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The BB-Paraoxonase Genotype Is Associated with Impaired Brachial Reactivity after Acute Hypertriglyceridemia in Healthy Subjects

Department of Geriatric Medicine and Metabolic Diseases, Second University of Naples, I-80138 Naples, Italy; and Department of Experimental Pathology, University of Bologna (M.B., C.F.), I-40100 Bologna, Italy

Address all correspondence and requests for reprints to: Prof. Giuseppe Paolisso, IV Divisione di Medicina Interna e Malattie dell’Invecchiamento, Department of Geriatric Medicine and Metabolic Diseases, Second University of Naples, Piazza Miraglia 2, I-80138 Naples, Italy. E-mail: gpaoliss{at}tin.it

	Abstract

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The possible relationship between paraoxonase (PON) gene polymorphism and brachial reactivity in healthy adult subjects in the presence of acute hypertriglyceridemia (HT), as a prooxidant factor, was investigated. In 101 healthy subjects the response to flow- induced vasodilatation was measured before and after Intralipid infusion. In the same subjects the A/B PON polymorphism was detected. The frequency was 0.545 for AA genotype, 0.356 for the AB genotype, and 0.099 for the BB genotype. At baseline all genotype groups had a similar increase in brachial artery diameter and flow. After Intralipid infusion, subjects sharing the BB genotype had a significant decrease vs. baseline values in changes in brachial artery diameter (P for trend < 0.001 vs. the other genotypes), but not in flow. In a subgroup of 55 subjects distributed among the 3 PON genotypes the same study protocol was repeated by buccal nitroglycerine administration to study the endothelium-independent vasodilatation. Again, subjects with the BB genotype had the worse vasodilation (P for trend < 0.001). Furthermore, subjects sharing the BB genotype had the lowest endothelium-independent and -dependent changes in diameter (P for trend < 0.001 vs. the other genotypes) independently of gender ratio, basal plasma triglycerides concentrations, and changes in plasma triglycerides concentrations. In conclusion, our study demonstrates that transient HT decreases vascular reactivity more in subjects with the PON BB genotype than in those with the other PON genotypes.

	Introduction

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PREVIOUS STUDIES have demonstrated an association between the common polymorphism at codon 192 in the human paraoxonase 1 gene (PON1) and the increased risk for coronary heart disease (1, 2, 3, 4). The relationship between PON1 gene polymorphism and atherosclerosis seems to be due to a change in antioxidant properties of the high density lipoprotein (HDL) cholesterol-associated enzyme paraoxonase (PON) (1). On the other hand, endothelial dysfunction has been suggested as an early marker of atherosclerosis (5, 6, 7). In particular, patients with coronary heart disease (CHD) have an impaired endothelium-dependent relaxation in both brachial (8) and coronary arteries (9), with a close correlation between the two sites, thus indicating a systemic nature of endothelial dysfunction. Thus, brachial reactivity has been considered a good method for studying endothelial function in subjects with and without atherosclerosis (10). Interestingly, an acute rise in plasma triglycerides concentrations has been shown to be a prooxidant factor (11), to provoke endothelial dysfunction (12), and to impair brachial reactivity (5). Such a finding is in agreement with the evidence that elevated plasma triglycerides concentrations are an independent risk factor for CHD in noninsulin-dependent diabetes mellitus (13). Due to the pivotal role played by oxidative stress in endothelial dysfunction and brachial reactivity (14), and as the HDL cholesterol-associated enzyme PON might contribute to the control of antioxidant activities, it might be postulated that subjects sharing different PON genotypes might have a different risk of endothelial dysfunction. Due to the fact that PON gene polymorphism is associated with increased risk of CHD (2, 3, 4), one can hypothesize this different endothelial behavior to be the link between PON gene polymorphism and CHD. Indeed, to the best of our knowledge the association between PON polymorphism and endothelial dysfunction has not been investigated. Thus, we aim at investigating the possible relationship between PON gene polymorphism and brachial reactivity in healthy adult subjects in the presence of acute hypertriglyceridema as a prooxidant factor.

	Materials and Methods

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Study protocol

One hundred and one subjects (45 men and 56 women; mean age, 36.2 ± 14.8 yr) participated after giving informed consent. All individuals were Caucasians and were living in South Italy. Only 34 subjects were light smokers. None was hypertensive or had clinical signs or family history of CHD. All subjects had normal glucose tolerance and were also shown to have normal fasting plasma triglycerides concentrations. All subjects were studied after an overnight fast (at least 12 h). In all subjects the response to flow-induced vasodilatation was measured twice before and after 1 h after Intralipid (Pharmacia-Upjohn, Piscataway, NJ) infusion (0.15 g/kg given as a bolus followed by a continuous infusion of 0.15 g/kg·h until the experiment was finished). To investigate whether triglyceridemia affects endothelial function in different PON genotypes in an endothelium-dependent or -independent manner, flow- and nitroglycerine (NTG)-induced vasodilatation was studied. For this reason, in a subgroup of 55 subjects distributed among the 3 different PON genotypes, a second series of experiments was made with endothelium-independent (NTG-induced) vasodilatation tested before and after a 1-h infusion of Intralipid. The dose of NTG used was of 0.4 mg buccal NTG. The study was approved by the ethical committee of our institution.

Anthropometric determinations

Weight and height were measured using a standard technique. Body mass index was calculated as body weight (kilograms)/height (meters)². Fat-free mass was measured using a four-terminal bioimpedence analyzer (RJL Spectrum Bioelectrical Impedance, IA 101/SC Akern, RJL System, Florence, Italy).

Brachial reactivity

Brachial reactivity was detected using high frequency ultrasound technique as reported previously (15). Briefly, all subjects were kept at rest in the supine position in a temperature-controlled room (22 C) while heart rate and blood pressure were continuously monitored by a noninvasive technique (Finapress, OMHEDA 2003; Englewood, CO) (16). The left arm was immobilized in the extended position to allow consistent access to brachial artery for imaging. Brachial artery diameter and flow velocity were imaged using a 7.5-MHz linear array transducer ultrasound system (Apogee CX, Interspec ATL, Ambler, PA). Brachial arterial diameter and blood flow velocity were recorded at an interval of 1 min. After that, a blood pressure cuff was placed over the ipsilateral upper arm just above the transducer and inflated for 5 min at 200 mm Hg, then suddenly deflated. The postischemic scan was performed 60 s after cuff deflation, and brachial artery diameter and flow were measured at 1-min intervals for 5 min. All images were recorded on videotape for subsequent off-line analysis on the same instrument by a single observer blinded to the PON gene polymorphism.

Intraobserver variability for measuring brachial artery diameter and flow was assessed by comparing a minimum of three separate baseline measurements in each patient. The coefficient of variation for baseline arterial diameter was 2.1%, and that for baseline arterial flow was 9.7%. These values were not dissimilar from those reported by other researchers (17).

PON polymorphism screening

DNA was extracted from white cells according to the method of Sambrook et al. (18) from cells obtained from a fasting blood sample. The gene polymorphism (A-glutamine and B-arginine alleles) corresponding to position 191 was analyzed by restriction isotyping using the procedure of Humbert et al. (19). Briefly, the primer was used to amplify this polymorphic region. DNA (500 ng) was denatured at 94 C for 30 s, annealing at 61 C for 30 s, and extension at 72 C for 30 s, with a final extension time of 6 min. The PCR product (170 bp) was digested with the Hsp 92II in the presence of BSA (37 C over 3 h). The digested products were separated by acrylamide gel (8%) electrophoresis and identified ethidium bromide staining.

Analytical technique

All blood samples were drawn in dark test tubes to which lithium heparin was added and immediately centrifuged at 4 C. The plasma glucose concentration was determined immediately. All other blood samples were frozen at -20 C for further metabolite and hormone determinations.

Plasma glucose was determined by the glucose oxidase method (glucose autoanalyzer, Beckman Coulter, Inc., Fullerton CA), and plasma insulin was determined using a commercial double antibody solid phase RIA [Linco Research, Inc., St. Charles, MO; coefficient of variation (CV), 4.8 ± 0.2%; cross- reactivity with proinsulin, 0.2%]. Plasma HDL cholesterol was determined according to the method of Penttila et al. (20). Commercial enzymatic methods were used in the determination of serum total cholesterol (Monotest, Roche, Milan, Italy; CV, 3.6 ± 0.7%) (21) and triglycerides (Peridecrome, Roche; CV, 4.3 ± 0.5%) concentrations (22). Serum low density lipoprotein (LDL) cholesterol levels were calculated by the Friedwald formula (23). Plasma free fatty acid levels were determined according to the method of Dole et al. (24).

Statistical analysis

All data were presented as the mean ± SD. Data for the brachial artery diameter and flow were expressed as percent changes from baseline values calculated as the maximal change within the interval of observation. Changes in plasma triglycerides were calculated as thedifference between Intralipid treatment and baseline values. The distribution of paraoxonase genotypes frequencies was compared with the Hardy-Weinberg equilibrium model using the ² test. The Pearson product-moment correlation was used. Paired t test allowed calculation of differences between baseline and Intralipid infusion within the same genotype group. One-way ANOVA with Scheffè’s test was used to analyze differences in clinical and laboratory findings among genotype groups. Analysis of covariance allowed adjusting changes in diameter and flow (either endothelium dependent or independent) for gender ratio (categorized as M = 0 and F = 1), basal plasma triglycerides, and changes in plasma triglycerides concentrations. P < 0.05 was chosen as the level of significance.

	Results

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Baseline data

All subjects were adult and not obese. Analysis of the distribution of the genotypes revealed that the frequency was 0.545 for the AA genotype, 0.356 for the AB genotype, and 0.099 for the BB genotype. When tested, such distribution was compatible with the Hardy-Weinberg equilibrium. Anthropometric, clinical, and laboratory findings were similar among genotype groups (Table 1). In particular, no significant differences with regard to body mass index, fasting plasma glucose, triglycerides, free fatty acids, or total, LDL, and HDL cholesterol levels were found. In the whole population baseline brachial artery diameter and artery flow were 3.09 ± 0.34 mm and 73.9 ± 17.9 mL/min, respectively, without significant differences among the genotype groups. Reactive hyperemia provoked by occlusion of the distal forearm resulted in a significant increase in brachial artery diameter (8.4 ± 4.0%; P < 0.001) and brachial artery flow (8.4 ± 13.0%; P = 0.008) in all subjects studied without differences among the three genotype groups (Table 2).

In the Intralipid study similar and significant increases in plasma triglycerides and free fatty acid concentrations in all genotypes was found (Table 2). As far as brachial artery diameter and flow are concerned, Intralipid infusion was associated with a significant reduction in flow-induced change in diameter in all genotype groups. Nevertheless, subjects with the BB genotype had the strongest reduction in this parameters compared with subjects with the AA and AB genotypes (P for trend < 0.001; Table 2). In contrast, changes in brachial artery flow from baseline values were similar in all genotype groups (Table 2). At the end of Intralipid infusion and after adjusting for gender ratio, basal triglycerides, and changes in plasma triglycerides concentrations, subjects sharing the BB genotype still had the lowest changes in diameter (0.8 ± 0.4%) compared with AA (2.8 ± 1.0%) and AB (2.6 ± 0.9%) genotypes (P for trend < 0.001). In contrast, changes in flow among the three genotype were not significant despite adjustment for gender ratio, basal triglycerides, and changes in plasma triglycerides concentrations (data not shown).

At baseline, arterial blood pressure (115 ± 3.5/80 ± 1.8 mm Hg) was not different among the three groups. At the end of the Intralipid study blood pressure did not significantly change compared with baseline values and did not differ among the three study groups.

No significant correlation between flow-induced vasodilatation and baseline fasting plasma triglycerides, free fatty acid, and total cholesterol levels in any genotype group was found (data not shown).

NTG study

The 55 subjects studied were distributed among the 3 different PON genotypes; in particular, 25 subjects shared the AA genotype, 20 shared the AB genotype, and 10 shared the BB genotype. As shown in Table 3, NTG administration was associated with a significant increase in brachial artery diameter in all genotype groups. Nevertheless, after Intralipid infusion, a significant reduction in NTG-induced vasodilatation was found in all 3 groups, with the strongest reduction in the subjects sharing the BB genotype (P for trend < 0.001 In contrast, NTG-induced changes in brachial artery flow from baseline values were not significant after administration of NTG alone or after Intralipid infusion plus NTG). At the end of Intralipid infusion and after adjusting for gender ratio, basal triglycerides, and changes in plasma triglycerides concentrations, subjects sharing the BB genotype still had the lowest changes in diameter (7.4 ± 0.9%) compared with AA (13.1 ± 3.2%) and AB (11.2 ± 2.9%) genotypes (P for trend < 0.001). In contrast, changes in flow among the three genotypes were still not significant despite adjustment for gender ratio, basal triglycerides, and changes in plasma triglycerides concentrations (data not shown).

	Discussion

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A major determinant of endothelium function and brachial reactivity is the oxidative stress, which might contribute to quench nitric oxide (14). Hypertriglyceridemia has been shown to be a prooxidant factor (11) and to impair the endothelial response in healthy subjects (5). How plasma oxidative stress levels are regulated is still debated. More recently, it has been outlined that paraoxonase, the product of the PON genes, inhibits LDL and HDL oxidation and preserves their function (4). To efficiently participate in the protection of LDL particles against oxidative modification, PON should be present locally in the arterial wall, where the attack by oxidizing radicals is currently thought to occur (3, 4). A coordinate increase in paraoxonase as well as in apolipoprotein J/apolipoprotein A-1 complex in human aortic tissue during the development of atherosclerosis has been also documented by immunolocalization and has been interpreted as a sign of an adaptive process whose role is to protect the artery wall from the increasing oxidative stress associated with the progress of atherosclerosis (3). Furthermore, PON was found to use efficiently not only lipoprotein-associated peroxides but also hydrogen peroxides, which are the major free radicals produced by the arterial wall cells during atherogenesis and are responsible for LDL oxidation (4). The ability of PON to hydrolyze (in addition to peroxides) may thus play an important role in eliminating potent oxidants that are involved in atherosclerosis (4). Interestingly, the antioxidant effect of paraoxonase enzyme activity is associated with different gene polymorphisms. In fact, the PON BB genotype is associated with lesser protection of LDL against the accumulation of lipid peroxides (25) and more frequent CHD (3, 4). Our data provide strong physiopathological support for a role for the PON genotype in the development of CHD, as we demonstrated that adult healthy subjects sharing the PON BB genotype have impaired vascular reactivity and thus are more prone to endothelium dysfunction. Such impaired vascular reactivity, evident after transient acute (5) and chronic (26) hypertriglyceridemia and reversed by atorvastastin administration (26), is associated with a significant increase in oxidative stress (11). Thus, we can hypothesize that subjects with the PON BB genotype have a lower antioxidant capacity and therefore are more exposed to the risk of atherosclerosis as demonstrated by the lower vascular reactivity in the presence of a prooxidant factor. Such a hypothesis is also supported by results showing that subjects with the PON BB genotype have a greater accumulation of lipid peroxides than those with the AA or AB genotype when exposed to prooxidant factors (25, 27).

Noteworthy, in our data hypertriglyceridemia impaired brachial artery vasodilatation in an endothelium-dependent and -independent manner, and the subjects sharing the BB PON polymorphism had worse vasodilatation in both of these experimental conditions. Thus, one can hypothesize that hypertriglyceridemia, via a free fatty acid-mediated increase in oxidative stress, might impair both the production and the action of nitric oxide at endothelium level. This hypothesis is also in agreement with previous data (5). In our study we found that subjects sharing the BB genotype after Intralipid infusion had a significant decrease from baseline values in changes in brachial artery diameter, but not in flow. Indeed, such an apparent discrepancy might be explained by an increase in local blood pressure, which, in turn, had no systemic effect, as demonstrated by the absence of difference in change in systemic arterial blood pressure among the three genotype study groups. Alternatively, one can hypothesize that brachial arterial wall thickness was able to magnify the difference in diameter and hide the changes in flow.

Despite the well known association among PON activity, CHD, and oxidative stress, our study has some potential limitations. Some subjects (n = 35) were light smokers, and a smoking habit might affect our results. Indeed, looking at the distributions of such subjects in the 3 genotype groups, we found that only 1 subject had the BB genotype, whereas 20 and 12 had the AA and AB genotypes, respectively. Such a distribution makes it unlikely that a smoking habit might have influenced our data. The relationship between lower vascular reactivity and more elevated oxidative stress in the subjects with the BB genotype is apparently in contrast with the evidence that the PON BB genotype is associated with the strongest enzymatic activity against paraxon (28). Notwithstanding, the results reported by Mackness et al. (25) clearly indicate that the activity of the enzyme against such a nonphysiological substrate as paraoxon cannot be interpreted as directly predictive of a specific level of cardiovascular risk. The use of an artificial lipid emulsion such as Intralipid for transiently increasing plasma triglycerides and free fatty acid concentrations is a further possible limitation of our study. Another approach might be to examine the brachial reactivity after the ingestion of the fatty meal, as reported by Vogel et al. (29). However, these researchers did not exclude the effect of vasoactive hormones, such as insulin or intestinal peptides, which increase after a fatty meal and are not affected by Intralipid infusion at least at the rate used in our study. Furthermore, the rise in plasma triglycerides and free fatty acid concentrations is much more reproducible after the infusion of Intralipid than after a fatty meal, as also demonstrated by the fact the steady state plasma triglycerides and free fatty acid levels were similar in all genotype groups.

In conclusion, our study shows that transient hypertriglyceridemia decreases vascular reactivity more in subjects with the PON BB genotype than in those with the other genotypes. Such data seem particularly important in light of the fact that the PON BB genotype has been associated with a more elevated frequency of CHD and that impaired vascular reactivity is an early sign of endothelium dysfunction, which is normally associated with atherosclerosis. Further studies will need to investigate whether peripheral arteries and coronaries have a similar response to elevated plasma triglycerides and free fatty acids and whether transient and chronic hypertriglyceridemia have similar effects on vascular reactivity.

Received August 4, 2000.

Revised October 27, 2000.

Accepted November 2, 2000.

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