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

Abstract

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...

Oxidized Low-Density Lipoprotein Enhances Myogenic Tone in the Rabbit Posterior Cerebral Artery Through the Release of Endothelin-1

“…First, native LDL had little influence on myogenic tone. Although the role of native LDL in the regulation of vascular tone is inconsiderable, 38,44 studies have noted that at a higher concentration it has the potential to impair vascular function. 39,45 Second, LysoPC generated during the oxidative modification of LDL 9 had a potentiating effect equivalent to that of Ox-LDL, which suggests that LysoPC is the essential augmenting element.…”

Impact of Nitric Oxide on Renal Hemodynamics and Glomerular Function: Modulation by Atherogenic Lipoproteins?

“…In this respect, oxidized Lp(a) was far more potent than ox idized LDL 1119]. Furthermore, in our model the effect of oxidized LDL could be increased by raising the transmural pressure within the pathophysiological range [120], impli cating a potential interference between hypercholesterole mia and hypertension. The importance of the interaction be tween atherogenic lipoproteins with nitric oxide for the en dothelium-dependent dilation was clearly demonstrated in prospective studies in humans: lowering plasma LDL with the HMG-CoA reductase inhibitor lovastatin improved en dothelium-dependent dilations in coronary arteries [ 121].…”

“…In vitro studies could demonstrate that HDL also protects against attenua tion of nitric oxide-mediated vasodilation in aortic rings [137], It has been suggested that HDL takes up lysophos phatidylcholine from oxidized LDL, thereby eliciting its beneficial effect [133], Ourlaboratory investigated whether HDL also protects renal arteries from the damaging influen ce of oxidized LDL and Lp(a). Indeed, HDL prevented per meation of oxidized LDL into the media or rabbit renal arteries and protected against attenuation of endotheliumdependent dilations induced by oxidized LDL [120] or ox idized Lp(a) [138], Other experimental data suggest that the protective effect of H DL against damage induced by athero genic lipoproteins is not restricted to the vasculature: in iso lated juxtaglomerular cells. HDL prevented the stimulation of renin release induced by oxidized LDL or Lp(a) [139].…”

Lipoproteins and cardiovascular reactivity

“…Vasoconstrictor responses to serotonin in large vessels are often enhanced by hypercholeshypercholesterolaemic men [59]. Similar results were obtained both prior to and during the infusion of l-NMMA terolaemia [41][42][43][44]. Galle & Bassenge [26] have extensively studied the effects of LDL-C and ox-LDL on the vascular in a dose previously shown to inhibit NO synthase.…”

“…In cultured arterial smooth muscle cells, cholesterol enrichment of the plasma membrane increases unstimucoronary artery responses to infusions of ACh during angiography in humans have reported that high levels of lated calcium influx and cytosolic calcium levels [45]. As calcium channel blockers abolish this effect on calcium HDL protect against the abnormal contractile responses to ACh [44,60,61]. Zeiher et al [61] demonstrated that uptake, it has been hypothesized that an increase in the cholesterol content of the cell membrane induces alterations elevated HDL levels were associated with a smaller coronary artery response to cold pressor testing in patients with in the conformation or position of calcium channel proteins, thereby exposing or activating previously 'silent' ion channels hypercholesterolaemia.…”