(Hypertension. 1997;29:1058-1063.)
© 1997 American Heart Association, Inc.
Articles |
Increased Membrane Ratios of Metabolite to Precursor Fatty Acid in Essential Hypertension
From the Institute of Medical Pathology, Chair of Internal Medicine, University of Verona (Italy).
Correspondence to Prof Roberto Corrocher, Institute of Medical Pathology, Chair of Internal Medicine, Policlinico Borgo Roma, 37134 Verona, Italy.
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Abstract |
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Abstract Desaturase enzymes are responsible for the conversion of essential fatty acids to the longer-chain eicosanoid precursors. These enzymes require zinc as an essential cofactor, and the following ratios—C20:4/C18:2, C20:5/C18:3, and C22:6/C20:5—are considered indexes of their activity. We analyzed these parameters in plasma and erythrocyte membranes of 105 essential hypertensive patients, 20 white coat hypertensive patients, and 100 age-matched normotensive control subjects. Dietary analysis excluded significant quantitative and qualitative differences in fatty acid dietary intake between essential hypertensive patients and normotensive control subjects. Zinc levels and C20:4/C18:2, C20:5/C18:3, and C22:6/C20:5 ratios were significantly higher in essential hypertensive patients than control subjects, whereas white coat hypertensive patients showed intermediate values for all these parameters. These data provide evidence for an alteration in fatty acid metabolism of essential hypertensive patients, consistent with increased activity of desaturase enzymes. The consequent greater bioavailability of eicosanoid precursors, and in particular of arachidonic acid, could affect several vascular functions and have a bearing on the pathogenesis or complications of hypertension.
Key Words: zinc • fatty acids • hypertension, essential • hypertension, white coat • fatty acid desaturases
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Several disturbances of cell membrane functions have been described in EH, with the result that a "membrane hypothesis" for its pathogenesis has been proposed. Fatty acids are key components of cell membranes and have important modulating effects on several membrane properties, such as fluidity,1 ion transport systems,2 calcium binding to the inside of the membrane,3 and prostaglandin synthesis,4 all of which have often been found to be abnormal in EH. The fatty acids C20 and C22 (eicosanoid precursors) derive from the bioconversion of linoleic (C18:2
6) and
-linolenic (C18:3 3) acids through desaturation and
elongation steps; desaturation processes are catalyzed by rate-limiting
activities of 
4-5-6 desaturases. All these enzymes are bound
to the microsomal lipid bilayer and require zinc to express their
activity.5 The 6 desaturase converts C18:2 6 to
dihomo-
-linolenic acid (DGLA; C18:3 6) and C18:3 3 to
stearidonic acid; 5 desaturase is responsible for the biosynthesis
of arachidonic acid (C20:4) from DGLA and EPA (C20:5)
from stearidonic acid. Finally, 4 desaturase converts EPA to
DHA4 (Fig 1
). Desaturase activity is
usually assayed in vitro or in animals by measuring the rate of
conversion of radiolabeled precursor fatty acids to their respective
products.6 Ethical and practical reasons prevent this
method from being adopted in humans; thus, indirect information can be
gathered from analysis of cell membrane lipid composition,
which is known to reflect desaturation activities.7
Linoleic and -linolenic acids are "essential" fatty
acids because they cannot be synthesized in vivo and exclusively
reflect dietary intake, whereas the fatty acids C20 and C22 derive from
the diet as well as from essential fatty acid metabolism,
via the above-mentioned pathway. Thus, the C20:4/C18:2, C20:5/C18:3,
and C22:6/C20:5 ratios may be considered an expression of
desaturase-elongase activity, when C20 and C22 fatty acid dietary
intake is controlled.
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A large cross-sectional study has recently focused attention on the relations between BP and serum fatty acids,8 and other investigations6 have demonstrated that desaturase enzyme activity is altered in spontaneously hypertensive rats, but no studies are available to date assessing the relationships among fatty acid metabolism, desaturase activity, and BP in humans.
Erythrocytes provide a simple, highly suitable model for the study of systemic fatty acid metabolism because these cells lack desaturase and elongase enzymes and their membrane fatty acid composition closely resembles that of circulating lipoproteins, which in turn are assembled in the liver. We therefore decided to evaluate RBC C20:4/C18:2, C20:5/C18:3, and C22:6/C20:5 ratios and zinc status in a group of EH patients compared with normotensive subjects.
The study also included subjects presenting the condition known as WCH. The general definition of WCH is persistent raised clinic BP together with normal ambulatory BP; the prevalence among hypertensive individuals has been reported to be around 20%.9 Since 16% of our EH patients were found to have WCH, we also compared this subgroup with EH patients and normotensive subjects with respect to the above-mentioned parameters.
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Methods |
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Patients
Two groups of 100 normotensive control subjects (mean age, 45.9±16 years) and 125 EH patients matched for age and dietary habits were selected as described below.
For the control group, we used data from a cross-sectional study in a population sample of 100 healthy subjects selected as previously described.10 Briefly, an initial selection of 500 healthy subjects was obtained by means of tables of random numbers; a further selection was performed by the three practitioners operating in the area, who were familiar with the details of the clinical histories and lifestyles of the subjects. All subjects known to be suffering from chronic disease or acute intercurrent illness, as well as pregnant women and subjects taking steroids, nonsteroidal anti-inflammatory drugs, and antiplatelet and hypolipidemic drugs or contraceptive pills, were excluded.
EH patients were recruited from among the patients referred to our Hypertension Outpatient Clinic. Office BP was evaluated by the same physician following the directives of the British Hypertension Society11 : Subjects who had diastolic BP greater than 95 mm Hg at three visits over 3 months, without any treatment, were considered hypertensive and recruited. These patients then underwent 24-hour ambulatory BP monitoring performed with a SpaceLabs 90207 device as previously described.12 Following the indications of the first International Consensus Document on Ambulatory BP Monitoring,13 we considered patients with daytime BP greater than 135/85 mm Hg to be hypertensive and patients with daytime BP less than 135/85 mm Hg to have WCH (20 subjects=16% of the EH group). Cuffs of appropriate width and length were used to avoid overestimation or underestimation of BP values11 ; ambulatory BP findings with more than 20% technical errors were excluded.
None of the subjects were institutionalized or on a special diet, and none were taking trace elements or vitamin supplements. A 7-day food record was randomly obtained from a representative sample of subjects (50 EH patients and 30 normotensive control subjects) to exclude any significant differences between EH patients and control subjects with respect to dietary intake of fatty acids.
EH patients and normotensive control subjects were divided into three groups according to age: group 1, subjects 39 years old or younger; group 2, subjects 40 to 59 years old; and group 3, subjects 60 years old or older. Patients with secondary hypertension (as assessed by clinical, biochemical, and instrumental tests) were excluded. Informed consent was obtained from all participants according to the ethics guidelines of the Declaration of Helsinki.
RBC Membrane Fatty Acid Analysis
Blood samples (15 mL) were collected after overnight fasting
with the use of EDTA-containing Vacutainer tubes. RBCs were separated
by centrifugation at 1000g for 15 minutes
(4°C), the buffy coat was removed, and the RBCs were washed three
times with 154 mmol/L NaCl. Analysis of RBC membrane fatty
acids (250 µL of packed RBCs hemolyzed in an equal volume of
double-distilled water) was performed on total lipids extracted with
4.5 mL isopropanol/chloroform (11/7 [vol/vol]) containing 0.45
mmol/L 2,6-di-ter-p-cresol (BHT) as antioxidant. A gas
chromatographic method (Hewlett-Packard 5980
chromatograph), based on the fatty acid direct
transesterification technique, was used as previously
described.14 Analyses were performed in duplicate
on each sample. Peak identification and quantification were done with
commercially available reference fatty acids (Sigma Chemical Co). The
areas of the peaks were measured by an automatic plotter-integrator
(Hewlett-Packard 3392A). Fatty acid composition data were expressed as
grams per 100 g fatty acid methyl esters. Fatty acids from C12:0
to C26:0 were measured, with unidentified peaks accounting for less
than 0.5% of the total.
Serum zinc concentration was determined by flame atomic absorption spectrometry with a Perkin-Elmer 372 double-beam spectrophotometer equipped with an air-acetylene flame burner and hollow cathode lamp (operating at 15 mA). Atomic absorption was measured at 213.9 nm. The spectral bandwidth was 0.7 nm. Standard solutions containing 30 µmol/L zinc were prepared in double-distilled water. All analyses were performed in duplicate. The coefficient of variation was less than 5%.
RBC membrane cholesterol was determined by an enzymatic method (CHOD-PAP "High performance," Boehringer Biochemia Robin), as previously described.15 Precinorm L (Boehringer Biochemia Robin) was used as control serum.
Statistical Evaluation
Statistical analysis was carried out with the aid of an
Apple Macintosh SE/30 computer using the Systat 5.2.1 program (Systat
Inc) Differences between two groups were tested by Student's
t test and differences between more than two groups by
one-way ANOVA; simple correlations were determined by Pearson's
correlation coefficient. Values of P<.05 were considered
significant.
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Results |
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Dietary analysis showed no significant differences between EH patients and control subjects in either dietary intake of single fatty acids (in particular for C20:4, C20:5, and C22:6) or the C20:4/C18:2, C20:5/C18:3, and C22:6/C20:5 ratios (Table 1
).
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Table 2 summarizes the clinical and biochemical features
of EH and WCH patients and normotensive subjects. In general, WCH
patients were younger than EH patients and normotensive subjects, but
body mass index and plasma lipids were similar in all three groups. EH
patients had a mean BP of 145±13/94±6 mm Hg (World Health
Organization stages I or II).
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Serum zinc was significantly higher in EH patients than in normotensive subjects, whereas WCH patients presented intermediate values (P=NS).
EH patients showed a significant decrease in RBC membrane
cholesterol, C18:2 6, and C18:3 3 and an increase in
C20:4, C22:6, C20:4/C18:2 ratio, C20:5/C18:3 ratio, and C22:6/C20:5
ratio (Fig 2) compared with normotensive control
subjects. No significant differences were found in saturated fatty
acids, monounsaturated fatty acids, polyunsaturated
fatty acids, or the ratio of saturated to polyunsaturated fatty acids.
Moreover, plasma zinc correlated significantly and negatively with
C18:2 (r=-.220) and C18:3 (r=-.268) and
positively with the C20:4/C18:2 (r=.231) and C20:5/C18:3
(r=.289) ratios (data not shown).
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WCH patients showed a higher C20:5/C18:3 ratio than control subjects, whereas no differences were observed between WCH and EH patients. Moreover, in WCH patients, the C20:4/C18:2 ratio was lower than in EH patients but higher than in normotensive subjects.
To establish possible differences in desaturase activities caused by
age or sex, we reevaluated EH patients and normotensive subjects,
comparing the same parameters in the different age groups
(see "Methods") and in men and women. No age- or sex-related
differences were found in the EH or normotensive groups, suggesting
that zinc and fatty acid ratios (as indexes of desaturase activity)
were independent of these variables (data not shown). On the other
hand, comparison for age and sex (Tables 3 and 4) of EH patients and normotensive
subjects confirmed the differences observed in the population as a
whole.
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In other words, EH was invariably associated with increased zinc and higher fatty acid ratios regardless of age or sex.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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We designed our research to investigate whether the metabolic pathway leading to the progressive elongation and desaturation of C18 fatty acids is altered in EH. A recent study has provided evidence that
5-6 desaturase activity is increased in
spontaneously hypertensive rats compared with normotensive control
rats,6 but no similar studies have so far been published
on humans, because methodological and ethical difficulties in the
assessment of desaturase/elongase activity have limited research in
this field.
Whereas precursor essential fatty acids derive only from the diet,
their metabolites result not only from dietary consumption but also
from desaturase/elongase metabolic activity4
(Fig 1
). To assess this activity, we measured the ratios of metabolite
to precursor of RBC membrane fatty acids (which merely reflect the
fatty acid composition of circulating lipoproteins synthesized in the
liver) in groups of EH patients and normotensive subjects consuming
both quantitatively and qualitatively similar diets.
An increased proportion of C20 and C22 fatty acids per unit of precursor essential fatty acid was found in RBC membranes of EH patients compared with those of normotensive subjects. Albeit in smaller samples of patients, two other research groups have also found decreased linoleic and increased arachidonic acid contents in platelets16 and RBC membranes17 of EH patients, in agreement with our own data.
Our observations may depend on different dietary intakes of
C20:4, C20:5, and C22:6 in the two groups studied. However,
considerable direct and indirect evidence makes this unlikely. First,
analysis of dietary records, obtained from one third and
one half of normotensive subjects and EH patients, respectively, failed
to show any significant differences between diet of the two groups.
Calories, protein and lipid, and carbohydrate intakes as well as
arachidonic acid, EPA, DHA, and their ratios to the
respective precursors did not differ between the groups. Despite the
possible limitations inherent in the food questionnaire method, gross
differences can be excluded. A second factor is the method of
participant recruitment.10 Only individuals with a first
diagnosis of hypertension were admitted to the study, so few or no
changes in lifestyle occurred before the selection visit. It is
therefore unlikely that previous dietary advice for EH may explain the
differences observed in membrane fatty acid composition in our
population. Careful analysis of the 3 polyunsaturated fatty
acid content in the RBC membranes of our population further argues
against a bias caused by different dietary fat intake. C20:5 and C22:6
fatty acids are almost exclusively found in foods of marine origin,
which are not often consumed in this region of Northern Italy, with the
result that both EPA and DHA were present in traces on the RBC
membranes in our population. In foods that contain 3 polyunsaturated
fatty acids, the DHA/EPA ratio is relatively fixed and independent of
absolute intake, as our dietary records also show (Table 1). Thus,
the higher DHA/EPA ratio found in EH patients compared with
normotensive control subjects suggests that an additional factor
besides diet is capable of influencing the relative proportions of EPA
and DHA. EPA (C20:5) is converted to DHA (C22:6) by a one-step -4
desaturating process4 ; thus, the observed difference in
the RBC membrane ratio seems to indicate increased activity of this
enzymatic system in EH patients.
We adopted very restrictive criteria to include only healthy subjects in the control group, thus avoiding the influence of pathological processes on the parameters tested. We included in our study population a large number of subjects over a wide age range in order to reach conclusions that were as generally applicable as possible. We conducted the study in unrestricted living conditions, but individuals taking preparations containing vitamins or other nutrients that might have influenced the parameters studied were not admitted. All our participants had normal nutritional indexes such as body mass index, hemoglobin, packed cell volume, and serum albumin. Finally, the same data obtained in the population as a whole were confirmed when statistical analysis was carried out on specific sex and age groups, suggesting that hypertension status was constantly associated with increased ratios of metabolite to precursor irrespective of sex or age.
Cholesterol metabolism has already been shown to be altered in cell membranes of EH patients.18 19 Our results concerning erythrocyte membrane cholesterol, although not specifically investigated, confirmed that abnormal membrane lipid metabolism is a general feature of EH patients.
Our observations concerning zinc status and the peculiar condition defined as WCH independently support the view that desaturase activity is stimulated in EH. Zinc levels paralleled the metabolite-to-precursor fatty acid ratios, being constantly higher in hypertensive patients than normotensive subjects. In line with these results, zinc ions have been identified as constitutive cofactors of desaturase activity in human, animal, and in vitro studies.5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 We were unable to quantify dietary zinc intake precisely in our population, and we cannot rule out the possibility that an increased zinc intake may have had an effect on the present results. However, both human and animal studies have shown an association between high intracellular zinc levels and hypertension,21 and although there is no experimental evidence that zinc increases vascular tone, several hypotheses have been adduced to explain this association.
Since zinc inhibits the Ca2+-ATPase pump that catalyzes Ca2+ efflux from the cell,22 excess intracellular zinc could lead to increased free Ca2+ in arterial smooth muscle, thereby increasing arterial tone. This hypothesis is supported by the depressed Ca2+-ATPase activity observed in spontaneously hypertensive rat erythrocytes.23 In addition, zinc promotes the release of intracellularly stored Ca2+.24 Finally, zinc is a cofactor of enzymatic systems involved in the regulation of blood pressure, such as angiotensin-converting enzyme.25 Zinc metabolism in hypertension thus warrants thorough investigation.
WCH is still a matter of controversy, as regards both its origin and consequences. In particular, uncertainty persists as to whether it is associated with target-organ damage, whether there are associated metabolic abnormalities, and whether it carries a benign prognosis. Its prevalence is generally estimated to be around 20% of the hypertensive population9 ; our figure of 16% is in agreement with this. The results obtained in this subgroup of patients were different from those obtained in both EH patients and normotensive control subjects, in general presenting values somewhere between those of the other two groups. Several abnormalities, often with similar behaviors, have been reported elsewhere in WCH patients compared with EH patients and normotensive subjects. For example, Weber et al26 reported that WCH patients had higher total and low-density lipoprotein cholesterol levels than normotensive subjects, in which respect they resembled individuals with sustained hypertension; similar data were demonstrated for blood glucose. Recently published echocardiographic and carotid ultrasonographic results26 27 are also consistent with the view that WCH cannot be considered an entirely "innocent" condition but rather mimics, to a lesser extent, sustained hypertension. Interestingly, the smaller group of our WCH patients seems to confirm this trend with regard to fatty acid and zinc metabolism.
In conclusion, distinct differences in cell membrane fatty acid
composition seem to exist among EH patients, WCH patients, and
normotensive subjects, probably because of abnormal fatty acid
desaturation. Whether these abnormalities are relevant in the
pathogenesis of hypertension remains to be seen. However, one is
tempted to suspect that the central point on which desaturase activity
turns in EH patients consists in the increased availability of
arachidonic acid. This may influence the
bioavailability of eicosanoids, a family of mediators involved in the
control of vascular reactivity, including both antihypertensive
(prostaglandin E2) and prohypertensive
(thromboxane A2, prostaglandin
F2, prostaglandin
endoperoxides) substances.28 None of these
arachidonic acid metabolites was measured in our
patients, so any speculation about a possible role for abnormal
eicosanoid production needs caution. Increased
arachidonic acid availability may also interfere with
the generation of neutrophil toxic oxygen products,29
which have been recently involved in the pathophysiology of
cardiovascular disease.30 Finally,
abnormal fatty acid desaturation is likely to differentially affect
membrane functions, with possible modifications of membrane fluidity,
ion channel behavior, and membrane-bound enzyme activities and
receptors. Further studies are necessary to better clarify the
significance of our findings and to test such hypotheses.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by grants from the National Research Council (No. 91.00338.48), the Ministry of the University and of Scientific and Technological Research (60%), and the Veneto Region Department of Health.
Received August 12, 1996; first decision September 16, 1996; accepted October 16, 1996.
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