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Symposium Reports |
1 Cardiovascular and Diabetes Research, The Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, UK 2 Kings College London, London, UK
Abstract
Type 2 diabetes and obesity are major risk factors for the development of cardiovascular atherosclerosis. Resistance to the metabolic effects of insulin on its traditional target tissues (muscle, liver and adipose tissue) is a central pathogenic feature of these disorders. However, the role of insulin resistance in non-canonical tissues, such as the endothelium, is less clear. Several large studies support a role for insulin resistance in the development of premature cardiovascular atherosclerosis independent of type 2 diabetes and obesity. A key step in the initiation and progression of atherosclerosis is a reduction in the bioactivity of endothelial cell-derived nitric oxide. Nitric oxide is a signalling molecule which has a portfolio of potential antiatherosclerotic effects. The presence of insulin receptors on endothelial cells is well documented, and the endothelium has now emerged as a potentially important target tissue for insulin, with insulin-stimulated production of nitric oxide a feature of the action of insulin on endothelial cells. The role of insulin resistance at the level of the endothelial cell in vascular pathophysiology is unclear. A number of studies in humans and gene-modified mice have demonstrated a close association between insulin resistance and nitric oxide bioactivity. In this review, we discuss the link between insulin resistance and endothelial cell function in humans and demonstrate the complimentary information provided by murine models of obesity and insulin resistance in our understanding of the vasculopathy associated with type 2 diabetes and obesity.
(Received 22 June 2007;
accepted after revision 21 September 2007; first published online 12 October 2007)
Corresponding author M. T. Kearney: Cardiovascular and Diabetes Research, The Leeds Institute of Genetics, Health and Therapeutics, The LIGHT Laboratories, Clarendon Way, University of Leeds, Leeds LS2 9JT, UK. Email: m.t.kearney{at}leeds.ac.uk
Background
Type 2 diabetes (Cubbon et al. 2007) and obesity (Hubert et al. 1983) are major risk factors for the development of cardiovascular atherosclerosis and its complications. Resistance to the metabolic effects of insulin on its traditional target tissues (muscle, liver and adipose tissue) is a hallmark and key pathophysiological feature of these disorders. Several large studies support a role for global (whole-body) insulin resistance in the development of premature cardiovascular atherosclerosis independent of type 2 diabetes and obesity (Pyörälä et al. 2000). However, the role of insulin resistance in non-canonical tissues, such as the endothelium, is less clear. A key step in the initiation and progression of atherosclerosis is a reduction in the bioactivity of endothelial cell-derived nitric oxide (NO). Nitric oxide O is a signalling molecule which has a portfolio of potential antiatherosclerotic effects (Wheatcroft et al. 2003b). The presence of insulin receptors on endothelial cells is well documented, and the endothelium has now emerged as a potentially important target tissue for insulin. Seminal studies from the laboratories of Alain Baron (Steinberg et al. 1996) and Michael Quon (Zeng & Quon, 1996; Zeng et al. 2000; Montagnani et al. 2002) have identified insulin-stimulated production of NO from the endothelium as a potentially important physiological effect of insulin.
The role of insulin resistance at the level of the endothelial cell in vascular pathophysiology is unclear. A number of studies in humans and gene-modified mice have demonstrated a close association between insulin resistance and NO bioactivity. In this review, we discuss the link between insulin resistance and endothelial cell function in humans and demonstrate the complimentary information provided by murine models of obesity and insulin resistance in our understanding of the vasculopathy associated with type 2 diabetes and obesity.
Nitric oxide bioavailability and accelerated atherosclerosis
Compelling evidence supports endothelial dysfunction as a key early event in the pathogenesis of atherosclerosis (Ross, 1999). The term ‘endothelial dysfunction’ encompasses a range of abnormalities, the most extensively studied being a reduction in the bioavailability of NO. Nitric oxide is an antiatherosclerotic signalling molecule released by many cells, including the vascular endothelium. Nitric oxide has potent vasodilator (Creager et al. 1990), anti-inflammatory (Kataoka et al. 2002), antiproliferative (Tanner et al. 2000), antioxidant (Clapp et al. 2004) and antiplatelet effects (Schäfer et al. 2004). A reduction in NO bioavailability is present in atherosclerotic vessels before vascular structural changes occur. Consonant with this, longitudinal studies have shown that impaired NO-dependent vasodilatation is a predictor of future cardiac events (Schachinger et al. 2000) and the development of coronary artery atherosclerosis (Bugiardini et al. 2004).
Determinants of nitric oxide bioavailability
Nitric oxide is generated by a family of nitric oxide synthases (NOSs) from L-arginine in a reaction that requires oxygen, NADPH and the essential cofactors tetrahydrobiopterin (BH4), flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN). Nitric oxide production and bioavailability are regulated/dysregulated at several levels (see Fig. 1).
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(2) Abnormalities of agonist-mediated NO release. The activation of eNOS occurs through a number of distinct intracellular signalling pathways, which may be affected in disease states. In very early atherosclerosis, there is reduced responsiveness to receptor-dependent stimuli, such as acetylcholine, whereas responsiveness to receptor-independent stimuli, such as the calcium ionophore A23187 [GenBank] , is unchanged (Flavahan, 1992). These data indicate that in this setting there is blunting of NO production in response to extracellular stimuli, whereas eNOS expression and potential maximal activation are unaffected.
(3) Calcium-dependent and -independent eNOS activation. Classical activation of eNOS (e.g. by acetylcholine) involves a rise in intracellular Ca2+ and binding of Ca2+–calmodulin to the enzyme. Recently, a Ca2+-independent regulatory pathway for eNOS has been described (Dimmeler et al. 1999), which may be of particular relevance to obesity. Both shear stress and agonists, such as insulin, have been shown to increase endothelial NO production via the activation of phosphatidylinositol 3-kinase (PI3K) and protein kinase B (PKB/Akt), which phosphorylates eNOS.
(4) Inactivation of NO by reactive oxygen species (ROS). The evidence that production of ROS such as superoxide within the vascular wall plays an important role in the development of endothelial dysfunction is compelling (Cai & Harrison, 2000). Superoxide leads to endothelial and vascular dysfunction in several ways, as follows: (a) it reacts rapidly with NO to inactivate it (White et al. 1994); (b) the reaction between NO and superoxide produces peroxynitrite, which may itself exert toxic effects through protein nitrosylation (Harrison, 1997); and (c) species such as H2O2 and peroxynitrite (and the loss of NO) may activate redox signalling cascades that induce deleterious changes in endothelial cell phenotype. In a murine model of obesity (without diabetes), we demonstrated that although basal ROS production in aortae is similar in lean and obese mice, there is a substantial release of H2O2 in response to acetylcholine (Noronha et al. 2005). There are several potential sources of ROS in the vascular wall, such as xanthine oxidase, mitochondria, dysfunctional NOSs and the phagocyte-type NADPH oxidase(s) that has recently emerged as a major source of superoxide in the vasculature (Li & Shah, 2004) and in adipose tissue of obese mice (Furukawa et al. 2004).
(5) Alteration of tetrahydrobiopterin (BH4) availability. Tetrahydrobiopterin is a critical cofactor for eNOS activation. The rate-limiting enzyme in BH4 biosynthesis is GTP cyclohydrolase 1 (GTPCH1). Importantly, in the setting of BH4 deficiency, eNOS can generate superoxide rather than NO (Alp & Channon, 2004). Furthermore, BH4 itself is rapidly degraded by ROS such as superoxide, so that a vicious cycle can ensue whereby oxidative stress worsens BH4 deficiency. Recent data have shown that BH4 deficiency is an important mechanism for endothelial dysfunction, and that the administration of BH4 (or sepiapterin, which increases BH4 production) can improve endothelial function in fructose-fed diabetic rats (Shinozaki et al. 2000). However, its role in insulin resistance and obesity is unclear. There is some evidence to support a role for insulin in upregulation of GTPCH1 activity, an effect blocked by wortmannin (Ishi et al. 2001). The effect of changes in insulin signalling on GTPCH1 activity is incompletely explored in in vivo models. Recent studies of mice with endothelial cell-specific overexpression of GTPCH1 demonstrated that these mice had enhanced eNOS activity and were protected against endothelial dysfunction in a model of (insulin deficient) type 1 diabetes (Alp et al. 2003)
Effect of insulin on endothelial cell nitric oxide release
The presence of insulin receptors on endothelial cells is well documented (Zeng & Quon, 1996). It has been suggested that insulin-mediated vasodilatation contributes to glucose uptake by increasing delivery to skeletal muscle (Steinberg et al. 1996), although this is controversial (Laine et al. 1998). It has been shown that eNOS may be activated in a calcium-independent fashion by insulin (for review see Wheatcroft et al. 2003b). In a series of in vitro studies, Quon and co-workers dissected the pathway by which insulin stimulates NO release from endothelial cells in vitro (Montagnani et al. 2002). They first demonstrated that insulin stimulates NO production from human umbilical vein endothelial cells (HUVECs). The effect of insulin to stimulate NO production was blunted by the non-selective NOS inhibitor NG-monomethyl-L-arginine, the phosphatidylinositol 3-kinase inhibitor wortmannin and the tyrosine kinase inhibitor genestein (Zeng & Quon, 1996). These data support important roles for eNOS, PI3K and the insulin receptor tyrosine kinase, respectively, in insulin-mediated NO release. In addition to this, Kuboki et al. (2000) demonstrated that insulin regulates eNOS transcription in endothelial cells. Of relevance to these studies, Federici et al. (2004) showed that HUVECs from subjects with the GR927R IRS-1 variant (which is known to lead to impaired activation of PI3K) exhibit impaired eNOS activation and expression. Consistent with these findings, we have demonstrated that insulin has a significant vasodepressor action in vivo in healthy young (Kearney et al. 1996) and elderly humans (Kearney et al. 1998). In mice, we have shown insulin-mediated vasorelaxation to be endothelium and NO dependent (Wheatcroft et al. 2004). In a murine model, we have shown that hyperinsulinaemia with intact insulin signalling leads to increased eNOS expression, increased basal vascular NO production and a reduction in blood pressure (Wheatcroft et al. 2003a). Thus, insulin in the presence of intact signalling would appear to have beneficial effects on endothelial function.
Obesity, insulin resistance and reduced nitric oxide bioavailability: studies in humans
Obesity is characterized by reduced NO bioavailability (see Williams et al. 2002 for review), providing at least one putative mechanistic link with future atherosclerosis. In obese non-diabetic humans, Steinberg et al. (1996) demonstrated that the increase in blood flow into the leg in response to methacholine, an endothelium-dependent muscarinic agonist, is blunted, with the abnormality being proportional to the degree of obesity. Consonant with this, Laine et al. (1998) showed that the ED50 for bradykinin to increase leg blood flow is double in obese subjects compared with lean subjects. Nitric oxide production in response to Ca2+-independent stimuli is also abnormal in obese humans. Arcaro et al. (1999) showed that the blood flow response to shear stress is blunted in obese subjects. Likewise, Tack et al. (1998) demonstrated that the forearm vasodilator response to insulin is blunted, and Westerbacka et al. (1999) confirmed a similar response in large vessels. In otherwise healthy subjects, we have shown that obesity is characterized by abnormalities of metabolic and blood pressure homeostasis, heightened systemic inflammation, insulin resistance and significant impairment of shear stress-induced changes in forearm conduit artery blood flow (Williams et al. 2005). We correlated endothelial function with these abnormalities and found that blood pressure, inflammatory markers, serum insulin and lipids were all negative correlates of impaired endothelial function (Williams et al. 2006); a finding that illustrates the complexity of the potential mechanisms of endothelial dysfunction in obese humans. To explore the relationship between body fat and endothelial function in patients with coronary artery disease, we measured vasorelaxation responses to acetylcholine in saphenous vein rings ex vivo. In 77 patients with optimal blood pressure and cholesterol levels, waist and body mass index were significant negative correlates of maximal relaxation in response to acetylcholine (Momin et al. 2007).
In non-diabetic but insulin-resistant young Asian men, we recently demonstrated a reduction in basal production of NO in resistance vessels and blunted vasodilatation in response to shear stress in conduit arteries (Murphy et al. 2007). Interestingly, this reduction in NO bioavailability was associated with a reduction in the number and function of circulating endothelial progenitor cells. These cells are thought to be important in repair/replacement of dysfunctional endothelium (Urbich & Dimmeler, 2004).
Animal models of obesity and insulin resistance
Endothelial dysfunction has also been demonstrated in several animal models of obesity/insulin resistance. Winters et al. (2000) demonstrated blunting of the vasorelaxant effect of acetylcholine in aortic rings of leptin-deficient ob/ob mice. In Zucker fatty rats, endothelial dysfunction and blunting of insulin-mediated activation of eNOS (Walker et al. 1999) has been demonstrated. More recently, we also demonstrated that both insulin- and acetylcholine-mediated NO release are blunted in a feeding model of obesity in mice (Noronha et al. 2005).
Since hyperinsulinaemia apparently does not lead to endothelial dysfunction (at least in the models we have studied; Wheatcroft et al. 2003a), we investigated the role of impaired insulin signalling in the pathogenesis of endothelial dysfunction. Reduced expression of the insulin receptor and downstream signalling molecules has been demonstrated in obese humans (Goodyear et al. 1995) and rodents (Youngren et al. 2001). To explore the effect of abnormal insulin signalling on endothelial function and vascular homeostasis (independent of changes in adiposity), we examined the effect of a knockout for the insulin receptor (IRKO) on vascular homeostasis. These mice provide a useful model of the human condition, with mild whole-body insulin resistance. It has been suggested that before the onset of overt diabetes there is a long period of insulin resistance (Haffner et al. 1990) that leads to endothelial dysfunction and an increased risk of atherosclerosis.
We explored this possibility in mice heterozygous for a knockout for the insulin receptor (Wheatcroft et al. 2004). We demonstrated that male mice heterozygous for a knockout for the insulin receptor (IRKO) aged 2 months have reduced basal and insulin-stimulated production of NO but have preserved acetylcholine-mediated NO release. At 6 months of age, male IRKO mice had similar metabolic dysregulation to 2-month-old mice but had substantial blunting of acetylcholine-mediated vasorelaxation (IRKO Emax (effective concentration to achieve maximum effect) 66 ± 5% versus wild-type 87 ± 4%, P < 0.01). We demonstrated that this is at least in part due to increased endothelial cell ROS production. We demonstrated increased ROS production using a number of complimentary approaches, as follows. (a) Acetylcholine-mediated vasorelaxation was restored by the superoxide dismutase mimetic Mn(III) tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride (MnTMPyP) (Emax to acetylcholine with MnTMPyP 85 ± 5%). (b) Using aortic sections, we demonstrated increased superoxide production using dihydroethidium (DHE) staining (174 ± 15 versus 140 ± 18 units of fluorescence, P < 0.05). (c) In coronary microvascular endothelial cells isolated from wild-type and IRKO mice, we demonstrated increased ROS using fluorescence activated cell sorting (FACS) analysis. (d) In isolated coronary microvascular endothelial cells, we demonstrated increased ROS using lucigenin-enhanced chemiluminescence (Duncan et al. 2006).
While these data demonstrate an association between insulin resistance at a whole-body level and reduced NO bioavailability, the effect of cell-specific insulin resistance on NO bioavailability and the pathophysiology of atherosclerosis remain unclear (Semenkovich, 2007). For instance, two recent publications produced conflicting results regarding the effect of macrophage-specific insulin resistance on the development of atherosclerosis in murine models. The first report suggested that macrophage-specific insulin resistance protected against the development of atherosclerosis (Baumgartl et al. 2006). The second produced results suggesting that macrophage-specific insulin resistance led to the development of more complex atherosclerotic plaques (Han et al. 2006). The recent publication of details regarding mice with endothelial cell-specific deficiency of the insulin receptor did not provide data on NO bioavailability or the development of atherosclerosis (Vicent et al. 2003). Future studies using different models of both gain and loss of insulin action in the endothelial cell are required to address this question.
Conclusion
There is now compelling evidence supporting a strong association between insulin resistance and a reduction in endothelial cell-derived nitric oxide. It appears that this results from both increased production of reactive oxygen species and diminished eNOS-derived NO biosynthesis in response to insulin and other physiological stimuli. The exact effect of endothelial cell-specific insulin resistance on the biology of the vascular wall warrants future studies.
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Acknowledgements
The studies from the author's laboratory were funded by The British Heart Foundation.
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