Inhibition of cyclic AMP- and cyclic GMP-mediated dilations in isolated arteries by oxidized low density lipoproteins.

Galle, Jan; Bauersachs, Johann; Busse, Rudi; Bassenge, E.

doi:10.1161/01.atv.12.2.180

Cited by 37 publications

(22 citation statements)

References 34 publications

(23 reference statements)

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“…However, NOS and PDE activities were unchanged in tissue homogenates, which argues against such a nonspecific effect. Previous investigations showed that the sensitivity of sGC to NO is reduced in atherosclerotic aorta, a reduction that may be mediated in part by oxidized lipoproteins (55)(56)(57). Indeed, our preliminary data indicate that oxidized LDL down-regulates endothelial cell sGC expression (unpublished data).…”

Section: Discussionsupporting

confidence: 62%

Reduced cGMP signaling associated with neointimal proliferation and vascular dysfunction in late-stage atherosclerosis

Melichar¹

2004

Proceedings of the National Academy of Sciences

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Atherosclerosis is associated with alterations in nitric oxide (NO)͞ cGMP signaling. In early stages of the disease, inflammatory and possibly other cells produce reactive oxygen species that scavenge vasoprotective NO. In addition to the oxidative stress, expression and activity of enzymes downstream to NO formation may also be affected. Here, we show in the aortas of chronically hypercholesterolemic rabbits (a model of late-stage atherosclerosis), both subunits and specific activity of the NO receptor soluble guanylyl cyclase (sGC) were significantly reduced, whereas overall NO synthase activity was unaffected. These changes were most prominent in the neointimal layer, wherein cGMP-dependent protein kinase I (cGK) levels also were reduced. Additionally, a protein (p38 nt ) that was constitutively tyrosine-nitrated was detected, and its expression was significantly reduced in atherosclerotic aorta. Phosphorylation of the cGK substrate vasodilator-stimulated phosphoprotein (VASP) at Ser-239, an established biochemical endpoint of NO͞cGMP signaling, also was reduced. Thus, late-stage atherosclerosis is associated not only with enhanced NO breakdown but also with altered NO reception and cGMP signaling. Preferential downregulation in neointima suggests a direct connection of these changes to neointimal proliferation and vascular dysfunction and provides a rationale for future pharmacotherapy using classical and novel sGC activators.hypercholesterolemia ͉ soluble guanylyl cyclase ͉ vasodilator-stimulated phosphoprotein ͉ cGMP-dependent protein kinase A therosclerosis is major risk factor to cardiovascular diseases such as coronary heart disease and stroke. The pathophysiology of atherosclerosis is highly complex, multifactorial, and yet to be fully understood (1). A common feature observed is malperfusion of tissues as a result of luminally obstructive atherosclerotic plaques, augmented vascular tone, and reduced sensitivity to endothelium-dependent vasodilators in atherosclerotic arteries from humans (2) and cholesterol-fed animals (3).Nitric oxide (NO) is an important antiatherosclerotic autocoid, which exerts antiproliferative and vasodilatory effect on vasculature and antiaggregatory effect on platelets. Vascular dysfunction in atherosclerosis is partly attributed to reduced tetrahydrobiopterin-dependent (4-7) production or bioavailability of endothelium-derived NO (8), which is supported by the observation of reduced activity and expression of endothelial NO synthase III (NOS-III) (9) in atherosclerotic vessels (10, 11). Additionally, the tissue half-life of NO is further reduced by reactive oxygen species (superoxide, O 2 Ϫ ) that scavenge NO and thereby impair its vasoprotective activity (12). Therefore, formation of O 2 Ϫ , by NADPH oxidase (13, 14) or xanthine oxidase (15) or uncoupled endothelial NOS (16) and͞or its decomposition, by superoxide dismutase (SOD) (17)(18)(19), are thought to play important roles in the pathogenesis of atherosclerosis.Endothelium-derived NO stimulates the production of the se...

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Section: Discussionsupporting

confidence: 62%

Reduced cGMP signaling associated with neointimal proliferation and vascular dysfunction in late-stage atherosclerosis

Melichar¹

2004

Proceedings of the National Academy of Sciences

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“…21 LDL and HDL were isolated by sequential ultracentrifugation 22 and concentrated and desalted by gel filtration as described recently. 18 Lipoproteins prepared by this method are referred to as native and were kept in the dark at 4°C for no longer than 3 weeks.…”

Section: Preparation Of Lipoproteins and Oxidation Of Ldlmentioning

confidence: 99%

“…910 Various in vitro investigations studying vascular effects of Ox-LDL have demonstrated decreased formation of EDRF, 1115 inactivation of EDRF, 16 -17 or interference with the EDRF effector pathway, the guanylate cyclase-stimulating cascade. 18 ' 19 The mechanisms responsible for attenuation of endothelium-dependent dilations in hypertension are much less understood. Whereas most investigations of endothelial function in hypertension refer to the chronic state of the disease, some animal studies indicate that an acute rise in blood pressure also attenuates dilator responses to acetylcholine, an agent that stimulates EDRF release.…”

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confidence: 99%

Oxidized lipoproteins inhibit endothelium-dependent vasodilation. Effects of pressure and high-density lipoprotein.

et al. 1994

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Hypertension and atherogenic low-density lipoproteins cause attenuation of endothelium-dependent dilations in vivo. We investigated a potential interference of high transmural pressure with the effects of low-density lipoproteins on endothelium-dependent dilation in vitro. Furthermore, we determined whether high-density lipoproteins preserve endothelial function. Endothelium-intact rabbit renal arteries were isolated, placed in an organ bath, perfused intraluminally with Tyrode's solution, and exposed to different degrees of transmural pressure and native or oxidized lowdensity lipoproteins. In preconstricted arteries perfused under low-pressure conditions (30 mm Hg), acetylcholine dose dependently elicited endothelium-dependent dilations that were not altered by increasing the perfusion pressure to 100 mm Hg for 90 minutes (high-pressure conditions). Incubation of the arteries with native or oxidized low-density lipoproteins (0.2 and 1 mg/mL for 60 minutes, respectively) under low-pressure conditions did not attenuate acetylcholine-induced dilations. However, under high-pressure conditions dilations were dose dependently attenuated by oxidized but not by native lowdensity lipoproteins. Endothelium-independent dilations to E ndotheliaJ cells regulate vascular tone in part by releasing endothelium-derived relaxing factor (EDRF) 1 and other vasoactive agents such as endothelin.2 Many studies have focused on the potential impairment of endothelial function under various pathophysiological conditions. Hypertension and hypercholesterolemia, which are independent risk factors for the development of arteriosclerosis, 3 ' 4 are associated with an attenuation of endothelial function. For example, inhibition of endothelium-dependent dilations has been observed in patients with essential hypertension, 5 -6 or in coronary arteries of hypercholesterolemic patients.Attenuation of endothelium-dependent dilations in hypercholesterolemia is likely to be related to high levels of low-density lipoprotein (LDL), especially to its more atherogenic form, the oxidatively modified LDL (Ox-LDL), which accumulate in atherosclerotic arteries. 910 gryceroltrinitrate (0.001 to 3 /imol/L) were not affected. Preincubation of the segments with high-density lipoproteins (0.5 mg/mL, 30 minutes) prevented attenuation of dilator responses. The attenuation of endothelium-dependent dilations by oxidized low-density lipoproteins under high-pressure conditions was accompanied by a transmural, dose-dependent infiltration of the vessel wall with lipoprotein, as detected by light microscopy of cryostat sections stained with Sudan III. This infiltration was prevented by high-density lipoprotein. Under low-pressure conditions no lipoprotein infiltration was visible. In segments incubated with native low-density lipoprotein, no lipoprotein infiltration was detectable. We suggest that the inhibitory effect of oxidized low-density lipoprotein on endothelium-dependent dilations is related to the arterial infiltration with lipid, which depends on the...

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“…13 - 15 Recently, it was shown that preincubation of isolated smooth muscle strips with Ox-LDL diminished not only the relaxant response to sodium nitroprusside (SNP) but also the SNP-induced accumulation of cyclic GMP (cGMP). 16 To investigate whether such impaired response of guanylyl cyclase also occurs during hypercholesterolemia in vivo, we compared the activities of guanylyl cyclase obtained from aortas of cholesterol-fed rabbits with those obtained from control tissues. Since the regulation of vascular tone is also modulated by cyclic AMP (cAMP), we also measured adenylyl cyclase activities in atherosclerotic and control aortas.…”

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confidence: 99%

Hypercholesterolemia is associated with a reduced response of smooth muscle guanylyl cyclase to nitrovasodilators.

Schmidt

Klatt

Mayer

1993

Arterioscler Thromb

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A diminished relaxant response of atherosclerotic arteries to nitrovasodilators has been frequently observed in advanced stages of hypercholesterolemia. In the present study, we investigated whether this effect might be a result of reduced activity of smooth muscle guanylyl cyclase. Experimental atherosclerosis was induced by feeding rabbits a cholesterol-rich diet (1%) over a period of 4 months. Aortas were removed and homogenized, and guanylyl cyclase activity was measured in the 100 OOOg supernatants. Sodium nitroprusside, which stimulated cyclic GMP (cGMP) formation in control tissues almost 200-fold (from 3 to 585 pmol cGMP • mg" 1 • min" 1 ), increased enzyme activities in atherosclerotic aortas onlỹ 90-fold (from 3 to 257 pmol cGMP-mg" 1 • min" 1 ). Similarly, the maximal stimulatory effects of 5-nitrosoglutathione were reduced from 200-fold (controls) to 114-fold in atherosclerotic tissues. Basal guanylyl cyclase activities were identical in both atherosclerotic and control vessels. Hypercholesterolemia also reduced the activity of smooth muscle adenylyl cyclase. In control aortas, basal and NaF-stimulated enzyme activities were 24 and 349 pmol cAMP • mg" 1 • min" 1 , respectively, whereas cAMP formation was reduced in atherosclerotic aortas to 7 (basal) and 96 (NaF) pmol cAMP • mg" 1 • min"

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Inhibition of cyclic AMP- and cyclic GMP-mediated dilations in isolated arteries by oxidized low density lipoproteins.

Cited by 37 publications

References 34 publications

Reduced cGMP signaling associated with neointimal proliferation and vascular dysfunction in late-stage atherosclerosis

Reduced cGMP signaling associated with neointimal proliferation and vascular dysfunction in late-stage atherosclerosis

Oxidized lipoproteins inhibit endothelium-dependent vasodilation. Effects of pressure and high-density lipoprotein.

Hypercholesterolemia is associated with a reduced response of smooth muscle guanylyl cyclase to nitrovasodilators.

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