Non-esterified fatty acids and blood pressure elevation: a mechanism for hypertension in subjects with obesity/insulin resistance?

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Abstract

The prevalence of hypertension in individuals with obesity or type II diabetes is substantially elevated. Increased levels of non-esterified fatty acids (NEFAs) in abdominally obese subjects were reported to contribute in the development of various disturbances related to the metabolic syndrome, such as hepatic and peripheral insulin resistance (IR), dyslipidaemia, β-cell apoptosis, endothelial dysfunction and others. However, the involvement of NEFAs in the development of hypertension has been much less studied in comparison to other mechanisms linking IR and central obesity with blood pressure (BP) elevation. This article reviews the existing evidence on the relation between NEFA and hypertension in an attempt to shed a light on it. In vivo data from both animal and human studies support that acute plasma NEFA elevation leads to increase in BP levels, whereas epidemiological evidence suggests a link between increased NEFA levels and hypertension. Further, accumulating data indicate the existence of several pathways through which NEFAs could promote BP elevation, that is α1-adrenergic stimulation, endothelial dysfunction, increase in oxidant stress, stimulation of vascular cell's growth and others. The above data support a possible important role of NEFA in hypertension development in patients with obesity and the metabolic syndrome and raise hypotheses for future research.

Introduction

In the initial modern descriptions of the insulin resistance (IR) or metabolic syndrome, IR was proposed to be the primary disorder, causally related to the development of the rest disturbances, that is impaired glucose tolerance or type II diabetes, hypertension and hypertriglyceridaemia.1, 2 However, central obesity, a factor promptly added to the above cluster,2, 3 was soon found to be connected in a more complex way with IR (i.e. to be not a consequence but rather a cause of IR), as well as to play important roles in the development of the rest disorders of the syndrome.4

One of the most important factors connecting obesity with the development of related metabolic abnormalities is the elevated release of free or non-esterified fatty acids (NEFAs) from abdominal adipocytes in patients with central obesity, which results in increase in plasma NEFA concentration and turnover.5, 6 NEFAs have been shown to induce both hepatic and peripheral IR,7, 8 to activate apoptotic pathways in pancreatic β cells,9 to promote endothelial dysfunction10 and to increase the production of plasminogen activator inhibitor-1.11 Most importantly, increased NEFA supply of the liver, primarily owing to the incomplete insulin-mediated suppression of lipolysis in this type of subjects, is the initial step for the development of the characteristic lipid disorders of the metabolic syndrome.12

With regard to hypertension, several studies have clearly shown a causal association of IR and compensatory hyperinsulinaemia with blood pressure (BP) elevation, through mechanisms like sodium retention, stimulation of the sympathetic nervous system, promotion of vascular cell's growth or impairment of insulin-mediated vasodilatation in insulin-resistant states.13 On the other hand, central obesity is also known to induce the development of hypertension through increased activity of adipose tissue renin–angiotensin–aldosterone (RAAS), sympathetic activation and other mechanisms, usually in close connection with IR.14, 15

NEFA elevation has been previously implicated to be one of the latter mechanisms linking abdominal obesity to BP elevation.15, 16 However, the research interest in this mechanism has never been particularly intense, despite the accumulation of a considerable amount of data supporting a possible relevant role for NEFAs. Therefore, the aim of this review was to summarize the existing evidence on the direct effects of NEFA elevation on BP, as well as possible pathophysiologic mechanisms connecting NEFAs with BP increase, in an attempt to shed an up-to-date light on this association and to raise hypotheses for future research.

Search strategy

A systematic literature search of MEDLINE/PubMed and EMBASE databases was performed to identify English-language articles published from 1966 until May 2006 that reported data on the association between NEFA and hypertension. Search terms used were ‘non-esterified fatty acids’, ‘free fatty acids’, ‘NEFA’, ‘FFA’ in combination with ‘blood pressure’ and ‘hypertension’. Reference lists of identified articles were also evaluated for additional relevant papers and information. Articles providing information on the effect of NEFAs on BP levels or on possible mechanisms linking NEFA with the development of hypertension were included.

The effect of NEFAs on BP levels

The first indications on the association of NEFAs with BP elevation came from an in vivo study in minipigs17 (Table 1). In this study, Intravenous infusions of Intralipid (a triglyceride emulsion containing primarily glycerol esters of two NEFAs, oleic and linoleic acid) and heparin (to activate endothelial lipoprotein lipase, which in turn, hydrolyses the ester bond and releases NEFA in the circulation)16, 18 were performed, in order to increase circulating NEFA levels. This NEFA elevation was associated with a significant increase in peripheral vascular resistance and a rise in BP of approximately 30 mm Hg.17

Table 1 Studies reporting direct effects of plasma NEFA elevation on BP levels

Subsequently, Grekin et al. observed that infusion of sodium oleic (which derives from combination of oleic acid with sodium) in portal or femoral veins of rats resulted in acute increases in mean BP of 29 and 13 mm Hg, respectively. Moreover, chronic (1 week) administration of sodium oleic was associated with an elevation of 16 mm Hg in mean BP vs baseline.19 Portal infusion of sodium oleic also resulted in an increase in plasma catecholamines, suggesting that BP elevation could be related to sympathetic activation. In another study of the same group, acute and chronic portal infusions of oleic acid, as well as acute infusion of linoleic acid were again associated with significant increases in BP.20

Previous human studies provided indirect evidence in favour of an association between NEFA and the development of hypertension. Egan et al.21 observed that baseline plasma levels and turnover rate of NEFAs were increased in obese compared to lean individuals, but similar between obese hypertensive and obese normotensive subjects. However, the decrease in plasma NEFA levels after insulin administration was much smaller in obese hypertensive than obese normotensive subjects; in other words, obese hypertensives displayed resistance in insulin-mediated NEFA reduction. Another finding connecting high levels of NEFAs with hypertension was that BP levels were significantly correlated with NEFA levels and turnover rate, but not glucose disposal rate. These correlations remained significant after adjustment for fasting insulin levels, IR and other parameters.21

Data from the population-based Paris Prospective Study also support these associations. In almost 3000 non-diabetic, non-hypertensive men followed for 3 years, baseline NEFA elevation was a highly significant risk factor for the subsequent development of hypertension (hazard ratio of 1.58) after controlling for several known risk factors and other abnormalities of the metabolic syndrome.22

In addition to the above data, several human studies have clearly shown that acute plasma NEFA elevation leads to increase in BP (Table 1).23, 24, 25, 26, 27 Most of these studies aimed primarily to evaluate the effect of NEFAs on other parameters (i.e. endothelial function) with complicated experiments and are described in detail below, in the sections of the possible pathways linking NEFAs with hypertension. Of particular interest, however, is a study suggesting a possible link between NEFA elevation, family history of hypertension and BP regulation. In this study, 4-h Intralipid and heparin infusions were performed in lean healthy subjects with negative or positive family history of hypertension. Although NEFAs increased similarly in both groups during the infusion, diastolic BP (DBP), mean BP (MBP) and pulse pressure increased significantly only in subjects with a family history of hypertension. Systolic BP (SBP) increased in both groups, but the increase was significantly greater in subjects with positive than those with no family history of hypertension (14±2 vs 10±2 mm Hg).26

Based on such data, it can be speculated that in subjects that typically exhibit chronic NEFA elevation, that is those with central obesity, IR and type II diabetes,4, 5, 6 this NEFA increase can be an important factor promoting the development of hypertension in subjects with normal BP levels, or deteriorating BP control in patients with already elevated BP. Further, some of the above data21, 22 support not only a close association between NEFA and BP, but also that this relation could be independent from the degree of IR and other parameters of the metabolic syndrome. This can be another interesting possibility, but needs further examination by background and epidemiological studies. The following sections describe pathophysiologic mechanisms that can be possibly involved in a NEFA–hypertension relationship.

NEFA and α1-adrenergic activation

In the above-mentioned study from Grekin et al.,20 the increase in BP following portal oleic acid infusion was blunted from prazosin, an α1-adrenergic antagonist, but not from an angiotensin II receptor inhibitor, findings indicating the involvement of an α1-adrenergic mechanism in this BP elevation (Figure 1). These observations in favour of an α1-adrenergic-mediated action of NEFAs are in agreement with previous findings from Egan et al. in humans. This group reported an increase in vascular tone and vascular responsiveness in α1-adrenergic stimulation in obese hypertensive patients,28, 29, 30 which could not be explained from resistance in the vasodilating action of insulin.31 Assuming that this increase is caused by NEFA elevation, the investigators studied the infusion of Intralipid and heparin in hand veins of two groups of normotensive subjects. Local NEFA increase substantially reduced the dose of phenylephrine required to produce 50% of the maximal venoconstrictor response, whereas the response to angiotensin II was not altered.32

Figure 1
figure1

Possible pathways connecting elevation of plasma NEFAs with BP increase (NEFAs, non-esterified fatty acids; RAAS, renin–angiotensin–aldosterone system; VSMCs, vascular smooth muscle cells; NO, nitric oxide).

In a subsequent study, the involvement of α1- or both α1- and α2-adrenergic mechanism was examined, again by local infusion of Intralipid and heparin in normotensive individuals. The relevant increase in oleic and linoleic acid was again related to an increased vasoconstrictor response to phenylephrine, which is a non-selective α1- and α2-adrenergic agonist but not to clonidine, which is a rather selective α2-agonist.33 In conjunction with the above study, elevation of plasma NEFAs after infusion of Intralipid alone or Intralipid and heparin in lean normotensive subjects similarly reduced the dose of phenylephrine required to raise MBP by 20 mm Hg.34 These data suggest that raising levels of plasma NEFAs and/or triglycerides enhance α1-adrenoceptor-mediated venoconstriction and pressor sensitivity. Other investigators reported comparably adverse effects of NEFAs on vascular function. For example, the post-ischaemic vasodilatory response of brachial artery in healthy lean subjects was significantly reduced after transient hypertriglyceridaemia that increased plasma NEFA levels.35

NEFA, nitric oxide and endothelial dysfunction

Previous studies in vitro suggest an interference of NEFA with nitric oxide (NO) production from endothelial cells. Both oleic and linoleic acids were reported to cause dose-dependent reduction of endothelial NO synthase (NOS) activity in bovine pulmonary artery endothelial cells.36 In another study, addition of NEFAs in endothelial cells in culture was associated with dose-dependent reductions of NO production. This reduction was also attributed to a decrease in NOS activity, as NOS concentration in endothelial cells remained unaltered.37 Further, in ex vivo experiments in rabbit femoral artery rings oleic acid inhibited the acetylcholine-mediated vasodilatation, which is endothelium-dependent. In contrast, the endothelium-independent vasodilatating action of sodium nitroprusside was not altered, a finding indicating that NEFAs were only interfering with endothelium-dependent vasodilatation.36

In addition to the above findings, elegant in vivo experiments provided detailed information for the effects of NEFAs on endothelial function in humans. Steinberg et al.23 observed that intra-arterial infusion of metacholine in femoral artery of lean healthy individuals during intravenous normal saline infusion resulted in an increase of leg blood flow up to about 300% in relation to baseline levels. After 2 h of systemic administration of either low- or high-dose Intralipid and heparin, which both increased plasma NEFA concentration, repeat of metacholine infusion caused a significantly lower increase in leg blood flow than before (maximum increase up to about 200%). Similarly, plasma NEFA elevation with the use of somatostatin, which inhibited insulin production, thus increasing lipolysis, produced a comparable disturbance of endothelium-dependent vasodilatation. In contrast, elevated NEFAs did not interfere with endothelium-independent vasodilatation, caused by sodium nitroprusside infusion. In all these experiments, during Intralipid and heparin infusion SBP measured invasively was 3–6 mm Hg higher than during the respective saline infusion, whereas DBP was not significantly different.23 Another in vivo study confirmed these findings on NEFAs causing endothelial dysfunction, showing that NEFA elevation resulting from 2-h infusion of long- or medium-chain triglycerides and heparin depressed the acetylcholine-induced increase in forearm blood flow. However, in this latter study, MBP changes in all the experiments were small and insignificant.38

NEFAs were also shown to interfere with basic NO production. In particular, Steinberg et al.24 measured leg blood flow before and after infusion of N-monomethyl-L-arginine (L-NMMA), which is an inhibitor of endothelial NOS, in two groups of lean healthy subjects. In one group the leg blood flow response measurements were performed during saline infusion and in the other, after a 2-h infusion of Intralipid and heparin. In the group not receiving Intralipid and heparin, a decrease of leg blood flow of about 17% was observed after the L-NMMA infusion. This reduction practically reflected the contribution of NO in preservation of vascular tone under normal circumstances. However, after Intralipid and heparin administration, the L-NMMA-induced leg blood flow decrease was only 9%, which suggests that short-term NEFA elevation decreased basic NO release for about 50%.24

Effects of NEFAs on insulin-mediated vasodilatation

In healthy subjects, acute administration of insulin is long known to produce endothelium-dependent vasodilatation.39, 40 However, numerous studies have shown that this action of insulin is severely impaired in subjects with various components of the metabolic syndrome41, 42 and this impairment is considered a basic mechanism linking IR and compensatory hyperinsulinaemia with BP elevation.13, 43

In a different protocol of the above-mentioned study,24 the investigators evaluated the possible involvement of NEFAs in this impairment of insulin action. Lean healthy individuals underwent two sets of euglycaemic hyperinsulinaemic clamp experiments with and without parallel increases of Intralipid and heparin. The subjects were divided into two groups, one receiving Intralipid and heparin infusion of short (2 or 4 h) and the other of long (8 h) duration. Short infusion did not produce any significant changes, but long infusion was associated with significant reductions in glucose uptake during the clamp of about 35%, in insulin-induced leg blood flow increase of 40% and in insulin-mediated NO production of 80%. In both the groups, the changes in IR during NEFA elevation was strongly correlated with the changes in insulin-mediated leg blood flow increase, which suggests a similar impact of NEFAs in the tightly coupled metabolic and vascular actions of insulin.24 As far as BP is concerned, basic MBP levels were similar between the groups and did not change during the clamps performed without Intralipid and heparin infusion. Short plasma NEFA elevation did not cause significant changes in MBP either before or during the clamp experiment. However, long plasma NEFA elevation was associated with an increase of 10 mm Hg in MBP both before and during the clamp. As a result, MBP during the clamp in the group with the long NEFA elevation was significantly higher than that in the group with the short elevation.

This effect of NEFAs on insulin-mediated vasodilatation can be partly explained from their action on phosphatidyloinositol 3-kinase (PI3-K), an enzyme playing a central role in insulin intracellular signalling. Both insulin-mediated glucose uptake in skeletal muscle cells and insulin-mediated NO production from endothelial cells take place through activation of PI3-K pathway.44, 45 NEFAs have been repeatedly shown to interfere with insulin-mediated glucose uptake in skeletal muscle cells by inhibiting intracellular insulin signalling through blocking of PI3-K activation.46, 47 Therefore, it is highly possible that NEFA interfere with insulin-mediated vasodilatation through the same mechanism.

Taken together, the above findings suggest that plasma NEFA elevation for about 2 h in healthy humans results in the reduction of basic vascular NO production and endothelium-dependent vasodilatation, as well as slight increases in BP. Long-term elevations (8 h) on the other hand, additionally blunt insulin-mediated glucose uptake and vasodilatation and produce more pronounced BP increases. It has been postulated that chronic NEFA elevation in insulin-resistant states, apart from interfering with insulin-mediated glucose uptake, is the main factor responsible for the observed endothelial dysfunction and impaired insulin-mediated vasodilatation (Figure 1).10 Thus, it can also be one of the basic mechanisms for the increase incidence of hypertension in these patients.

NEFA and oxidant stress

An additional mechanism connecting NEFA and BP elevation could be an increase of oxidative stress.16 In vitro studies support the notion that NEFAs can induce oxidant stress.48 In vivo, elevation of NEFAs with Intralipid and heparin infusions has been shown to increase the concentrations of various biomarkers of oxidant stress.49, 50 On the other hand, the contribution of oxidant stress in hypertension development is supported by preliminary animal data,51 and indirect evidence from studies where diet rich in fruits and vegetables, containing high amounts of antioxidant substances, significantly reduced BP.52

Egan et al.16 suggested that a relatively high intake of antioxidants could be responsible for the limited BP increases in some of the above studies.23, 38 To test this hypothesis, the investigators administered Intralipid and heparin for 4 h in healthy individuals being for the former 3 weeks on a diet low in antioxidants. This infusion was associated with significant increases in SBP and DBP of 10 and 3 mm Hg, respectively, whereas respective infusion of saline and heparin did not significantly affect BP.25 However, it is obvious that to effectively assess the effect of antioxidants in NEFA-induced BP increase, a comparison of two groups receiving diets of low and high concentrations of antioxidants should be performed.

In a more recent study, these investigators examined basic BP levels and the effects of NEFA elevation in obese hypertensive and lean normotensive subjects under their usual diet, the Dietary Approaches to Stop Hypertension combination diet (DASH-CD), which is rich in antioxidants, and a low-antioxidant diet.27 SBP, DBP and MBP declined significantly in obese hypertensives after 3 and 4 weeks on the DASH-CD compared with values on their usual and the low-antioxidant diet. After 4 weeks on the DASH-CD, BP in obese hypertensives was 8.1/7.4 mm Hg lower than on the low-antioxidant diet. In lean normotensives, SBP tended to rise during the low-antioxidant diet, but the difference compared with that of the DASH-CD was not significant. After 4 h of Intralipid and heparin infusion, SBP increased significantly in obese hypertensives (about 4–5 mm Hg) and in lean normotensives (from 8 to 13 mm Hg) on all three diets and DBP followed similar trends. However, during this acute elevation of FFA, SBP and DBP in both the groups remained lower on the DASH-CD than on the usual and low-antioxidant diets.27 Although these data are intriguing, as direct mechanisms connecting oxidative stress with hypertension development have not yet been established, future studies should explore this potential pathway linking NEFAs with BP elevation.

Possible trophic actions of NEFAs

Another possible mechanism connecting NEFAs with BP increase is their possible mitogenic actions on the vascular wall, as increased proliferation of vascular smooth muscle cells (VSMCs) has been long connected to vascular hypertrophy and arterial stiffness, one of the basic mechanisms of hypertension development.53, 54 In vitro studies have reported that unsaturated NEFAs, including oleic and linoleic acid, can directly activate the typical and atypical isoforms of protein kinase C (PKC) in various cell types, including VSMCs.55, 56, 57, 58 Among other deleterious effects on human vasculature, PKC has been shown to play a central role in mitogenic processes in VSMCs.59, 60 Several studies have clearly shown that NEFAs induce proliferation of VSMCs via PKC activation,55, 56, 57 implicating a potential involvement of plasma NEFA elevation in vascular remodelling and hypertension in obese subjects. In addition, oleic and linoleic acid were reported to increase the trophic action on VSMC of other growth factors, for example insulin-like growth factor-1 (IGF-1).61 In the cardiovascular system, IGF-1 is produced from VSMCs after stimulatory effects of various factors, including insulin; thus, its release is also elevated in states of IR and hyperinsulinaemia.62

Other pathways potentially connecting NEFAs with BP elevation

In addition to the mechanisms described so far, preliminary evidence for other actions of NEFAs that can contribute in the development of hypertension also exist (Table 2). For example, NEFAs can counteract with RAAS in several points. In some of the above-mentioned studies, oleic acid did not only induce VSMC proliferation, but also stimulated the mitogenic response of these cells in angiotensin II, findings supporting a synergistic effect of NEFAs and angiotensin II on vascular growth.56, 57 NEFAs were also reported to activate the expression of angiotensinogen gene in preadipocytes,63 an action possibly contributing in the upregulation of adipose tissue RAAS in subjects with central obesity. Further, an oxidized derivative of linoleic acid was recently reported to stimulate aldosterone production from rat adrenal cells, providing an alternative explanation for unexpectedly elevated aldosterone levels in some obese subjects.64

Table 2 Pathophysiologic mechanisms possibly connecting elevation of NEFA with hypertension

In addition, previous in vitro studies suggest that both oleic and linoleic acids are endogenous inhibitors of Na+,K+-ATPase.65, 66 Reduction of Na+,K+-ATPase activity in VSMCs through increase in intracellular Na+ and decrease of passive Na+–Ca2+ exchange or through partial depolarization of cell membrane and activation of voltage-dependent Ca2+ channels would result in increased intracellular Ca2+ concentration and a relative elevation of vascular tone. Thus, inhibition of Na+,K+-ATPase has been suggested to promote the development of hypertension.67 Reduced activity of Na+,K+-ATPase has been noted in both animal models and humans with obesity and type II diabetes and has been long implicated in the development of hypertension in these states.68, 69 Therefore, it can be speculated that NEFA elevation is a basic mechanism for this downregulation of Na+,K+-ATPase activity.

Conclusions

NEFA elevation has been extensively studied as a cause of IR, β-cell apoptosis, dyslipidaemia, endothelial dysfunction and other disturbances in subjects with obesity and type II diabetes. Less attention has been specifically paid to the possible involvement of NEFAs in the development of hypertension, which is a major contributing factor in increased cardiovascular morbidity and mortality of such subjects. However, several studies on related actions also provide information implicating a connection of NEFAs with BP elevation. A close examination of these data reveals an important acute effect of plasma NEFA elevation on BP as well as several pathways through which NEFA increase can lead to hypertension. Thus, it can be speculated that in subjects with features of the metabolic syndrome chronic NEFA elevation could be an important mechanism contributing to either the development of hypertension in previously normotensives or inadequate BP control in patients with already elevated BP. The above data underline the need for future studies to elucidate this important field.

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Acknowledgements

This paper was not supported by any source and represents an original effort on our part.

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Correspondence to P A Sarafidis.

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Keywords

  • non-esterified fatty acids
  • hypertension
  • obesity
  • insulin resistance
  • type II diabetes

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