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Zoltan Ungvari

Publications and source records attributed to Zoltan Ungvari.

28 records · Page 2Linked to original sources
PubMed2003

Aging-induced proinflammatory shift in cytokine expression profile in coronary arteries.

The phenotypic and functional changes of coronary arteries with aging promote ischemic heart disease. We hypothesized that these alterations reflect an aging-induced proinflammatory shift in vascular regulatory mechanisms. Thus, in isolated coronary arteries of young (3-month-old) and aged (25-month-old) male Fischer 344 rats the expression of 96 cytokines, chemokines, and their receptors were screened by a cDNA-based microarray technique. In aged vessels expressions of tumor necrosis factor (TNF)-alpha (3.3x), interleukin (IL)-1beta (3.0x), IL-6 (2.9x), IL-6Ralpha (2.8x) and IL-17 (6.1x) genes were significantly increased over young vessels. Quantitative reverse transcriptase-polymerase chain reaction confirmed these results. Western blotting demonstrated that protein expressions of TNF-alpha, IL-1beta, IL-6, and IL-17 were also significantly increased in vessels of aged rats compared with those of young rats. Immunofluorescent double labeling showed that in aged vessels IL-1beta and IL-6 are predominantly localized in the endothelium, whereas TNF-alpha and IL-17 are localized in smooth muscle. Thus, a proinflammatory shift in the profile of vascular cytokine expression may contribute to the aging-induced phenotypic changes in coronary arteries, promoting the development of ischemic heart disease in the elderly.

Aged↗
PubMed2003

Increased superoxide production in coronary arteries in hyperhomocysteinemia: role of tumor necrosis factor-alpha, NAD(P)H oxidase, and inducible nitric oxide synthase.

OBJECTIVE: In coronary arteries, hyperhomocysteinemia (HHcy, a known risk factor for coronary heart disease) impairs flow-induced dilations, which can be reversed by superoxide dismutase (SOD). To evidence increased O2*- generation and elucidate its source, we characterized changes in activity (lucigenin chemiluminescence, hydroethidine staining) and expression of arterial pro- and antioxidant systems (Western blotting, immunohistochemistry, cDNA microarray, reverse-transcription polymerase chain reaction) in the coronary arteries of rats by using methionine diet-induced HHcy. METHODS AND RESULTS: The increased generation of O2*- by HHcy coronary arteries was inhibited by SOD, diphenyleneiodonium, apocynin, and apocynin plus amino guanidine but was unaffected by allopurinol and rotenone. Also, diphenyleneiodonium-sensitive NADPH-driven O2*- generation was increased in HHcy vessels. In HHcy arteries expression of the smooth muscle-confined NAD(P)H oxidase subunit nox1 and that of iNOS was increased. Expression of p67phox, p22phox, and p47phox subunits and that of endothelial nitric oxide synthase, Cu,Zn-SOD, Mn-SOD, extracellular SOD (mRNA), and xanthine oxidase was unchanged. Microarray analysis showed increased expression of tumor necrosis factor (TNF)-alpha (confirmed by reverse-transcription polymerase chain reaction, Western blotting, and immunohistochemistry) that was localized in smooth muscle. In vitro incubation (18 hours) of HHcy arteries with anti-TNF-alpha antibody decreased O2*- production, whereas incubation of control vessels with TNF-alpha increased O2*- generation and nox1 expression. CONCLUSIONS: In coronary arteries, HHcy increases TNF-alpha expression, which enhances oxidative stress through upregulating a nox1-based NAD(P)H oxidase and inducible nitric oxide synthase. Thus, TNF-alpha induces a proinflammatory vascular phenotype in HHcy that potentially contributes to the development of coronary atherosclerosis.

Animals↗
PubMed2002

Aging-induced phenotypic changes and oxidative stress impair coronary arteriolar function.

We aimed to elucidate the possible role of phenotypic alterations and oxidative stress in age-related endothelial dysfunction of coronary arterioles. Arterioles were isolated from the hearts of young adult (Y, 14 weeks) and aged (A, 80 weeks) male Sprague-Dawley rats. For videomicroscopy, pressure-induced tone of Y and A arterioles and their passive diameter did not differ significantly. In A, arterioles L-NAME (a NO synthase blocker)-sensitive flow-induced dilations were significantly impaired (Y: 41+/-8% versus A: 3+/-2%), which could be augmented by superoxide dismutase (SOD) or Tiron (but not L-arginine or the TXA(2) receptor antagonist SQ29,548). For lucigenin chemiluminescence, O(2)(.-) generation was significantly greater in A than Y vessels and could be inhibited with SOD and diphenyliodonium. NADH-driven O(2)(.-) generation was also greater in A vessels. Both endothelial and smooth muscle cells of A vessels produced O(2)(.-) (shown with ethidium bromide fluorescence). For Western blotting, expression of eNOS and COX-1 was decreased in A compared with Y arterioles, whereas expressions of COX-2, Cu/Zn-SOD, Mn-SOD, xanthine oxidase, and the NAD(P)H oxidase subunits p47(phox), p67(phox), Mox-1, and p22(phox) did not differ. Aged arterioles showed an increased expression of iNOS, confined to the endothelium. Decreased eNOS mRNA and increased iNOS mRNA expression in A vessels was shown by quantitative RT-PCR. In vivo formation of peroxynitrite was evidenced by Western blotting, and immunohistochemistry showing increased 3-nitrotyrosine content in A vessels. Thus, aging induces changes in the phenotype of coronary arterioles that could contribute to the development of oxidative stress, which impairs NO-mediated dilations.

1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium ↗
PubMed2002

Impaired nitric oxide-mediated flow-induced coronary dilation in hyperhomocysteinemia: morphological and functional evidence for increased peroxynitrite formation.

Hyperhomocysteinemia (HHcy) is a newly recognized risk factor for myocardial infarction, however, the effect of HHcy on endothelium-dependent flow-induced dilation of coronary arteries is not known. Thus, changes in diameter of small intramural coronary arteries (diameter, approximately 145 microm) isolated from control rats and rats with methionine diet-induced HHcy were investigated by videomicroscopy. Increases in intraluminal flow (from 0 to 40 microl/min) elicited dilations of control vessels (maximum, 25 +/- 2 microm), responses that were absent in HHcy arteries. The nitric oxide (NO) synthase inhibitor L-NAME inhibited flow-induced dilation of control coronaries, whereas it had no effect on responses of HHcy arteries. Dilations of control and HHcy arteries to the NO donor sodium nitroprusside were not different. Responses to flow in HHcy coronary arteries were unaffected by administration of L-arginine or the prostaglandin H(2)/thromboxane A(2) receptor antagonist SQ 29,548. However, in the presence of superoxide dismutase (plus catalase) or the superoxide scavenger Tiron increases in flow elicited L-NAME-sensitive dilations of HHcy coronaries (maximum, 18 +/- 5 microm). Also, superoxide dismutase significantly reduced the enhanced superoxide production of HHcy coronaries (measured by the lucigenin chemiluminescence method). Single vessel Western blotting showed an increased tyrosine nitrosation (a stable biomarker of tissue peroxynitrite formation) in HHcy coronaries. Also, extensive prevalence of 3-nitrotyrosine immunoreactivity was observed in HHcy coronaries that was confined primarily to the subendothelial layers of smooth muscle. We propose that in HHcy an increased level of superoxide scavenges NO forming peroxynitrite, which increases protein nitrosation. The reduced bioavailability of NO impairs flow-induced dilations of coronary arteries, which may contribute to the development of coronary atherosclerosis and ischemic heart disease.

Animals↗
PubMed2002

Increased NO-mediated and reduced TxA2-dependent responses in skeletal muscle arterioles in pregnancy.

The contribution of skeletal muscle microvessels to pregnancy-induced decrease in peripheral vascular resistance and its underlying mechanisms are not fully understood. We aimed to test the hypothesis that pregnancy enhances arteriolar dilation and reduces constriction by increasing NO-mediation and decreasing reactivity to TxA2. Thus, changes in diameter of isolated, pressurized gracilis muscle arterioles (d: approximately 180 microm) of non-pregnant (NP) and pregnant (P) rabbits to vasoactive agents were measured by videomicroscopy. Acetylcholine (ACh) elicited significantly greater dilations in P than in NP arterioles that could be inhibited by L-NAME, a NO synthase blocker. Dilations to the NO donor SNP did not differ between P and NP arterioles. Constrictions to norepinephrine and the TxA2 receptor agonist U46619 were significantly attenuated in P as compared to NP arterioles. L-NAME increased norepinephrine-induced arteriolar constrictions eliminating the difference between responses of NP and P arterioles. L-NAME enhanced constrictions to U46619 in P and NP arterioles, but the constrictions were still greater in NP vessels. The number of vascular TxA2 receptors-characterized by the TxA2 analog [125I]-BOP in aortic membrane preparations-was significantly less in P as compared to NP rabbits (NP: 284 +/- 83, P: 62 +/- 14 fmol/mg protein, p<0.01). Thus, pregnancy up-regulates endothelial NO- and down regulates TxA2-mediation of responses of skeletal muscle arterioles. These changes in the local regulation of microvascular tone are likely to favor a dilated state of skeletal muscle arterioles, which may contribute to the decreased peripheral vascular resistance during normal pregnancy.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2002

Different roles of PKC and MAP kinases in arteriolar constrictions to pressure and agonists.

Protein kinase C (PKC) and mitogen-activated protein (MAP) kinases have been implicated in the modulation of agonist-induced contractions of large vessels. However, their role in pressure- and agonist-induced constrictions of skeletal muscle arterioles, which have a major role in regulating peripheral resistance, is not clearly elucidated. Thus constrictions of isolated rat gracilis muscle arterioles (approximately 80 microm in diameter) to increases in intraluminal pressure and to norepinephrine (NE) or angiotensin II (ANG II) were assessed in the absence or presence of chelerythrine, PD-98058, and SB-203580 (inhibitors of PKC, p42/44 and p38 MAP kinase pathways, respectively). Arteriolar constriction to NE and ANG II were significantly reduced by chelerythrine (by approximately 90%) and unaffected by SB-203580, whereas PD-98058 decreased only ANG II-induced constrictions (by approximately 60%). Pressure-induced increases in wall tension (from 0.1 to 0.7 N/m) resulted in significant arteriolar constrictions (50% maximum) that were abolished by chelerythrine without altering smooth muscle intracellular Ca(2+) concentration ([Ca(2+)](i)) (fura 2 microfluorimetry). PD-98058 and SB-203580 significantly decreased the magnitude of myogenic tone (by 20% and 60%, respectively) and reduced the sensitivity of the myogenic mechanism to wall tension, causing a significant rightward shift in the wall tension-myogenic tone relationship without affecting smooth muscle [Ca(2+)i]. MAP kinases were demonstrated with Western blotting. Thus in skeletal muscle arterioles 1) PKC is involved in both myogenic and agonist-induced constrictions, 2) PD-98058-sensitive p42/44 MAP kinases modulate both wall tension-dependent and ANG II-induced constrictions, whereas 3) a SB-203580-sensitive p38 MAP kinase pathway seems to be specifically involved in the mechanotransduction of wall tension.

Angiotensin II↗
PubMed2002

Increases in endothelial Ca(2+) activate K(Ca) channels and elicit EDHF-type arteriolar dilation via gap junctions.

In skeletal muscle arterioles, the pathway leading to non-nitric oxide (NO), non-prostaglandin-mediated endothelium-derived hyperpolarizing factor (EDHF)-type dilations is not well characterized. To elucidate some of the steps in this process, simultaneous changes in endothelial intracellular Ca(2+) concentration ([Ca(2+)](i)) and the diameter of rat gracilis muscle arterioles (approximately 60 microm) to acetylcholine (ACh) were measured by fura 2 microfluorimetry (in the absence of NO and prostaglandins). ACh elicited rapid increases in endothelial [Ca(2+)](i) (101 +/- 7%), followed by substantial dilations (73 +/- 2%, coupling time: 1.3 +/- 0.2 s) that were prevented by endothelial loading of an intracellular Ca(2+) chelator [1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid]. Arteriolar dilations to ACh were also inhibited by intraluminal administration of the Ca(2+)-activated K(+) (K(Ca)) channel blockers charybdotoxin plus apamin or by palmitoleic acid, an uncoupler of myoendothelial gap junctions without affecting changes in endothelial [Ca(2+)](i). The presence of large conductance K(Ca) channels on arteriolar endothelial cells was demonstrated with immunohistochemisty. We propose that in skeletal muscle arterioles, EDHF-type mediation is evoked by an increase in endothelial [Ca(2+)](i), which by activating endothelial K(Ca) channels elicits hyperpolarization that is conducted via myoendothelial gap junctions to the smooth muscle resulting in decreases in [Ca(2+)](i) and consequently dilation.

Acetylcholine↗
PubMed2002

Xanthine oxidase-derived reactive oxygen species convert flow-induced arteriolar dilation to constriction in hyperhomocysteinemia: possible role of peroxynitrite.

We hypothesized that in hyperhomocysteinemia (HHcy), flow-induced arteriolar constriction is due to an enhanced generation of reactive oxygen and/or nitrogen species, causing an impairment of nitric oxide (NO) and prostaglandin mediation of the response. Changes in diameter of isolated, pressurized (at 80 mm Hg) gracilis muscle arterioles (diameter approximately 170 microm) from control and methionine diet-induced HHcy rats were measured by videomicroscopy. Increases in intraluminal flow (from 0 to 25 microL/min) resulted in NO- and prostaglandin-mediated dilations of control arterioles (maximum, control, 30+/-4 microm) but elicited significant constrictions of HHcy arterioles (maximum, HHcy, -32+/-3 microm), which were abolished by the thromboxane A(2) receptor blocker SQ 29,548. Intraluminal administration of superoxide dismutase plus catalase did not affect flow-mediated dilations of control arterioles, but in HHcy arterioles, it reversed the flow-induced constrictions to dilations (maximum 18+/-4 microm), which were abolished by an NO synthase inhibitor. Flow-induced constrictions of HHcy arterioles were prevented by the presence of the xanthine oxidase inhibitor oxypurinol [but not by the NAD(P)H-oxidase inhibitor diphenyleneiodonium] and by urate, a known peroxynitrite scavenger. Also, authentic peroxynitrite elicited arteriolar constrictions (-31+/-8 microm) that were eliminated by urate and SQ 29,548. Thus, we suggest that in HHcy, xanthine oxidase-derived superoxide scavenges NO released to flow, forming peroxynitrite, which promotes release of thromboxane A(2), resulting in arteriolar constriction.

Animals↗
PubMedDate not supplied

Mechanosensitive production of reactive oxygen species in endothelial and smooth muscle cells: role in microvascular remodeling?

Changes in the hemodynamic environment (e.g., hypertension, increased blood flow/shear stress) are known to lead to vascular remodeling; however, the underlying mechanisms by which hemodynamic forces control gene expression in vascular cells are not yet completely understood. This review considers how mechanosensitive generation of reactive oxygen species (ROS) by NAD(P)H oxidases and other sources interacts with downstream signaling systems [including activation of nuclear factor kappa B (NF-kappaB) and AP-1] that modulate the phenotype of endothelial and smooth muscle cells, leading to vascular remodeling. We propose a model for an interaction between direct mechanosensitive ROS signaling and pathways activated by pressure-induced upregulation of prooxidant paracrine signaling mechanisms [local renin-angiotensin system, TNF-alpha- converting enzyme (TACE)/tumor necrosis factor alpha (TNF-alpha) system, and endothelin signaling].

ADAM Proteins↗