Potentiation of Vasculopathy by Insulin
1996; Lippincott Williams & Wilkins; Volume: 93; Issue: 9 Linguagem: Inglês
10.1161/01.cir.93.9.1613
ISSN1524-4539
Autores Tópico(s)Apelin-related biomedical research
ResumoHomeCirculationVol. 93, No. 9Potentiation of Vasculopathy by Insulin Free AccessResearch ArticleDownload EPUBAboutView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticleDownload EPUBPotentiation of Vasculopathy by Insulin Implications From an NHLBI Clinical Alert Burton E. Sobel Burton E. SobelBurton E. Sobel From the Medical Center Hospital of Vermont, Burlington. Originally published1 May 1996https://doi.org/10.1161/01.CIR.93.9.1613Circulation. 1996;93:1613–1615Clinical alerts (safety bulletins) emanating from data monitoring and policy boards of large-scale clinical trials are both hallmarks and progenitors of progress. A recent clinical alert from the National Heart, Lung, and Blood Institute based on experience in the Bypass Angioplasty Revascularization Investigation (BARI) multicenter, international, randomized patient assignment trial is a cogent example.1 The trial compares two possible initial revascularization procedures for patients with multivessel coronary artery disease: (1) coronary artery bypass graft surgery (CABG) and (2) angioplasty (percutaneous transluminal coronary angioplasty [PTCA]). The observation that gave rise to the clinical alert was that for patients with type I or type II diabetes mellitus who were being treated with oral hypoglycemic agents or insulin, the 5-year mortality rate was 35% after initial revascularization with PTCA, significantly greater than the 19% mortality for patients treated with CABG, even though the angioplasties themselves were not unsuccessful or associated with undue complications. Mortality in both groups was considerably greater than the 9% mortality associated with PTCA and with CABG in nondiabetic patients and in diabetic patients not being treated with insulin or oral hypoglycemic agents. The clinical alert concluded that "BARI's results indicate that CABG should be the preferred treatment for patients with diabetes on drug or insulin therapy who have multivessel coronary artery disease and need a first coronary revascularization."1 The implications are intriguing.The BARI observations imply that in patients with diabetes mellitus in whom exogenous insulin is being given or in whom endogenous insulin is high (in view of the insulin resistance associated with type II diabetes mellitus and the stimulation of pancreatic β-cells resulting from the use of oral hypoglycemic agents), progression of vascular disease after surgery or PTCA is accelerated compared with that in nondiabetic patients or in diabetic patients who are not being treated with drugs. Furthermore, deterioration after PTCA by far exceeds that after surgery. Thus, the response of an "injured" vessel (ie, one subjected to angioplasty) appears to be particularly adverse.If, in fact, the high mortality after CABG reflects a negative impact of diabetes on native coronary arteries that have not been subjected to trauma and the much higher 5-year mortality after PTCA reflects the adverse response in injured vessels, the BARI results would be consistent with deleterious direct effects of insulin or its precursors on vessel walls, particularly evident after local trauma.In the context of much recent research, the BARI observations implicate direct, adverse effects on vessel walls of insulin, proinsulin, and other precursors (referred to here in the aggregate as dysinsulinemia) in the pathogenesis of macroangiopathy. Thus, they imply that "anti-insulin" strategies targeting elaboration of insulin, the insulin receptor, or intracellular signaling in response to insulin may be helpful in retarding vasculopathy, particularly in patients with type II diabetes and other insulin-resistant states.Fibrinolysis and AtherogenesisBoth the fibrinolytic system in blood and its counterpart in the walls of vessels (referred to here as the proteo[fibrino]lytic system) have been implicated as pathogenetic factors in the increased cardiovascular risk and macroangiopathy associated with hyper(pro)insulinemia in patients with type II, non–insulin-dependent diabetes mellitus (Table) (reviewed in Reference 22 ). Impairment of fibrinolysis in blood may exacerbate atherogenesis by predisposing to thrombosis and hence bombarding luminal surfaces of vessels with mitogens from microthrombi likely to be present more often or for longer intervals, as judged from elevated thrombin activity in vivo in patients with diabetes.3 Impaired fibrinolysis in blood attributable to increased plasma concentrations of plasminogen activator inhibitor type 1 (PAI-1)4567 has been associated with dysinsulinemia. Perhaps of even greater importance, insulin and its precursors directly increase synthesis of PAI-1 not only in human hepatoma cells but also in vessel walls and endothelial cells.89 Infusion of proinsulin in vivo, as well as insulin itself, increases PAI-1 in blood in laboratory animals and increases expression of PAI-1 mRNA in vessel walls.10 Thus, insulin-induced effects on the fibrinolytic system in blood may be paralleled by more pathogenetically important effects on the proteo(fibrino)lytic system within vessel walls mediating direct and adverse effects of insulin on vessels predisposing to the accelerated vasculopathy after PTCA identified in patients with dysinsulinemia in the BARI trial.Several observations imply that among the many possible systems involved in mediating direct adverse effects of insulin on the vessel wall, the proteo(fibrino)lytic system is a probable contributor. These observations include the following.1. Induction of vasculopathy by diverse means, including exposure of luminal surfaces to an angioplasty balloon, hypercholesterolemia, or a thrombus,111213 in animals is associated with increased vascular wall expression of PAI-1 protein and PAI-1 mRNA.2. Atherosclerotic vessels in human beings exhibit increased expression of vessel wall PAI-1.141516173. Decreased proteo(fibrino)lytic system activity within vessel walls is likely to cause accumulation of extracellular matrix (ECM). Accumulation of ECM may provide a scaffold and a potential stimulus for vascular smooth muscle cell migration and proliferation typical of formation of neointima. The reason why inhibition of vessel wall proteo(fibrino)lysis may predispose to accumulation of ECM is that matrix protein degradation is mediated primarily by metalloproteinases within the vessel wall—enzymes that exist as zymogens and are converted to active enzymes by plasmin evolved by activation of plasminogen by plasminogen activators within the vessel wall.1819 Accordingly, decreased activation of plasminogen associated with inhibition of the proteo(fibrino)lytic system within the vessel wall is likely to be associated with decreased activity of metalloproteinases and hence decreased degradation and increased accumulation of ECM.4. Insulin and proinsulin in vivo increase PAI-1 protein and mRNA expression in vessel walls in experimental animals.10Lessons From the BARI Clinical AlertThe BARI observations demonstrate that coronary disease after PTCA is markedly accelerated when diabetes is associated with dysinsulinemia. The acceleration is particularly evident after PTCA compared with the population as a whole and compared with that after CABG in diabetic patients treated with insulin or oral hypoglycemic agents. A tenable hypothesis consistent with these results is that diabetic patients have an increased risk of progression of coronary disease in native vessels in the absence of trauma that accounts for the substantially higher mortality they experience after CABG compared with that in nondiabetic patients (their initial surgery is no more complicated, and thrombotic graft occlusion is no more frequent). By contrast, the disparity between mortality after PTCA compared with that after CABG in the insulin- or hypoglycemic agent–treated diabetic patients (almost twofold greater mortality) and the lack of such a disparity in outcomes after the two interventions in nondiabetic subjects are consistent with increased vulnerability of vessels subjected to angioplasty (injury) to accelerated progression of vascular disease initiated by the injury (again, not associated with an increased incidence of early complications or thrombotic occlusion at the time of the intervention).Viewed from one perspective, the BARI results mandate caution in selecting angioplasty as a primary treatment modality for patients with occlusive coronary artery disease and diabetes requiring drug treatment, despite the potentially favorable impact of advances in the field, including the development of stents. In addition, however, they strongly suggest that dysinsulinemia exerts direct, deleterious effects on vessels, which underlies the high mortality after PTCA. This view is consistent with observations many years ago implicating oral hypoglycemic agents in increased cardiovascular mortality despite their beneficial effects on the deranged carbohydrate metabolism in patients with type II diabetes.20Derangements in the vascular intramural proteo(fibrino)lytic system secondary to increased PAI-1 within the vessel wall itself are likely to be among the many factors that may mediate adverse effects of insulin or proinsulin on vessel walls.Elimination of the adverse effects of dysinsulinemia on vessel walls predicated on identification of the specific cellular and molecular biological mechanisms responsible may improve prevention of or retard vasculopathy in patients with type II diabetes and in other subjects with insulin-resistant states. The BARI clinical alert will undoubtedly stimulate research designed to elucidate mechanisms by which dysinsulinemia may adversely affect vessel walls. The mechanisms delineated should be useful targets for attenuating development of vasculopathy in diverse insulin-resistant states and perhaps ultimately for enhancing the long-term efficacy of angioplasty and related interventions when dysinsulinemia is present.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. Table 1. Adverse Effects on the Balance Between Thrombosis and Fibrinolysis Implicated in Patients With DiabetesFactors predisposing to thrombosisPlatelet hyperaggregabilityDecreased platelet cAMPDecreased platelet cGMPIncreased thromboxane synthesisElevated concentrations of procoagulantsIncreased fibrinogenIncreased von Willebrand factor procoagulant activityIncreased thrombin activity (suggested by increased fibrinopeptide A)Decreased concentration and activity of antithrombotic factorsDiminished activity of antithrombin IIIDiminished sulfation of endogenous heparinFactors attenuating fibrinolysisDecreased tissue-type plasminogen activator and activityIncreased plasminogen activator inhibitor type 1 synthesis activity (directly increased by insulin and insulin-like growth factorDecreased concentrations of α2-antiplasminFootnotesCorrespondence to Burton E. Sobel, MD, Department of Medicine, Medical Center Hospital of Vermont, Fletcher House 311, Burlington, VT 05401. References 1 Clinical Alert From the National Heart, Lung, and Blood Institute, National Institutes of Health, Bypass Over Angioplasty for Patients With Diabetes. September 21, 1995. Google Scholar2 Schneider DJ, Sobel BE. Effect of diabetes on the coagulation and fibrinolytic systems and its implications for atherogenesis. Coron Artery Dis.1992; 3:26-32. CrossrefGoogle Scholar3 Marongiu F, Conti M, Mameli G, Sorano GG, Cossu E, Cirillo R, Balestrieri A. Is the imbalance between thrombin and plasmin activity in diabetes related to the behaviour of antiplasmin activity? Thromb Res.1990; 58:91-99. CrossrefMedlineGoogle Scholar4 Vague P, Juhan-Vague I, Aillaud MF, Badier C, Viard R, Alessi MC, Collen D. Correlation between blood fibrinolytic activity, plasminogen activator inhibitor level, plasma insulin level and relative body weight in normal and obese subjects. Metabolism.1986; 35:250-253. CrossrefMedlineGoogle Scholar5 McGill JB, Schneider DJ, Arfken CL, Lucore CL, Sobel BE. Factors responsible for impaired fibrinolysis in obese subjects and NIDDM patients. Diabetes.1994; 43:104-109. CrossrefMedlineGoogle Scholar6 Auwerx J, Bouillon R, Collen D, Geboers J. Tissue-type plasminogen activator antigen and plasminogen activator inhibitor in diabetes mellitus. Arteriosclerosis.1988; 8:68-72. LinkGoogle Scholar7 Juhan-Vague I, Vague P, Alessi MC, Badier C, Valadier J, Aillaud MF, Atlan C. Relationships between plasma insulin, triglyceride, body mass index, and plasminogen activator inhibitor 1. Diabete Metab.1987; 13:331-336. MedlineGoogle Scholar8 Schneider DJ, Baumann PQ, Absher MP, Sobel BE. Augmented porcine coronary arterial expression of plasminogen activator inhibitor type 1 (PAI-1) induced by insulin and fatty acids. Circulation. 1995;92(suppl I):I-170. Abstract. Google Scholar9 Nordt TK, Schneider DJ, Sobel BE. Augmentation of the synthesis of plasminogen activator inhibitor type-1 by precursors of insulin: a potential risk factor for vascular disease. Circulation.1994; 89:321-330. CrossrefMedlineGoogle Scholar10 Nordt TK, Sawa H, Fujii S, Sobel BE. Induction of plasminogen activator inhibitor type-1 (PAI-1) by proinsulin and insulin in vivo. Circulation.1995; 91:764-770. CrossrefMedlineGoogle Scholar11 Sawa H, Lundgren C, Sobel BE, Fujii S. Increased intramural expression of plasminogen activator inhibitor type-1 after balloon injury: a potential progenitor of restenosis. J Am Coll Cardiol.1994; 24:1742-1748. CrossrefMedlineGoogle Scholar12 Sawa H, Fujii S, Sobel BE. Potentiation by hypercholesterolemia of the induction of aortic intramural synthesis of plasminogen activator inhibitor type-1 by endothelial injury. Circ Res.1993; 73:671-680. CrossrefMedlineGoogle Scholar13 Sawa H, Fujii S, Sobel BE. Augmented arterial wall expression of type-1 plasminogen activator inhibitor induced by thrombosis. Arterioscler Thromb.1992; 12:1507-1515. 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