Number 22, 2004
Endothelial Dysfunction
Featured research
G972R IRS-1 variant impairs insulin regulation of endothelial nitric oxide synthase in cultured human endothelial cells
Federici M, Pandolfi A, De Filippis EA, et al. Circ Res. 2004;109:399405
Endothelial dysfunction ie, reduced nitric oxide availability, a pivotal step in the pathogenesis of atherosclerosis is a feature of insulin-resistant states such as type 2 diabetes, obesity, and hypertension. Impaired insulin-mediated vasodilation might contribute to vascular damage in insulin-resistant states. The aim of this work was to investigate insulin regulation of nitric oxide synthesis in human umbilical vein endothelial cells (HUVECs) carrying an insulin receptor substrate-1 (IRS-1) gene variant known to be associated with impaired activation of insulin signaling downstream of IRS in transfected cells. The results demonstrate that genetic impairment of the IRS-1/phosphatidylinositol 3-kinase [PI(3)K])/phosphoinositide-dependent protein kinase-1 (PDK-1)/Akt (also known as protein kinase B) insulin signaling cascade determines impaired insulin-stimulated nitric oxide release. They also suggest that the G972R-IRS-1 gene polymorphism, through a direct impairment of Akt/endothelial nitric oxide synthase (eNOS) activation in endothelial cells, may contribute to the genetic predisposition to develop endothelial dysfunction and cardiovascular disease.
Commentary
Insulin resistance is associated with atherosclerosis and coronary artery disease. Both the metabolic alterations occurring in the insulin resistant state and the possible detrimental effects of hyperinsulinemia have been proposed to explain this association. Insulin promotes vasodilation and increases blood flow, thus participating in the regulation of hemodynamic homeostasis. Insulin signaling is mediated by complex multiple cascade pathways characterized by spatial and temporal features. It is initiated by its binding to the insulin receptor. This activates the tyrosine kinase activity of the receptor, leading to its autophosphorylation and to the subsequent phosphorylation of IRS-1. IRS-1 phosphorylation leads to interaction of IRS-1 with the PI(3)K p85 regulatory subunit. PI(3)K then produces phosphatidylinositol 3,4,5-P3 and 3,4-P2, which bind to the pleckstrin homology domain of at least two different protein kinases, namely PDK-1 and Akt (protein kinase B). It has been demonstrated that IRS-1 and PDK-1 are required for the insulin-stimulated production of nitric oxide in endothelial cells. The authors in the present work used HUVECs from carriers of the IRS-1 gene G972R variant to determine whether a polymorphism known to impair insulin action might reduce the ability of insulin to activate the signaling pathway that regulates the activity and expression of eNOS. In HUVECs naturally expressing the G972R-IRS-1 variant, they observed cell-specific impairment of insulin action, as revealed by defective insulin-stimulated activation and expression of eNOS. In the cells carrying this G972R-IRS-1 variant, the IRS-1/ PI(3)K/PDK-1/Akt insulin signaling cascade was impaired, as manifested by reduced IRS-1-associated PI(3)K activity and reduced insulin-stimulated Akt phosphorylation. This resulted in both insulin-stimulated expression of eNOS and impaired activation of eNOS. The results demonstrate a potential mechanism by which insulin resistance can be involved in vascular dysfunction and hence abnormalities. These data might have relevant clinical implications. Previous studies have indeed shown that the frequency of the G972R-IRS-1 polymorphism is significantly greater in patients with angiographic evidence of coronary artery disease than in control individuals. When adjusted for other risk factors, the relative risk of coronary artery disease associated with the G972R-IRS-1 polymorphism was 2.93-fold greater than that in wild-type individuals, and it increased to 6.97-fold in obese individuals and to 27.3-fold in those with clinical features of insulin resistance syndrome [1].
REFERENCES
1. Baroni MG, D'Andrea MP, Montali A, et al.
A common mutation of the insulin receptor substrate-1 gene is a risk factor for coronary artery disease.
Arterioscler Thromb Vasc Biol. 1999;19:29752980.
PMID: 10591678 [PubMed - indexed for MEDLINE]
Danielle Feuvray
Seven-year outcome in the RITA-2 Trial: coronary angioplasty versus medical therapy
J Am Coll Cardiol. 2003;42:11611170
Advances in medical therapy for the treatment of stable angina have, in the past 10 to 15 years, been of substantial importance. If, on diagnosis we utilize all the evidence-based treatments statins, aspirin, -blockers and angiotensin-converting enzyme inhibitors there is a potential 75% reduction in risk for significant cardiac events for at least 5 years. Often overlooked is the low event rate in patients with stable angina, for whom there is a death or nonfatal myocardial infarction rate of 23% per year. This means that, with improving medical therapy, there is time to optimize management medically, assess the patient for risk by means of exercise electrocardiography and echocardiography, and then, in those not at risk, decide on conservative or interventional treatment on the basis of symptoms and quality of life. The medical control of symptoms should include conventional hemodynamic agents, in addition to the metabolic approach using trimetazidine.
The findings of the Randomised Intervention Treatment of Angina-2 Trial confirm the importance of medical treatment albeit suboptimal by today's standards. It was a randomized trial of patients with stable angina, comparing medical treatment (n=514) with coronary angioplasty (n=504). Both arms can be criticized for low use of both statins and stents, reflecting the era when the trial commenced; however, bearing in mind that caveat, the results are of great interest. At 7 years follow-up, death or myocardial infarction had occurred in 73 (14.5%) of the patients who underwent percutaneous transluminal coronary angioplasty and in 63 (12.3%) of those who received medical treatment, with 43 deaths in each group, only 41% of which were cardiac-related. Once again, the low overall event rate has thus been confirmed and the importance of treating the patient, not just the anatomy, clearly emphasized. With no evidence that coronary angioplasty, with or without a stent, reduces myocardial infarction or death rates, the role of percutaneous coronary intervention in patients with stable angina is that of symptom relief. Mortality rates are related to baseline risk, which can be defined by noninvasive screening. Symptom relief is related to the optimal use of medical treatment and adequate dose titration of hemodynamic agents (eg, -blockers), combined with metabolic therapy such as trimetazidine. Medical treatment can be safely given time to be effective and, if symptoms persist, intervention is then recommended.
Graham Jackson
Arterial stiffness, wave reflections, and the risk of coronary artery disease
Circulation. 2004;109:184189
Increased arterial stiffness, determined invasively, has been shown to predict a higher risk of coronary atherosclerosis. However, invasive techniques are of limited value for screening and risk stratification in larger patient groups. We prospectively enrolled 465 consecutive, symptomatic men undergoing coronary angioplasty for the assessment of suspected coronary artery disease. Arterial stiffness and wave reflections were quantified noninvasively using applanation tonometry of the radial artery with a validated transfer function to generate the corresponding ascending aortic pressure waveform. Augmented pressure (AP) was defined as the difference between the second and the first systolic peak, and augmentation index (AIx) was AP expressed as a percentage of the pulse pressure. In univariate analysis, a higher AIx was associated with an increased risk for coronary artery disease (odds ratio [OR], 4.06 for the difference between the first and the fourth quartile [1.72 to 9.57; P <0.01]). In multivariate analysis, after controlling for age, height, presence of hypertension, high-density lipoprotein cholesterol, and medications, the association with coronary artery disease risk remained significant (OR, 6.91; P <0.05). The results were exclusively driven by an increase in risk with premature vessel stiffening in the younger patient group (up to 60 years of age), with an unadjusted OR between AIx quartiles I and IV of 8.25 (P <0.01) and a multiple-adjusted OR between these quartiles of 16.81 (P <0.05). We conclude that AIx and AP, noninvasively determined manifestations of arterial stiffening and increased wave reflections, are strong, independent risk markers for premature coronary artery disease.
Commentary
The reflection of pressure waves from the peripheral circulation back towards the aorta modulates the shape of the central aortic pressure waveform. The stiffer the aorta and large arteries, the greater the velocity at which the pressure wave travels, both anterograde and retrograde, and hence the earlier during systole the returning wave reaches the aorta. In addition, the stiffness of the small to medium-sized muscular arteries determines the total amount of reflection. Thus a large premature reflected wave suggests that the aorta and large arteries are stiff, whereas the small and medium-sized arteries have high vascular tone. The central aortic waveform can therefore be used as a global measure of large- and small-vessel health. The central aortic pressure can only be measured directly, invasively. However, the waveform can be derived by transforming the shape of the peripheral pulse pressure, which in turn can be derived by applanation tonometry.
Weber and colleagues used applanation tonometry and standard measures that combine reflected pulse wave amplitude and prematurity to determine prospectively the arterial stiffness in male patients undergoing diagnostic coronary angiography. Of the 465 patients examined, 59 did not have coronary artery disease. This group were significantly younger and taller, and had a lower prevalence of hypertension and antihypertensive medication. Surprisingly, on treatment, there was little difference in systolic blood pressure between groups, but diastolic pressure was greater and thus pulse pressure lower in those without coronary artery disease. The most persuasive finding was that, even when these factors where controlled by multivariate analysis, early and large pulse wave reflection predicted the presence of coronary artery disease. This was most obvious in patients younger than 60 years, 43% of whom in the lower quartile of measures of early reflection had normal coronary arteries, compared with just 8% in the upper quartile. Furthermore, it is likely that applanation tonometry would have been even more highly discriminatory if it were not for the fact that there was a greater prevalence of use of nitrate and angiotensin-converting enzyme inhibitors in those patients with coronary artery disease. These medications reduce both pulse wave velocity and reflected amplitude. The findings reinforce those from other studies that suggest pulse wave reflection is a useful noninvasive measure of vascular disease.
M. Marber
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