBF returned to 75% of control following reperfusion. In contrast, SHR and SHRSP exhibited a large (166 Ϯ 18% of baseline) and sustained (1 h) postischemic hyperperfusion. Acute blockade of the synthesis of -formamidine (HET0016; 1 mg/kg) reduced infarct size by 59% in SHR and 87% in SHRSP. HET0016 had no effect on the fall in rCBF during MCAO but eliminated the hyperemic response. HET0016 also attenuated vascular O2•Ϫ formation and restored endothelium-dependent dilation in cerebral arteries of SHRSP. These results indicate the production of 20-HETE is elevated in the cerebral vasculature of SHRSP and contributes to oxidative stress, endothelial dysfunction, and the enhanced sensitivity to ischemic stroke in this hypertensive model. 20-hydroxyeicosatetraenoic acid; middle cerebral artery occlusion; cytochrome P-450A; N-hydroxy-N'-(4-butyl-2-methylphenyl)-formamidine HYPERTENSION IS A MAJOR RISK factor for stroke, but the factors that contribute to the increased incidence and severity of ischemic stroke in hypertension remain to be determined (46). Previous studies have indicated that arachidonic acid (AA) is released into cerebrospinal fluid following cerebral ischemia (1,31,42,56). AA is converted by cytochrome P-450 (CYP) enzymes in cerebral arteries to a potent vasoconstrictor, 20-hydroxyeicosatetraenoic acid (20-HETE) (15,16,32). 20-HETE has been reported to play an important...

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Section: Discussionsupporting

confidence: 78%

Elevated production of 20-HETE in the cerebral vasculature contributes to severity of ischemic stroke and oxidative stress in spontaneously hypertensive rats

Dunn¹,

Renić²,

Flasch³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

127

132

View full text Add to dashboard Cite

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“…7 The delivery of CYP4A1 cDNA increased BP in Sprague-Dawley rat, whereas transferring antisense CYP4A1 cDNA into SHR decreased BP. 20 Our findings that Hap I of CYP4F2 regulatory region was associated with elevated urinary 20-HETE levels as well as increased risk for hypertension supported a prohypertensive effect of renal 20-HETE and CYP4F2 expression; however, Gainer et al 9 reported that a functional variant of CYP4A11 with reduced 20-HETE synthase activity was associated with hypertension, suggesting an antihypertensive action of 20-HETE. In vivo investigations of the synergistic or antagonistic effect of functional polymorphisms as well as haplotypes in the CYP4F2 and CYP4A11 genes would be the focus of further studies.…”

Section: Discussioncontrasting

confidence: 42%

Association of a Functional Cytochrome P450 4F2 Haplotype with Urinary 20-HETE and Hypertension

Liu

Zhao

Nie

et al. 2008

Journal of the American Society of Nephrology

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Cytochrome P450 4F2 (CYP4F2) catalyzes the -hydroxylation of arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE), a natriuretic and vasoactive eicosanoid that participates in the development of hypertension. The relationship among CYP4F2 genetic variants in the regulatory region, formation of renal 20-HETE, and hypertension is unknown. Here are reported seven genetic variants around the CYP4F2 intronic regulatory region. Four of these variants made up two common haplotypes, Hap I (c.Ϫ91T/c.Ϫ48G/c.Ϫ13T/c.ϩ34T) and Hap II (c.Ϫ91C/c.Ϫ48C/c.Ϫ13C/c.ϩ34G). Hap I included a major functional variant, c.Ϫ91T3 C, which was identified by reporter assay and electrophoretic mobility shift assay. Transfected into HEK293 cells, the Hap I construct showed a trend toward higher basal transcriptional activity and exhibited significantly greater LPS-stimulated activity than Hap II; these findings were the result of different NF-B binding affinity between the two constructs. In vivo, a case-control study demonstrated that homozygosity for Hap I doubled the risk for hypertension in a Chinese population, even after adjustment for risk factors including age, gender, and body mass index. This association was confirmed in a family-based association study. In addition, Hap I was associated with elevated urinary 20-HETE. These results indicate that a functional variant of the CYP4F2 regulatory region, which increases the binding affinity of NF-B, increases the risk for hypertension, likely by modulating the production of 20-HETE. The cytochrome P450 4F2 (CYP4F2) gene, prominently expressed in human kidney and liver, encodes an -hydroxylase that catalyzes the metabolism of arachidonic acid, 1 leukotriene B4, 2 and tocopherol. 3 The 20-hydroxyeicosatetraenoic acid (20-HETE), derived from arachidonic acid by CYP4F2 in the kidney, acts as a natriuretic and vasoactive eicosanoid and plays an important role in the control of renal function and systemic BP. 4,5 Considerable evidence showed that altered renal 20-HETE content and CYP genes were related to hypertension in animal models and in humans 6-10 ; however, the contribution of haplotypes in the CYP4F2 regulatory regiontorenal20-HETEexcretionaswellashumanhypertension remains unclear, because recent investigations indicated that the primary target variants for disease-gene association studies would be located in regulatory regions. 11 Hypertension is a common disease and an independent risk factor for stroke, heart failure, and ESRD. It is widely known that hypertension is a multifactorial disease whereby genetic determinants interact with environmental factors 12 ; however, the molecular mechanisms are still not well understood. Previously, we focused on a single-

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“…In this study, we applied an rAAV vector to deliver SLC directly into the tumor cells. This choice was based on the broad host range, excellent safety profile, and the ability of rAAV to integrate into the host genome as well as to provide long-term expression in infected hosts (20,52,57). Although studies have addressed the efficacy of AAV-mediated gene therapy in different human and mammalian cell types, the most efficient vector transduction in vivo has been reported in skeletal muscle and brain, followed by hepatocytes (4,22,29,52,58).…”

Section: Discussionmentioning

confidence: 99%

Local Expression of Secondary Lymphoid Tissue Chemokine Delivered by Adeno-Associated Virus within the Tumor Bed Stimulates Strong Anti-Liver Tumor Immunity

Liang

Zhong

Sun

et al. 2007

J Virol

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Development of an effective antitumor immune response depends on the appropriate interaction of effector and target cells. Thus, the expression of chemokines within the tumor may induce a more potent antitumor immune response. Secondary lymphoid tissue chemokine (SLC) is known to play a critical role in establishing a functional microenvironment in secondary lymphoid tissues. Its capacity to attract dendritic cells (DCs) and colocalize them with T cells makes it a good therapeutic candidate against cancer. In this study, we used SLC as a treatment for tumors established from a murine hepatocellular carcinoma model. SLC was encoded by recombinant adeno-associated virus (rAAV), a system chosen for the low host immunity and high efficiency of transduction, enabling long-term expression of the gene of interest. As a result, rAAV-SLC induced a significant delay of tumor progression, which was paralleled by a profound infiltration of DCs and activated CD4 ؉ T cells and CD8؉ T cells (CD3 ؉ CD69 ؉ cells) into the tumor site. In addition, rAAV-SLC treatment was also found to reduce tumor growth in nude mice, most likely due to inhibition of neoangiogenesis. In conclusion, local expression of SLC by rAAV represents a promising approach to induce immune-mediated regression of malignant tumors.

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Long-term modifications of blood pressure in normotensive and spontaneously hypertensive rats by gene delivery of rAAV-mediated cytochrome P450 arachidonic acid hydroxylase

Cited by 22 publications

References 38 publications

Elevated production of 20-HETE in the cerebral vasculature contributes to severity of ischemic stroke and oxidative stress in spontaneously hypertensive rats

Elevated production of 20-HETE in the cerebral vasculature contributes to severity of ischemic stroke and oxidative stress in spontaneously hypertensive rats

Association of a Functional Cytochrome P450 4F2 Haplotype with Urinary 20-HETE and Hypertension

Local Expression of Secondary Lymphoid Tissue Chemokine Delivered by Adeno-Associated Virus within the Tumor Bed Stimulates Strong Anti-Liver Tumor Immunity

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