| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
REVIEW |
Hypertension/Clinical Research Center, Department of Preventive Medicine, Rush University Medical Center, Chicago, Illinois 60612
Address all correspondence and requests for reprints to: Pantelis A. Sarafidis, M.D., Ph.D., Hypertension/Clinical Research Center, Department of Preventive Medicine, Rush University Medical Center, 1700 West Van Buren, Suite 470, Chicago, Illinois 60612. E-mail: psarafidis11{at}yahoo.gr.
 |
Abstract |
|---|
 Top Abstract IntroductionExperimental Data on the...Human Studies on the...Endothelin Levels in Insulin...Involvement of Endothelin in...Thiazolidinediones and...Effects of Endothelin on...ConclusionsReferences |
|---|
Evidence Acquisition: A literature search of MEDLINE database was performed to identify English-language articles published during the last 20 yr. Search terms used were endothelin, insulin, insulin resistance, and hyperinsulinemia in combination with blood pressure and hypertension. Reference lists of retrieved articles were also evaluated for relevant information.
Evidence Synthesis: Several mechanisms connect insulin resistance and compensatory hyperinsulinemia with blood pressure elevation in the context of the metabolic syndrome, i.e. sodium retention, sympathetic activation, and impairment of endothelial nitric oxide production. Accumulating evidence suggests that activation of the endothelin system seems to be another important, yet less discussed, mechanism. In vitro studies have shown that insulin stimulates both endothelin-1 production and action on the vascular wall. In vivo, high levels of insulin result in increase in circulating endothelin-1 in healthy individuals, and this effect is also seen in insulin-resistant subjects, a relationship not observed with nitric oxide production. Moreover, endothelin receptor antagonism effectively reduces blood pressure in animal models of insulin resistance and hypertension. On the other hand, elevation of endothelin-1 levels can further increase insulin resistance, forming possibly a deleterious circle.
Conclusions: Endothelin-1 may play a crucial role in the pathogenesis of hypertension in insulin-resistant states. Future research should examine the potential of endothelin receptor antagonism to help blood pressure control in patients with insulin resistance.
|
Introduction |
|---|
|
TopAbstractIntroductionExperimental Data on the...Human Studies on the...Endothelin Levels in Insulin...Involvement of Endothelin in...Thiazolidinediones and...Effects of Endothelin on...ConclusionsReferences |
|---|
In parallel to research progress in this field, from the mid-1980s, several groups have described the production from endothelial cells of a substance with vasoconstrictive properties, which was later named endothelin (ET) (4). Subsequent research revealed that endothelins are a group of four peptides (ET-1, ET-2, ET-3, and ET-4) that take part in the regulation of many biological functions in the cardiovascular and other systems (5, 6). Endothelial cells produce primarily ET-1, the principal circulating endothelin, and are the main source of this substance, but other cell types, i.e. vascular smooth muscle cells (VSMCs) or macrophages, can also secrete ET-1. The rest of the endothelin peptides are produced from various tissues and act mainly in an autocrine fashion. Two endothelin receptors have been isolated: ETA, which has a higher affinity for ET-1, and ETB, with higher affinity for ET-3. Endothelin-1, which is considered today the most powerful natural vasoconstrictor, is produced from endothelial cells under stimulatory effects from various factors (angiotensin II, vasopressin, noradrenalin, mechanical stress, and others) and acts mainly in the underlying layer of VSMCs through ETA receptors, causing vasoconstriction and increased VSMC proliferation. Although vasoconstriction is its predominant action, ET-1 can also act in ETB receptors present in endothelial cells in an autocrine fashion and promote production of NO and vasodilating prostaglandins (5, 6).
The precise role of ET-1 in the development of systemic hypertension has not yet been fully elucidated. However, studies in several animal models of hypertension have shown overexpression of ET-1 in the vascular wall and substantial reduction of BP with nonselective or ETA-selective endothelin receptor antagonism (7, 8). Moreover, elevated plasma levels and tissue expression of ET-1 were found in certain categories of hypertensives, such as African-Americans, salt-sensitive and low-renin patients, while clinical trials with ET-1 receptor blockers have already demonstrated significant BP-lowering effects (7, 8). Therefore, current knowledge indicates an important pathophysiological role of ET-1, at least in certain groups of hypertensive patients.
Data from in vitro, animal, and human studies accumulated during the past few years suggest that insulin both stimulates ET-1 production from endothelial cells and up-regulates its actions in VSMCs, effects that are preserved in the presence of IR. Furthermore, elevated circulating ET-1 levels were reported in patients with IR. Thus, increased ET-1 could play an important role in BP elevation and insulin-resistant states. The importance of impaired insulin-mediated NO release from endothelial cells for abnormal vascular function and possibly BP elevation in insulin-resistant states has been extensively studied and adequately summarized in previous in-depth reviews (2, 9). However, a possible role of a parallel disturbance in the major vasoconstricting endothelial substance, which is an increase in ET-1 activity, has not been described in detail. This review summarizes the existing evidence on the relation of insulin, IR, and ET-1, attempting to shed a light in a less discussed but not less important mechanism of hypertension development within the metabolic syndrome.
|
Experimental Data on the Effect of Insulin on Endothelin Production and Action |
|---|
|
TopAbstractIntroductionExperimental Data on the...Human Studies on the...Endothelin Levels in Insulin...Involvement of Endothelin in...Thiazolidinediones and...Effects of Endothelin on...ConclusionsReferences |
|---|
Apart from stimulation of ET-1 release, insulin was reported to double the number of ETA receptors in the cellular surface of VSMCs, both in culture and in vivo, in hyperinsulinemic animal models. This effect is due to an increase in ETA synthesis rather than a reduction in their breakdown (15). Moreover, the combination of insulin and ET-1 results in a much greater increase in cultured VSMC proliferation than the separate administration of each one (15). Another study confirmed the above findings, showing also that insulin can increase about 2-fold the number of surface ETA receptors, an effect coupled to a respective increase in ET-1 action on VSMCs in vitro, but has no effect on ETB receptor expression (16). In addition, blocking of ETA receptors in animal vascular beds resulted in increased vasodilating effect of insulin, a finding supporting that insulin is normally associated with stimulation of ET-1 production and action in the vascular wall (17, 18).
Recent data provide information about the intracellular mechanisms involved in insulin-mediated ET-1 production. In particular, Potenza et al. (19) have shown that insulin-stimulated secretion of ET-1 from primary endothelial cells is significantly reduced by pretreatment of cells with PD-98059, an inhibitor of the MAPK pathway but is not influenced from pretreatment with wortmannin, a specific inhibitor of the phosphatidyloinositol 3-kinase (PI3-K). Activation of PI3-K is central in insulin-mediated glucose uptake as well as insulin-mediated NO production and vasodilatation (9, 20), whereas MAPK pathway is involved in trophic and other deleterious effects of insulin in the vascular wall (21). Previous studies have clearly shown that in insulin-resistant states PI3-K pathway in skeletal muscle and vascular tissues is seriously impaired, whereas MAPK pathway is unaffected (22, 23). This imbalance in intracellular signaling can lead to an unopposed effect of ET-1 on the vasculature, as extensively discussed below.
|
Human Studies on the Effects of Insulin on Endothelin |
|---|
|
TopAbstractIntroductionExperimental Data on the...Human Studies on the...Endothelin Levels in Insulin...Involvement of Endothelin in...Thiazolidinediones and...Effects of Endothelin on...ConclusionsReferences |
|---|
Ferri et al. (26) extended these observations, reporting that circulating ET-1 concentration in patients with type 2 diabetes was more than 2-fold elevated during the clamp but returned to the basal levels in about 30 min after the experiment was over. In another study of this group, circulating ET-1 was also significantly elevated during the clamp in type 2 diabetic and obese hypertensive individuals, and a strong correlation was noted between the changes in fasting ET-1 and insulin levels observed before and after 12 wk of a low-calorie diet (14). These investigators attempted also to examine the effect of endogenous insulin on circulating ET-1 in vivo by measuring plasma ET-1 during an oral glucose tolerance test in 14 hypertensive and eight healthy individuals. In both groups plasma ET-1 was significantly elevated during the oral glucose tolerance test. However, although basal ET-1 levels were similar in the two groups, those on 120 and 180 min were significantly higher in hypertensives, a finding attributed to the respective higher endogenous insulin levels in this group (27).
In contrast to the above, some in vivo studies yielded different results. Katsumori et al. (28) did not observe an increasing effect of acute hyperinsulinemia on circulating ET-1 levels in either normal individuals or patients with type 2 diabetes. In other studies performed in healthy postmenopausal women (29), healthy men (30), and men with recently diagnosed uncomplicated hypertension (30), elevated insulin during the clamp was related to a significant reduction in circulating ET-1 of about 30%.
The conflict between these findings could be attributed to the possibility that the change in plasma levels of ET-1 does not directly reflect the change in its production from vascular endothelial cell because ET-1 acts mainly in a paracrine and autocrine fashion (5, 6). This is supported by that ET-1 secretion from endothelial cells takes place from the basal side and is directed toward the underlying layer of VSMCs (31). With complicated experiments, Cardillo et al. (32) overcame this confounder and confirmed the stimulatory effect of hyperinsulinemia in ET-1 production from vascular wall in vivo. This group studied the direct effect of insulin in vascular beds by examining the forearm blood flow (FBF) of healthy volunteers before and after local inhibition of ET-1 receptors, with or without simultaneous local intraarterial insulin infusion. Without insulin infusion FBF was similar before and after simultaneous blockade of ETA and ETB receptors. However, during local hyperinsulinemia ET-1 receptor blockade led to a significant increase of about 70% in FBF, a finding suggesting a direct stimulatory effect of insulin in ET-1 production. The investigators also performed blockade of NO production with NG-monomethyl L-arginine infusion in the presence of ET-1 receptor blockade. This NO production blocking did not significantly affect FBF in the absence of hyperinsulinemia. However, during insulin infusion, additional NO production blockade led to significant reduction in FBF, which returned to the basal levels (32). Overall, these findings confirm the physiological stimulatory effect of insulin on the production of both ET-1 and NO from the vascular wall. In normal individuals, the net result of these actions of insulin would be a decrease in vascular tone and promotion of vasodilatation (3), but this is not the case in insulin-resistant states, as discussed in detail below.
|
Endothelin Levels in Insulin-Resistant States |
|---|
|
TopAbstractIntroductionExperimental Data on the...Human Studies on the...Endothelin Levels in Insulin...Involvement of Endothelin in...Thiazolidinediones and...Effects of Endothelin on...ConclusionsReferences |
|---|
In addition, in various conditions associated with IR, significant correlations between the basal levels of insulin and ET-1 have been reported (34, 38). In a study including 69 type 1 and 40 type 2 diabetic patients, in those subjects with detectable plasma levels of C-peptide, plasma ET-1 levels were correlated with both C-peptide concentration and the total daily dose of exogenous insulin (39). Finally, a recent study examined the associations of ET-1 and big endothelin with various anthropometric and metabolic indexes in healthy men with familiar predisposition for hypertension (40). Big endothelin is the 38-amino acid precursor of ET-1, converted to it either in or outside endothelial cells (5, 6). In this study, ET-1 levels were not related to BP but showed significant correlations with body mass index and fasting insulin, whereas large endothelin concentration (which is considered to reflect better ET-1 production than circulating ET-1) correlated with IR, estimated with the homeostasis model assessment index (40).
|
Involvement of Endothelin in Hypertension Development in Insulin-Resistant States |
|---|
|
TopAbstractIntroductionExperimental Data on the...Human Studies on the...Endothelin Levels in Insulin...Involvement of Endothelin in...Thiazolidinediones and...Effects of Endothelin on...ConclusionsReferences |
|---|
In various animal models of IR increase of ETA receptor along with respective elevation of ET-1 action on the vascular wall has been noted (16, 41). Verma et al. (42) observed that Sprague Dawley rats that became hypertensive after a high-fructose diet had higher plasma insulin levels and higher ET-1 concentration in the vascular wall than normal controls. Administration of a nonselective ET-1 receptor antagonist in these animals resulted in BP reduction, without affecting insulin and ET-1 levels. In another study, insulin caused vasodilatation of the mesenteric arteries of normal rats but not rats with IR. However, during simultaneous administration of a selective ETA-receptor antagonist, the vasodilatating response of the arteries was similar in insulin-resistant and normal rats. Thus, insulin-mediated ET-1 release can be responsible, at least in part, for the impaired vasodilatation in insulin-resistant states (43).
Eringa et al. (44) examined the effect of insulin in rat arterioles and observed that insulin alone did not affect their diameter. Simultaneous ET-1 receptor blockade resulted in vasodilatation, which stopped with additional inhibition of NO release. On the other hand, the administration of insulin with simultaneous blocking of NO release or inhibition of PI3-K, which mediates NO production from endothelial cells, led to vasoconstriction that was interrupted with ET-1 receptor blockade (44). These findings also support that impairment of PI3-K pathway in insulin-resistant states does not affect at all ET-1 release, which can promote vasoconstriction without being opposed. A more recent study of the same group (45) expanded these notions; insulin produced dose-dependent vasoconstriction of rat skeletal muscle arterioles during PI3-K inhibition with wortmannin. On the other hand, insulin-induced vasoconstriction was abolished by inhibition of ERK1/2, which is part of the MAPK pathway, with PD-98059, whereas inhibition of ERK1/2 without inhibition of PI3-kinase uncovered insulin-mediated vasodilatation. In addition, the investigators noted that removal of the arteriolar endothelium abolished insulin-induced vasoconstriction, whereas insulin was associated with increases in ERK1/2 activity in both cultured endothelial cells and skeletal muscle arterioles.
Potenza et al. (19) also added important information on this field by studying the effects of insulin on spontaneously hypertensive rats (SHR) that had higher BP and IR compared with control Wistar-Kyoto (WKY) rats. In ex vivo preparations, insulin-induced relaxation of mesenteric arteries precontracted with norepinephrine (that depended on intact endothelium and was blocked by inhibition of PI3-K or NO synthase) was 20% lower in SHR, compared with WKY. Furthermore, preincubation of arteries with insulin significantly reduced the contractile effect of norepinephrine by 20% in WKY but not SHR rats. This effect of insulin to reduce norepinephrine-mediated vasoconstriction in SHR was evident only when insulin pretreatment was accompanied by ET-1 receptor blockade or MAPK inhibition.
Overall, in normal individuals insulin stimulates the production of both ET-1 and NO from the vascular wall. Several studies have clearly shown that this insulin effect on NO release is severely impaired in subjects with IR (2, 3, 9). In contrast, according to the majority of data presented in this review, the physiological stimulatory effect of insulin on ET-1 (24, 27, 32) is preserved in insulin-resistant states (14, 19, 25, 26, 27, 43, 44). This directly relates to the fact that insulin-induced ET-1 release from endothelial cells is mediated from the MAPK intracellular pathway (19, 45), which is not affected in insulin-resistant states (22, 23), in contrast to the severe impairment of PI3-K pathway, which mediates NO release (9). Therefore, in the presence of IR an imbalance between the two basic actions of insulin on endothelial cells is apparent, a fact favoring the appearance of relative vasoconstriction (Fig. 1
).
|
Juan et al. (52) reported that rats made hyperinsulinemic with continuous infusion of recombinant human insulin with specific pumps, and gradually developed IR, IGT, and hypertension, had higher ET-1 levels in relation to control animals, which received a continuous saline infusion. Furthermore, hyperinsulinemic rats presented a similar degree of ET-1 binding to the vascular wall with controls, although they were expected to have lower due to the higher circulating ET-1 levels and the presence of hypertension. The investigators argued that this clearly suggests an important role of ET-1 in hypertension development in these animals (52). In a recent study, this group expanded their previous observations and clearly presented the contribution of insulin-mediated ET-1 production in BP elevation in insulin-resistant, hyperinsulinemic animals (53). In rats under continuous administration of either insulin or saline, the investigators performed daily ip infusions of either a selective ETA-receptor antagonist or saline, creating four groups of animals. The two hyperinsulinemic groups had higher ET-1 levels than the respective controls. However, the two groups receiving ip ETA-receptor antagonist had similar BP levels, whereas between those receiving ip saline, hyperinsulinemic rats have significantly higher BP levels than controls. These findings clearly show that insulin-mediated ET-1 release is particularly important in the preservation of the constrictive part of vessels’ response to insulin and thus development of hypertension in insulin-resistant states.
Human studies also provide evidence in favor of a possible contribution of increased ET-1 activity in abnormal vascular function and, presumably, hypertension in insulin-resistant states. Cardillo et al. (54) have shown that selective ETA-blockade in the forearm resulted in significant increase in FBF in patients with type 2 diabetes but not healthy individuals, whereas nonselective ETA/ETB blockade in diabetic patients did not significantly modify the effects of ETA antagonism. Similarly, ETA/ETB blockade produced a significant increase in FBF from baseline and a significant potentiation of endothelium-dependent vasodilatation in hypertensive patients but not controls (55). Thus, ET-1 activity is increased in type 2 diabetes and hypertension, compared with the healthy state. Although no measurements of IR took part in these studies to establish differences between hypertensive or diabetic patients and controls, it could be hypothesized that IR could be an underlying factor for this elevated ET-1 activity.
This hypothesis is supported from a very recent study on 20 clinically healthy subjects, which differed only in the level of IR (insulin-resistant subjects had on average less than half insulin sensitivity, compared with insulin-sensitive subjects) (56). Combined ETA/ETB blockade in the forearm circulation produced a significant increase in endothelium-dependent vasodilatation in insulin-resistant subjects without affecting it in insulin-sensitive ones. However, to clearly establish a role for IR/hyperinsulinemia in increased ET-1 activity and BP elevation in humans, more complicated experiments, similar to the aforementioned animal studies (53) are needed. Given the difficulties to obtain similar experimental conditions in human subjects as well as possible differences in ETA-ETB relations in humans, compared with those known from in vitro and animal studies, evident in the above studies, in which ETB-blockade did not counteract ETA-blockade (54, 55, 56), the clarification of these associations seems a rather difficult task, left for future research.
|
Thiazolidinediones and Endothelin |
|---|
|
TopAbstractIntroductionExperimental Data on the...Human Studies on the...Endothelin Levels in Insulin...Involvement of Endothelin in...Thiazolidinediones and...Effects of Endothelin on...ConclusionsReferences |
|---|
, which play an important role in adipocyte differentiation and lipid and carbohydrate metabolism (57, 59). Apart from their hypoglycemic properties, thiazolidinediones were shown to exert numerous other beneficial metabolic and cardiovascular effects (58).
A few studies have specifically investigated the effects of thiazolidinediones on endothelin production and levels. In vitro data clearly show that all thiazolidinedione compounds (troglitazone, rosiglitazone, and pioglitazone) reduce basal ET-1 secretion from endothelial cells (60, 61, 62). These agents were also shown to inhibit thrombin- and C-reactive protein-induced ET-1 endothelial production (63, 64). In ex vivo experiments in the mesenteric vasculature of hypertensive deoxycorticosterone acetate-salt rats, which overexpress ET-1, Iglarz et al. (65) showed that rosiglitazone abrogated the increase in ET-1 production along with prevention of hypertrophic vascular remodeling and hypertension progression. PPAR- activation with thiazolidinediones was also shown to decrease the expression of ET-1 mRNA in the left ventricle along with regression of left ventricular remodeling in animal models of cardiac hypertrophy (66, 67). In humans with type 2 diabetes and microalbuminuria, pioglitazone reduced by about 60% the urinary ET-1 excretion (68), a marker of ET-1 production at the kidney level, which is involved in the pathogenesis of diabetic nephropathy (69). Moreover, rosiglitazone was recently shown to decrease plasma ET-1 levels by 11% in patients with the metabolic syndrome. Of note, this change was an independent predictor of improved endothelial function observed with rosiglitazone (70). In some of the background studies, similar results on ET-1 were also obtained with PPAR-
activators (62, 63, 65, 67), which do not directly affect IR; thus, it is not clarified whether these effects on ET-1 are related universally to PPAR activation or solely to decrease of IR with PPAR- agonists. In any case, these early findings represent another part of the associations between IR and endothelin that must be further investigated.
|
Effects of Endothelin on Insulin Actions |
|---|
|
TopAbstractIntroductionExperimental Data on the...Human Studies on the...Endothelin Levels in Insulin...Involvement of Endothelin in...Thiazolidinediones and...Effects of Endothelin on...ConclusionsReferences |
|---|
|
Conclusions |
|---|
|
TopAbstractIntroductionExperimental Data on the...Human Studies on the...Endothelin Levels in Insulin...Involvement of Endothelin in...Thiazolidinediones and...Effects of Endothelin on...ConclusionsReferences |
|---|
|
Footnotes |
|---|
First Published Online November 21, 2006
Abbreviations: BP, Blood pressure; ET, endothelin; FBF, forearm blood flow; IGT, impaired glucose tolerance; IR, insulin resistance; IRS, insulin receptor substrate; NO, nitric oxide; PI3-K, phosphatidyloinositol 3-kinase; PPAR, peroxisome proliferator-activated receptor; SHR, spontaneously hypertensive rats; VSMC, vascular smooth muscle cell; WKY, Wistar-Kyoto.
Received August 18, 2006.
Accepted November 13, 2006.
|
References |
|---|
|
TopAbstractIntroductionExperimental Data on the...Human Studies on the...Endothelin Levels in Insulin...Involvement of Endothelin in...Thiazolidinediones and...Effects of Endothelin on...ConclusionsReferences |
|---|
agonists explaining a possible blood pressure lowering effect. Am J Hypertens 19:646–653[CrossRef][Medline]: a nuclear regulator of metabolism, differentiation, and cell growth. J Biol Chem 276:37731–37734 on vascular endothelial function. Biochem Biophys Res Commun 254:757–763[CrossRef][Medline] agonists, regulate endothelial cell growth and secretion of vasoactive peptides. Atherosclerosis 158:113–119[CrossRef][Medline] and - activators on vascular remodeling in endothelin-dependent hypertension. Arterioscler Thromb Vasc Biol 23:45–51 activators inhibit endothelin-1-related cardiac hypertrophy in rats. Clin Sci (Lond) 103(Suppl 48):16S–20S and receptor- activators prevent cardiac fibrosis in mineralocorticoid-dependent hypertension. Hypertension 42:737–743This article has been cited by other articles:
 |
|
 |
|
  V. van Harmelen, A. Eriksson, G. Astrom, K. Wahlen, E. Naslund, F. Karpe, K. Frayn, T. Olsson, J. Andersson, M. Ryden, et al. Vascular Peptide Endothelin-1 Links Fat Accumulation With Alterations of Visceral Adipocyte Lipolysis Diabetes, February 1, 2008; 57(2): 378 - 386. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Schindler Review: The metabolic syndrome as an endocrine disease: is there an effective pharmacotherapeutic strategy optimally targeting the pathogenesis? Therapeutic Advances in Cardiovascular Disease, October 1, 2007; 1(1): 7 - 26. [Abstract] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
