Transfection of CYP4A1 cDNA decreases diameter and increases responsiveness of gracilis muscle arterioles to constrictor stimuli

Zhang, Fan; Wang, Mong Heng; Wang, Ji Shi; Zand, Barbara A.; Gopal, V. Raj; Falck, John R.; Laniado−Schwartzman, Michal; Nasjletti, Alberto

doi:10.1152/ajpheart.00627.2003

Cited by 17 publications

(11 citation statements)

References 25 publications

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“…40 Indeed, the inhibition of cytochrome P-450 (and hence 20-HETE generation) has been shown to attenuate myogenic responses in several artery preparations. 39,[41][42][43][44] It must be highlighted, however, that there is no direct evidence establishing linkages between the activities of (i) cytochrome P-450, (ii) K þ Ca channels and (iii) the myogenic response. Further, there are no proposed mechanisms to explain pressure-dependent modulation of cytochrome P-450 activity.…”

Section: Intracellular Signalling Events; Membrane Depolarizationmentioning

confidence: 99%

WITHDRAWN: The emerging role of Ca2+ sensitivity regulation in promoting myogenic vasoconstriction

Schubert

Lidington

Bolz

2007

Cardiovascular Research

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Growing evidence suggests that mechanisms which regulate the Ca2+ sensitivity of the contractile apparatus in vascular smooth muscle cells form the backbone of pressure-induced myogenic vasoconstriction. The modulation of Ca2+ sensitivity is suited to partially uncouple intracellular Ca2+ from constriction, thereby allowing the maintenance of tone with fully conserved function of other Ca2+-dependent processes. Following a brief review of 'classical' Ca2+-dependent signalling pathways involved in the myogenic response, the present review describes the emerging mechanisms that promote myogenic vasoconstriction via modulation of Ca2+ sensitivity. For the purpose of this review, Ca2+ sensitivity reflects the dynamic equilibrium between myosin light-chain kinase and myosin light-chain phosphatase activities in terms of its impact on vascular tone. Several signalling pathways (PKC, RhoA/Rho kinase, ROS) which have been identified as prominent regulators of Ca2+ sensitivity will be discussed. Although Ca2+ sensitivity modulation is clearly an important component of the myogenic response, attempts to integrate it into existing mechanistic models resulted in a two-phase model, with a predominant Ca2+-dependent 'initiation/trigger' phase followed by a Ca2+-independent 'maintenance' phase. We propose that the two-phase model is rather simplistic, because the literature reviewed here demonstrates that Ca2+-dependent and -independent mechanisms do not operate in isolation and are important at all stages of the response. The regulation of Ca2+ sensitivity, as an equal and complimentary partner of Ca2+-dependent processes, significantly enhances our understanding of the complex array of signalling pathways, which ultimately mediate the myogenic response.

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Section: Intracellular Signalling Events; Membrane Depolarizationmentioning

confidence: 99%

WITHDRAWN: The emerging role of Ca2+ sensitivity regulation in promoting myogenic vasoconstriction

Schubert

Lidington

Bolz

2007

Cardiovascular Research

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“…By extension, the intima may be expected to be the major site of vascular 20-HETE overproduction in rats treated with Adv-4A2. Pertinent to this point, recent reports have identified the intima and endothelial cells as a major site of CYP4A protein expression and a target for 20-HETE bioactions, [32][33][34][35][36] questioning the early notion that the vascular CYP4A-20-HETE pathway of arachidonic acid metabolism is limited to the smooth muscle. 12,37 To this end, our immunohistochemical analysis of CYP4A in arterial vessels taken from Adv-GFP rats indicated the presence of CYP4A positive signals not only in the media but also in the intima where CYP4A immunopositivity was greatly increased after Adv-4A2 administration.…”

Section: Discussionmentioning

confidence: 99%

Endothelial Dysfunction and Hypertension in Rats Transduced With CYP4A2 Adenovirus

Wang

Singh

Zhang

et al. 2006

Circulation Research

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112

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Abstract-Vascular cytochrome P450 (CYP) 4A enzymes catalyze the synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE), an eicosanoid which participates in the regulation of vascular tone by sensitizing the smooth muscle cells to constrictor and myogenic stimuli. This study was undertaken to investigate the consequences of CYP4A overexpression on blood pressure and endothelial function in rats treated with adenoviral vectors carrying the CYP4A2 construct. Intravenous injection of Adv-CYP4A2 increased blood pressure (from 114Ϯ1 to 133Ϯ1 mm Hg, PϽ0.001), and interlobar renal arteries from these rats displayed decreased relaxing responsiveness to acetylcholine, which was offset by treatment with an inhibitor of CYP4A. Relative to data in control rats, arteries from Adv-CYP4A2-transduced rats produced more 20-HETE (129Ϯ10 versus 97Ϯ7 pmol/mg protein, PϽ0.01) and less nitric oxide (NO; 4.2Ϯ1.6 versus 8.4Ϯ1 nmol nitriteϩnitrate/mg; PϽ0.05). They also displayed higher levels of oxidative stress as measured by increased generation of superoxide anion and increased expression of nitrotyrosine and gp91phox. Collectively, these findings demonstrate that augmentation in vascular 20-HETE promotes the development of hypertension and causes endothelial dysfunction, a condition characterized by decreased NO synthesis and/or bioavailability, imbalance in the relative contribution of endothelium-derived relaxing and contracting factors, and enhanced endothelial activation. T he endothelium plays a critical role in the short-and long-term regulation of the cardiovascular system. It serves as a protective barrier between tissues and circulating blood and functions to maintain vascular homeostasis by releasing bioactive factors in response to hemodynamic changes and blood borne signals. Such endothelial cell functions are impaired in many disease processes, including, diabetes, atherosclerosis, and hypertension.The expression of the cytochrome P450 (CYP) 4A and its catalytic activity as arachidonic acid -hydroxylase which produces 20-hydroxyeicosatetraenoic acid (20-HETE) has been linked to the regulation of vascular reactivity and tone and to the development of hypertension. This notion is substantiated by observations that 20-HETE promotes vasoconstriction, 1,2 that CYP4A expression and/or 20-HETE production is increased in vascular tissues of hypertensive animals, 3 and that interventions that decrease CYP4A expression and/or activity cause blood pressure to fall in animal models of hypertension. 4 -11 The vasoconstrictor action of 20-HETE is primarily attributed to inhibition of the large conductance Ca 2ϩ -activated K Their study demonstrated that 20-HETE attenuates acetylcholine-induced dilation in cremasteric arterioles of normotensive rats on a low salt diet and that inhibition of 20-HETE synthesis enhances arteriolar dilation to acetylcholine in hypertensive rats on a high salt diet. More recently, 20-HETE has been shown to functionally antagonize EDHF-mediated relaxation in small porcine coronary arteries. 20 In the pre...

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“…30 Myogenic responses were measured in freshly isolated segments from the third branch of mesenteric arteries (1-2 mm length) mounted between two micropipettes in the chamber (1 ml) of a pressure myograph as previously described. 60 …”

Section: Vascular Functionmentioning

confidence: 99%

Androgen-Sensitive Hypertension Associates with Upregulated Vascular CYP4A12–20-HETE Synthase

Mei

Cheng

et al. 2013

Journal of the American Society of Nephrology

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Although the mechanism underlying the effect of androgen on BP and cardiovascular disease is not well understood, recent studies suggest that 8,11,, a primary cytochrome P450 4 (Cyp4)-derived eicosanoid, may mediate androgen-induced hypertension. Here, treatment of normotensive mice with 5a-dihydrotestosterone increased BP and induced both Cyp4a12 expression and 20-HETE levels in preglomerular microvessels. Administration of a 20-HETE antagonist prevented and reversed the effects of dihydrotestosterone on BP. Cyp4a14(2/2) mice, which exhibit androgen-sensitive hypertension in the male mice, produced increased levels of vascular 20-HETE; furthermore, administration of a 20-HETE antagonist normalized BP. To examine whether androgen-independent increases in 20-HETE are sufficient to cause hypertension, we studied Cyp4a12-transgenic mice, which express the CYP4A12-20-HETE synthase under the control of a doxycycline-sensitive promoter. Administration of doxycycline increased BP by 40%, and administration of a 20-HETE antagonist prevented this increase. Levels of CYP4A12 and 20-HETE in preglomerular microvessels of doxycycline-treated transgenic mice approximately doubled, correlating with increased 20-HETE-dependent sensitivity to phenylephrine-mediated vasoconstriction and with decreased acetylcholine-mediated vasodilation in the renal microvasculature. We observed a similar contribution of 20-HETE to myogenic tone in the mesenteric microvasculature. Taken together, these results suggest that 20-HETE both mediates androgeninduced hypertension and can cause hypertension independent of androgen. 24: 128824: -129624: , 201324: . doi: 10.1681 The v-hydroxylation of arachidonic acid (AA) to 20-hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE) is catalyzed by members of the cytochrome P450 4 (CYP4) gene family and regulated by factors such as age, sex hormones, and dietary lipids. 1,2 CYP4 expression and 20-HETE synthesis have been implicated in the regulation of vascular and tubular function and the development of hypertension in experimental models. [3][4][5] Studies demonstrating that 20-HETE is a vasoconstrictor [6][7][8] suggest that increased 20-HETE synthesis and/or effects in the renal vasculature underlies its prohypertensive property. [9][10][11][12] This notion has been substantiated by several reports showing the following: (1) the synthesis of and vascular reactivity to 20-HETE are significantly higher in spontaneously hypertensive rats (SHRs), 13,14 (2) inhibition of vascular 20-HETE synthesis by CYP4A2 antisense oligonucleotides decreases BP in SHRs, 15,16 J Am Soc Nephrol

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Transfection of CYP4A1 cDNA decreases diameter and increases responsiveness of gracilis muscle arterioles to constrictor stimuli

Cited by 17 publications

References 25 publications

WITHDRAWN: The emerging role of Ca2+ sensitivity regulation in promoting myogenic vasoconstriction

WITHDRAWN: The emerging role of Ca2+ sensitivity regulation in promoting myogenic vasoconstriction

Endothelial Dysfunction and Hypertension in Rats Transduced With CYP4A2 Adenovirus

Androgen-Sensitive Hypertension Associates with Upregulated Vascular CYP4A12–20-HETE Synthase

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