Elsevier

American Heart Journal

Volume 146, Issue 2, August 2003, Pages 218-226
American Heart Journal

Curriculum in cardiology
Endothelial dysfunction: clinical strategies for treating oxidant stress

https://doi.org/10.1016/S0002-8703(02)94796-4Get rights and content

Abstract

Background

A growing body of evidence has demonstrated that oxidants play a critical role in the pathogenesis of endothelial dysfunction. Pathologic processes fundamental to development and progression of endothelial dysfunction such as the oxidation of LDL, the loss of bioavailable nitric oxide, and the vascular inflammatory response are all modulated by oxidant stress. Therapeutic strategies to reverse endothelial dysfunction have begun to focus on agents with the ability to ameliorate oxidant stress.

Methods

Preclinical and clinical studies evaluating the actions of antioxidants as well as traditional cardiovascular therapies in ameliorating oxidative stress and endothelial dysfunction were reviewed through the use of a MEDLINE search of English language articles published between the years of 1992 and 2002.

Results

Antioxidants appear to be an attractive candidate therapy, yet despite compelling preclinical evidence supporting their benefits, efforts to validate the use of vitamins C and E in a clinical setting have been conflicting. In contrast, conventional cardiovascular therapies such as ACE inhibitors, statins, insulin-sensitizing agents, and estrogens have been shown to alleviate endothelial dysfunction, often independent of their effects on systemic disease processes.

Conclusions

These agents restore endothelial function through their salutary effects on pathologic vascular oxidative processes.

Section snippets

Endothelial function and dysfunction

The vascular endothelium is a metabolically responsive tissue. This cellular monolayer has an ability to modulate both the contents of the vascular lumen and the adjacent compartment of vascular smooth muscle. Arguably, the most important substance responsible for endothelium-dependent vascular relaxation is nitric oxide (NO). NO is not only involved in relaxation of vascular smooth muscle but also partially mediates inhibition of platelet activation, adhesion, and aggregation, prevention of

Reactive oxygen species in endothelial dysfunction

Reactive oxygen species (ROS) consist of molecular oxygen and all of its aerobic cellular metabolites, including superoxide (O2), hydroxyl radical (OH), NO, and lipid radicals. Although they are not free radicals, hydrogen peroxide (H2O2), peroxynitrite (ONOO), and hypochlorous acid (HOCL) have oxidative properties and contribute to oxidant stress. Oxidants play a critical role in vascular homeostasis and function, mediating growth, apoptosis, and survival of endothelial and vascular smooth

NAD(P)H oxidase

NAD(P)H oxidase catalyzes the reduction of O2 through electron donation from NADPH or NADH, thereby generating O2. Relative to other enzymatic pathways, vascular NAD(P)H oxidase is the predominant source of vascular O2 cells. Preclinical data suggest that NAD(P)H–dependent O2 production promotes endothelial dysfunction. Angiotensin II is known to stimulate vascular smooth muscle (VSMC) O2 production through enhanced NAD(P)H oxidase activity.2 In experimental angiotensin-mediated

The antioxidant paradox

The assumption that oxidative stress mediates atherosclerotic endothelial dysfunction would implicate a potential for antioxidant therapies to ameliorate and perhaps reverse vascular pathology. A growing body of preclinical evidence exists to support the salubrious effects of antioxidants on endothelial function. Vitamin C, a potent water-soluble scavenger of free radicals, reduces monocyte adhesion to endothelial cells, inhibits LDL oxidation, decreases inactivation of NO, and stimulates eNOS

Lipid-lowering therapies

A variety of mechanisms, ranging from transient free fatty acid loading to overt hypercholesterolemia, can impair endothelial function. Oxidation of LDL cholesterol (oxLDL) is critical to the pathogenesis of endothelial dysfunction. Indeed, oxLDL exerts profound effects on the arterial vasomotor response, analogous to the effect observed in hypercholesterolemia or atherosclerosis. Vascular injury early in atherosclerosis renders the vascular wall permeable to lipoproteins such as VLDL

Insulin-sensitizing agents

Endothelial dysfunction is thought to be present in a wide spectrum of insulin-resistant states, including types II diabetes, obesity, and Syndrome X. Antioxidants improve endothelial dysfunction in non–insulin-dependent diabetes, suggesting a causal relation between oxidative stress and endothelial dysfunction.38 A plausible explanation for this association implicates hyperglycemia and its oxidative sequelae. Elevated glucose levels, through glyco-oxidation of glucose and formation of advanced

Homocyst(e)ine-lowering therapies

An independent risk factor for vascular disease, hyperhomocysteinemia is thought to promote vascular disease through endothelial dysfunction. Several lines of evidence suggest that hyperhomocysteinemia modulates endothelial responses through oxidant-dependent mechanisms. Upon exposure to the plasma, homocysteine (Hcy) auto-oxidizes to become homocystine, generating H2O2, superoxide, and hydroxyl radicals. Hcy-mediated reductions in gluthathione peroxidase augment H2O2 levels, and the surge in O2

Estrogens

Endothelium-dependent vasodilation is increased in premenopausal women and decreased in perimenopausal women relative to men, suggesting an estrogen-mediated benefit. Accordingly, improvements in endothelium-dependent vasodilation have been demonstrated with administration of estrogen.48 The predominant mechanism appears to be an upregulation of the transcription of nitric oxide synthase, although exogenous estrogen also limits LDL oxidation. Despite these benefits, conjugated estrogen therapy

Conclusions

Common to many disease processes that propagate endothelial dysfunction is a pathway of stress-induced activation of intracellular oxidative signaling and secondary modulation of vascular inflammatory gene expression, resulting in further oxidant elaboration. Accordingly, antioxidant strategies targeting these pathologic oxidative mechanisms have emerged as viable therapies to restore normal endothelial responses (Table I). Although not prescribed for their antioxidant potential per se, many

References (50)

  • K.J. Mather et al.

    Improved endothelial function with metformin in type 2 diabetes mellitus

    J Am Coll Cardiol

    (2001)
  • G. Raghuveer et al.

    Effect of vitamin E on resistance vessel endothelial dysfunction induced by methionine

    Am J Cardiol

    (2001)
  • J. Thambyrajah et al.

    A randomized double-blind placebo-controlled trial of the effect of homocysteine-lowering therapy with folic acid on endothelial function in patients with coronary artery disease

    J Am Coll Cardiol

    (2001)
  • K. Irani

    Oxidant signaling in vascular cell growth, death, and survivala review of the roles of reactive oxygen species in smooth muscle and endothelial cell mitogenic and apoptotic signaling

    Circ Res

    (2000)
  • K.K. Griendling et al.

    Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells

    Circ Res

    (1994)
  • S. Rajagopalan et al.

    Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activationcontribution to alterations of vasomotor tone

    J Clin Invest

    (1996)
  • J.B. Laursen et al.

    Role of superoxide in angiotensin II-induced but not catecholamine-induced hypertension

    Circulation

    (1997)
  • T.J. Guzik et al.

    Vascular superoxide production by NAD(P)H oxidaseassociation with endothelial dysfunction and clinical risk factors

    Circ Res

    (2000)
  • H. Azumi et al.

    Expression of NADH/NADPH oxidase p22phox in human coronary arteries

    Circulation

    (1999)
  • C. Cahilly et al.

    A variant of p22(phox), involved in generation of reactive oxygen species in the vessel wall, is associated with progression of coronary atherosclerosis

    Circ Res

    (2000)
  • T. Heitzer et al.

    Tetrahydrobiopterin improves endothelium-dependent vasodilation in chronic smokersevidence for a dysfunctional nitric oxide synthase

    Circ Res

    (2000)
  • G.M. Pieper

    Acute amelioration of diabetic endothelial dysfunction with a derivative of the nitric oxide synthase cofactor, tetrahydrobiopterin

    J Cardiovasc Pharmacol

    (1997)
  • R.H. Boger et al.

    Asymmetric dimethylarginine (ADMA)a novel risk factor for endothelial dysfunction: its role in hypercholesterolemia

    Circulation

    (1998)
  • E.M. Mervaala et al.

    Endothelial dysfunction and xanthine oxidoreductase activity in rats with human renin and angiotensinogen genes

    Hypertension

    (2001)
  • C. Cardillo et al.

    Xanthine oxidase inhibition with oxypurinol improves endothelial vasodilator function in hypercholesterolemic but not in hypertensive patients

    Hypertension

    (1997)
  • Cited by (84)

    • Vitamin C attenuates memory loss induced by post-traumatic stress like behavior in a rat model

      2020, Behavioural Brain Research
      Citation Excerpt :

      Examples of these diseases include diabetes, Alzheimer, atherosclerosis, traumatic brain injury and post-traumatic stress disorder (PTSD) [7–11]. Further evidence on the central role of ROS in mediating the etiology and pathogenesis of the above disorders comes from studies performed on preclinical and clinical models which showed that inactivating ROS or limiting their production is linked with improved treatment outcome and/or prevention of many of the above disorders [12]. In humans, vitamin C (ascorbic acid) is an essential water-soluble nutrient.

    • Role of Antioxidants in Horse Serum-mediated Vasculitis in Swine: Potential Relevance to Early Treatment in Mitigation of Coronary Arteritis in Kawasaki Disease

      2017, Pediatrics and Neonatology
      Citation Excerpt :

      Antioxidants possibly mitigated coronary artery lesions in KD in one case report.18 Vitamins E and the chain terminators A and C, may improve the endogenous defensive mechanism in oxidative injury of the vessel wall.10,13–16 The combination therapy with vitamins C and E had better results than single drug alone.

    • Fluvastatin Decreases Oxidative Stress in Kidney Transplant Patients

      2015, Transplantation Proceedings
      Citation Excerpt :

      Increased oxidative stress has been suggested to play a role in the pathophysiology of atherosclerosis in KTPs [3,12]. It has been demonstrated that oxidative stress may induce conversion of native LDL to oxidized LDL (oxLDL), foam cell formation which plays a pivotal role in atherosclerosis, increased transcription of inflammatory cytokines and chemokines, as well as disrupt nitrous oxide-mediated endothelial function, consequently increasing atherosclerosis [13,14]. Compared to the normal population, a 30 to 40 times increase of atherosclerotic events in ESRD patients has been linked to increased oxidative stress and consequent inflammation [3].

    • Peroxynitrite and fibrinolytic system-The effects of peroxynitrite on t-PA-induced plasmin activity

      2015, International Journal of Biological Macromolecules
      Citation Excerpt :

      Inflammatory processes and increased generation of reactive oxygen species (ROS) are implicated both in etiology and pathophysiology of numerous cardiovascular disorders [1]. Oxidative stress, associated with inflammatory process, alters normal functions of all components of the haemostatic system, including the dysfunction of endothelium, a considerable decrease of its antithrombotic properties [2] and changes of the haemostatic balance in favor of pro-coagulant conditions [3]. Oxidative and nitrative modifications of haemostatic proteins influence their physiological activities.

    View all citing articles on Scopus
    View full text