Journal of Health Science, 54(1) 1–16 (2008) 1 — Minireview — Pharmacological Interventions to Prevent Vascular Endothelial Dysfunction: Future Directions Pitchai Balakumar,∗,a Rajeshkumar U. Koladiya, b Subbiah Ramasamy, c Andiappan Rathinavel, d and Manjeet Singh a a Cardiovascular Pharmacology Division, I.S.F. Institute of Pharmaceutical Sciences and Drug Research, Ghal Kalan, Moga–142 001 Punjab, India, b Department of Pharmaceutical Science and Drug Research, Punjabi University, Patiala–147 002, Punjab, India, c Department of Biochemistry, School of Biological Sciences, Madurai Kamaraj University, Madurai–625 021, Tamilnadu, India, and d Department of Cardio-Thoracic Surgery, Madurai Medical College and Government Rajaji Hospital, Madurai–525 021, Tamilnadu, India (Received September 28, 2007; Accepted November 6, 2007) Endothelium forms an innermost lining of blood vessel and it regulates the vascular tone and permeability. A healthy vascular endothelium is antiatherogenic in nature because of its properties such as inhibition of platelet aggregation, adhesion cascades, smooth muscle cell proliferation and leukocyte adhesion. Vascular endothelial dys- function (VED) is associated with reduced synthesis and release of nitric oxide, proinﬂammatory and prothrombotic properties followed by diminished vasodilation. VED has been implicated in the pathogenesis of artherosclerosis, hypertension, myocardial infarction, heart failure, renal failure and stroke. Various pharmacological interventions such as angiotensin converting enzyme (ACE) inhibitors, statins, insulin sensitizers, L-arginine as well as agents that target endothelial nitric oxide synthase (eNOS) “coupling” such as folates or tetrahydrobiopterin (BH4) have been noted to improve the function of vascular endothelium. In this review, we discussed various recently developed pharmacological interventions to improve the function of endothelium. Moreover, the novel targets sites involved in the pathogenesis of vascular endothelial dysfunction have been delineated. Key words —— endothelial dysfunction, statin, angiotensin converting enzyme inhibitor, insulin sensitizer, L -arginine, novel target site INTRODUCTION other hand, endothelium dependent vasoconstric- tion is mediated by endothelin-1 (ET-1), vasocon- Endothelium is the layer of thin specialized ep- strictor prostanoids, angiotensin II (Ang II) and ithelium comprising simple squamous cells that line super oxide anion.5) Vascular endothelial dysfunc- the inner wall of the blood vessel. Endothelium tion (VED) has been associated with reduced va- regulates vascular homoeostasis through various lo- sodilation, proinﬂammatory and prothrombic prop- cal mediators that modulate vascular tone, platelet erties.6) VED leads to endothelial cell activation.7) adhesion, inﬂammation, ﬁbrinolysis and vascular The activated endothelium expresses cell-surface growth.1, 2) The vascular homeostasis is dependent adhesion molecules such as vascular cell adhe- on the integrity of the endothelium.3, 4) Endothe- sion molecule (VCAM)-1, intercellular adhesion lium maintains the balance between vasodilation molecule (ICAM)-1, endothelial-leukocyte adhe- and vasoconstriction. Endothelium-dependent va- sion molecule (ELAM or E-selectin) and von Wille- sodilation is mediated by various mediators such brand factor (vWF),8, 9) which all collectively lead as nitric oxide (NO), endothelium derived hyper- to formation of atherosclerotic plaques. A major polarizing factor (EDHF) and prostacyclin. On vasodilator released by the endothelium is NO. Ig- ∗ narro group had described that endothelium-derived To whom correspondence should be addressed: Cardiovas- relaxing factor is nothing but NO.10) NO is syn- cular Pharmacology Division, I.S.F. Institute of Pharmaceu- thesized from the substrate L-arginine through en- tical Sciences and Drug Research, Moga–142 001, Punjab, India. Tel.: +91-9815557265; Fax: +91-1636236564; E-mail: dothelial NO synthase (eNOS) in endothelial cell. firstname.lastname@example.org The cofactors such as nicotinamide adenine din- 2 Vol. 54 (2008) ucleotide phosphate (NADP), tetrahydrobiopterin ET-1 receptor antagonists,33–35) calcium chan- (BH4), ﬂavin-adenine dinucleotide (FAD), cys- nel blockers,36) insulin-sensitizing agents,37, 38) teine and reduced glutathione are necessary for antioxidants39) and various supplements such as the production of NO.11) NO regulates vascular arginine,40) tetrahydrobiopterin41) and folate42) tone by inhibiting various processes such as vas- have been primarily known to improve the function cular smooth muscle cell proliferation, platelet ag- of vascular endothelium. gregation, platelet and monocyte adhesion to the endothelium, neutrophil activation and adhesion, low densith lipoprotein (LDL) oxidation, expres- STATINS ON ENDOTHELIAL sion of adhesion molecules, ET-1 production and FUNCTION expression of pro-inﬂammatory cytokines like tu- mor necrosis factor alpha (TNF-α) interleukin-1 Statins are known to inhibit 3-hydroxy-3- (IL-1) and interleukin-6 (IL-6).4, 12) The hallmark methyl-glutaryl-CoA (HMG-CoA) reductase and of VED is impairment in endothelium dependent thus lower the LDL cholesterol43) . Evidences sug- vasodilation, which is mediated by reduced pro- gest that they are potent agents for improving en- duction of NO and elevated levels of asymmet- dothelial function and reducing cardiovascular risk ric dimethylarginine (ADMA).2) Further, in VED, and morbidity and mortality in patients with coro- the bioavailability of NO is reduced by reactive nary artery disease.44, 45) The beneﬁcial effects of oxygen species (ROS), which are derived from statins are not only related to their cholesterol low- macrophages, smooth muscle cells and endothelial ering effect; but also their antithrombotic, anti- cells with the help of nicotinamide adeine dinu- inﬂammatory and antioxidant effects.46–49) Statins cleotide phosphate-oxidase (NADPH-oxidase) and have been shown to induce the expression of xanthine oxidoreductase.13) ROS induce the pro- eNOS in human endothelial cells50) and prevent duction VCAM-1, ICAM-1, monocyte chemoat- the expression of caveolin, a negative regulator tractant protein-1 (MCP-1), IL-6 and oxidized low- of eNOS.51) Statins activate Akt/protein kinase B, density lipoprotein-1 (LOX-1).14, 15) Impaired en- which further activates eNOS.52) Moreover, statins dothelial function and decreased NO bioavailabil- appear to inhibit the synthesis of isoprenoids that ity in human endothelium play an important role are required for the posttranslational modiﬁcation in the development and progression of atheroscle- of important signaling molecules such as Rho, Rac rosis and coronary artery disease.16) The risk factors and Ras.53) Inhibition of Rho activation increases commonly associated with VED are hyperhomocys- the production of endothelial NO50) and reduces the teinemia,17) hypercholesterolemia,18) obesity,19) hy- expression of ET-1.54) Lovastatin was ﬁrst shown peruricemia,20–22) estrogen deﬁciency,23) aging24) to inhibit the production of proinﬂammatory cy- and chronic smoking.25) The VED has been asso- tokines. The atorvastatin therapy in an animal ciated with various cardiovascular disorders such as model of hypertension has improved the function atherosclerosis,18) hypertension,26) coronary artery of endothelium and concurrently lowered the ex- disease,27) chronic heart failure,28) chronic renal pression of p22phox and production of ROS.43) In failure,6) diabetes29) and stroke.30) The VED is a addition, statins reduce chemokine and chemokine major contributing factor for cardiovascular disor- receptor expressions in human endothelial cell and ders and various interventions are developed to pre- macrophages through inhibition of the geranylger- vent VED and thus the risk of cardiovascular events. anylpyrophosphate pathway and thus they possess The present review delineates various pharmacolog- anti-inﬂammatory effect.49) Several studies suggest ical interventions to prevent VED and associated that improvement in endothelial function is one of cardiovascular complications. the pleotrophic effects of statins independent of their lipid-lowering capabilities.55) The mechanisms involved in statins mediated improvement in en- PHARMACOLOGICAL dothelial function have been shown in Fig. 1. INTERVENTIONS Various studies have investigated the effect of statins in clinical measures of endothelial func- The pharmacological agents such as statins,31) tion such as ﬂow-mediated vasodilation or fore- angiotensin converting-enzyme inhibitors,32) arm blood ﬂow in response to infusion of va- No. 1 3 Fig. 1. The Mechanisms Involved in Statins Mediated Improvement in Endothelial Function Ang-II indicates angiotensin II; ET-1 indicates endothelin-1; Akt indicates protein kinase B; ADMA indicates asymmetric dimethylarginine; eNOS indicates endothelial nitric oxide synthase; ROS indicates reactive oxygen species; NO indicates nitric oxide. soactive agents such as acetylcholine. Treatment ANGIOTENSIN CONVERTING ENZYME with lovastatin improved the coronary vasomotor (ACE) INHIBITORS ON ENDOTHELIAL response to acetylcholine in patients with coro- FUNCTION nary artery disease.56) Pravastatin treatment im- proved endothelium-dependent coronary vasomo- Ang-II plays a major role in mediating vaso- tion within 24 hr in the absence of signiﬁcant constriction, thrombosis, inﬂammation and vascular cholesterol reduction.47) The endothelial dysfunc- remodeling.66) Ang-II has been shown to increase tion in hypercholesterolemics is due to an oxidative the production of super oxide through activation stress and atorvastatin treatment rapidly improved of membrane-bound NADPH oxidase.67) ACE in- both basal and stimulated endothelium-dependent hibitors may be potentially improving endothelium- vasodilation.57) Further, treatment with atorvastatin dependent vasodilation by preventing the forma- has been noted to improve forearm blood ﬂow and tion of ang-II and increasing the level of bradykinin decrease serum markers of oxidative stress and in- and consequently NO.68) ACE inhibitors protect en- ﬂammation.58) Recent clinical trials of statins show dothelial cells from oxidative stress-induced apop- improvement in endothelial function and reduc- tosis.69) Quinapril has been noted to improve the tion in cardiovascular risks, morbidity and mor- function of endothelium by decreasing TNF-α and tality in patients with coronary artery disease.45) C-reactive protein (CRP) levels.70) Zofenopril has Statins enhance endothelial function independent improved the production of NO and consequently of their lipid-lowering effects.44, 59) Short-term im- reduced oxidative stress in endothelial cells.71) Can- provement in endothelial function has been noted to desartan, an AT1 receptor antagonist has been be superior with pitavastatin as compared to ator- noted to improve endothelium-dependent vasore- vastatin therapy. Pitavastatin could be a poten- laxation.72) Irbasartan treatment improves periph- tially better therapeutic choice for lipid-lowering eral but not coronary endothelial dysfunction in pa- and early alterations in endothelial function.55) tients with coronary artery diseases.73) It is inter- Short-term lipid-lowering therapy with cerivastatin esting to note that ACE inhibitor such as enalapril improved endothelial function and NO bioavail- and angiotensin AT1 -receptor blocker like losartan ability after two weeks in patients with hyperc- is equally effective to reverse N(G)-nitro-L-arginine holesterolemia.60) The summary of clinical trials methyl ester (L-NAME)-induced experimental en- of statins in endothelial function is outlined in dothelial dysfunction.74) Table 1.44, 47, 55–65) Several clinical studies have demonstrated the 4 Vol. 54 (2008) Table 1. Overview of Clinical Trials of Statins on Endothelial Function Study Population Drug Conclusion Anderson et al., 199556) Coronary artery disease Lovastatin Treatment with lovastatin (62 mg/day) im- proved the coronary vasomotor response to acetylcholine Treasure et al., 199561) Coronary artery disease Lovastatin Lovastatin (80 mg/day) improved endothe- lium mediated responses in coronary artery of patients with atherosclerosis Dupuis et al., 199962) Hyperlipidemia, My- Pravastatin Pravastatin (40 mg/day) rapidly improved ocardial infarction endothelial function after 6 weeks of ther- apy Jarvisalo et al., 199944) Coronary artery disease Statins HMG CoA reductase inhibitors enhance endothelial function independent of their lipid-lowering effects Perticone et al., 200057) Hypercholesterolemic Atorvastatin Atorvastatin (10 mg/day) rapidly improved patients endothelium-dependent vasodilation Penny et al., 200163) Hypercholesterolemia Lovastatin Lovastatin (40 mg/day or greater) treatment reversed endothelial dysfunction Laufs et al., 200164) Healthy male Atorvastatin In subjects with normal vascular function atorvastatin (80 mg/day) improved endothe- lial function within 24 hr van de Ree et al., 200165) Type 2 diabetes mellitus Simvastatin Endothelial function is impaired in type 2 diabetes and is not restored after 6-weeks treatment with simvastatin (40 mg/day) John et al., 200160) Hypercholesterolemia Cerivastatin Short-term lipid-lowering therapy with cerivastatin improved endothelial function and NO bioavailability after two weeks Mercuro et al., 200259) Postmenopausal normo- Atorvastatin Atorvastatin (10 mg/day) improved cholesterolemic women endothelium-dependent vasodilation Wassmann et al., 200347) Angina pectoris Pravastatin Pravastatin (40 mg) treatment improved coronary endothelial function Wassmann et al., 200458) Normotensive patients Atorvastatin Atorvastatin (80 mg/day) treatment im- with known vascular proved forearm blood ﬂow and decreased disease or cardiovascu- serum markers of oxidative stress and in- lar risk factors ﬂammation Sakabe et al., 200755) Primary hypercholes- Pitavastatin Short-term improvement of endothelial terolemia Atorvastatin function was superior with pitavastatin (2 mg/day) compared to atorvastatin (10 mg/day) therapy beneﬁcial effects of ACE inhibitors in improve- On other hand, enalapril has improved stimulated ment of endothelial function in patients of dia- and basal NO-dependent endothelial function in betes, hypertension and coronary artery disease type 2 diabetic subjects.78) Further, enalapril has (Table 2).70, 75–83) In the Trial on Reversing EN- signiﬁcantly increased the postischemic vasodila- dothelial Dysfunction (TREND) study, normoten- tor response in patients with coronary hypercholes- sive patients with angiographically demonstrated terolemia.81) In healthy volunteers, triglyceride-rich coronary atherosclerosis were treated chronically lipoproteins-induced endothelial dysfunction was with quinapril, an ACE inhibitor with high tissue- prevented by losartan and quinapril and the preven- binding afﬁnity. These patients had restoration tive effect was more pronounced with quinapril.79) of endothelium-dependent vasodilation of coronary In mildly hypertensive patients without organ dam- vessels in absence of signiﬁcant reduction in blood age, zofenopril, beyond its blood pressure lowering pressure.75) Impairment of endothelial dependent effect and through its sustained antioxidant activity dilation in young subjects with type 1 diabetes has has markedly improved endothelial function.83) The not been improved by treatment with enalapril.77) summary of clinical trials of ACE inhibitors in en- No. 1 5 Table 2. Overview of Clinical Trials of ACE Inhibitor on Endothelial Function Study Population Drug Conclusion Mancini et al., 199675) Normotensive patients Quinapril Quinapril (40 mg/day) improved endothelial function with coronary artery in normotensive patients disease O’Driscoll et al., 199776) Type 2 diabetic subjects Enalapril In type 2 diabetic subjects without evidence of vas- cular disease, enalapril (20 mg/day) improved NO- dependent endothelial function Mullen et al., 199877) Young subjects with Enalapril Impairment of endothelial dependent dilation in type 1 diabetes mellitus young subjects with type 1 diabetes has not been im- proved by treatment with enalapril (20 mg/day) O’Driscoll et al., 199978) Type 2 diabetes melli- Enalapril Enalapril (10 mg twice daily) improved NO depen- tus dent endothelial function Wilmink et al., 199979) Healthy volunteers Quinapril Quinapril (40 mg/day) prevented endothelial dys- function induced by triglyceride rich lipoproteins McFarlane et al., 199980) Type 1 diabetes Perindopril Perindopril (4 mg/day) treatment for 3 months did not improve arterial endothelial function Esper et al., 200081) Coronary hypercholes- Enalapril Enalapril (5 mg/day) increased the post ischemic va- terolemia sodilator response in patients with coronary hyperc- holesterolemia Bae et al., 200182) Hypertriglyceridemia with Lisinopril No acute beneﬁcial effects of Lisinopril (10 mg/ day) coronary artery disease on endothelial function Kovacs et al., 200670) Post myocardial infarc- Quinapril Low dose of quinapril (10 mg/day) improved en- tion patients dothelial function Pasini et al., 200783) Mild hypertensive pa- Zofenopril Zofenopril (15 to 30 mg/day) beyond its blood pres- tients sure lowering effects and through its sustained an- tioxidant activity, improved the endothelial function dothelial function is outlined in Table 2. are on treatment with ramipril suggesting that ET receptor blockade may have important therapeutic effects when added to ACE inhibition in atheroscle- ET-1 RECEPTOR ANTAGONISTS ON rotic patients.87) Various studies suggest that en- ENDOTHELIAL FUNCTION dothelin receptor blockade would be an effective therapeutic approach in the management of patients ET-1 is a potent vasoconstrictor peptide pro- with pulmonary arterial hypertension.88) Treatment duced by vascular endothelium from big ET-1 via with bosentan, a nonselective ETA /ETB receptor speciﬁc cleavage by endothelium converting en- antagonist has been shown to be safe and improve zyme. ET-1 produces its effects through the stim- pulmonary haemodynamics in patients with heart ulation of ETA and ETB receptors. Numerous stud- disease.89, 90) Bosentan has been shown to improve ies have shown that plasma concentration of ET- vascular endothelial function in patients with sys- 1 is elevated in patients with cardiovascular dis- temic sclerosis.33) Treatment with sitaxsentan, a se- orders.35) Coronary endothelial function has been lective ETA receptor antagonist has been noted to shown to be preserved with chronic endothelin improve clinical status of patients with pulmonary receptor antagonism in experimental hypercholes- arterial hypertension.34) terolemia.84) Endothelin ETA receptor blockade re- stores NO-mediated endothelial function and in- hibits atherosclerosis.85) ETA receptor antagonism CALCIUM CHANNEL BLOCKERS ON has been demonstrated to have therapeutic poten- ENDOTHELIAL FUNCTION tial in the treatment of endothelial dysfunction and atherosclerosis.86) Dual ETA /ETB receptor block- Calcium channel blockers are traditionally used ade improves endothelial function and exerts direct as antihypertensive therapy. Amlodipine, a cal- vasodilator effects in atherosclerotic patients who cium channel blocker enhances the production of 6 Vol. 54 (2008) NO.91) Further, amlodipine activates eNOS, which patients with type 2 diabetes.37) potentiates the production of NO.92) Benidipine, a calcium channel blocker has restored endothe- lial function by promoting the production of NO L-ARGININE ON ENDOTHELIAL and accumulating cyclic guanosine monophosphate FUNCTION (cGMP), a second messenger of NO and prevent- ing lysophosphatidylcholine-induced activation of L-Arginine, a semi-essential amino acid, is the caspase-3.93) Azelnidipine, a novel calcium chan- substrate for eNOS and the precursor molecule nel blocker works as an anti-atherogenic agent by for synthesis of NO. L-arginine improves the inhibiting ROS dependent expression of VCAM-1 NO-mediated vasodilatory responses and seems to induced by TNF-α in endothelial cells.94) Nifedip- have a direct vasodilator effect on human vascula- ine improves endothelial function in hypercholes- ture.104) Further, L-arginine improves NO synthesis terolemia independently of an effect on blood pres- by antagonizing the deleterious effect of ADMA on sure and plasma lipids.95) Recently, efonidipine, a eNOS function.105) L-arginine has additional effects novel calcium channel blocker, has been shown to such as stimulating the release of insulin, growth improve endothelial function and reduce blood pres- hormone, glucagons, prolactin and inhibiting an- sure in nondiabetic patients with hypertension.36) It giotensin converting enzyme and reducing lipid per- has been reported that amlodipine showed less ef- oxidation106, 107) , which may improve the function fect than olmesartan in the endothelium dependent of endothelium. The dietary supplementation of L- coronary dilation in hypertensive patients.96) arginine decreased the platelet aggregation108, 109) and mononuclear cells adhesiveness.110) Oral sup- plementation of L-arginine signiﬁcantly improved INSULIN-SENSITIZING AGENTS ON endothelial function in patients of peripheral ar- ENDOTHELIAL FUNCTION terial occlusive disease (PAOD) with hyperhomo- cysteinemia.111) Further, L-arginine supplementa- An insulin-resistant diabetic state has been as- tion has partially restored endothelium-dependent sociated with obesity19) and VED.37) Therapeu- vasorelaxation and improved myocardial perfusion tic agents that promote the insulin sensitivity may in a swine model of chronic myocardial ischemia improve endothelial function. Thiazolidinediones with hypercholesterolemia-induced endothelial dys- group of insulin sensitizers such as troglitazone, function.112) There is currently insufﬁcient evidence pioglitazone and rosiglitazone have been noted to to recommend the use of L-arginine in patients with activate peroxisome proliferator activated receptor acute stroke.113) gamma (PPARγ) and decrease peripheral insulin resistance.97) Although, troglitazone is the ﬁrstly approved Thiazolidinedione as insulin sensitizing BH4 AND FOLATE ON ENDOTHELIAL agent, it has been withdrawn from the main mar- DYSFUNCTION kets such as U.S.A. and Japan because of its severe hepatotoxicity. Rosiglitazone inhibits proliferation BH4 is one of most potent naturally occur- and migration of vascular cells98–100) and endothe- ring reducing agents and an essential allosteric lial cell apoptosis.101) In endothelial cells, PPARγ factor in coupling of oxidase and reductase do- activators inhibit the expression of TNF-α, IL-6 and mains of eNOS,114) which regulates the produc- IL-1β and attenuate TNF-α-induced expression of tion of NO in endothelial cells.115) Deﬁciency of VCAM-1 and ICAM-1102) and thereby may protect BH4, an essential cofactor for eNOS, decreases against the inﬂammation of vascular endothelium. the generation of NO and increases the production Moreover, PPARγ activators act as vasorelaxants by of reactive oxygen species,116) which may lead to enhancing the production of endothelial NO.103) Re- VED. The infusion of BH4 has been noted to im- cent studies suggest that insulin sensitizers improve prove acetylcholine-mediated vasodilation.116) Fur- endothelial function in type 2 diabetes. Rosiglita- ther, BH4 ameliorates endothelial dysfunction in zone treatment has been shown to restore the func- fructose-fed rats. BH4 may be a promising agent tion of endothelium.38) Pioglitazone has improved for the treatment of oxidative stress-induced cardio- both endothelial function and insulin resistance in vascular disorders.41) Elevated plasma total homo- No. 1 7 cysteine (tHcy) concentration is termed as hyper- HERBAL DRUGS ON ENDOTHELIAL homocysteinemia, which is a risk factor for cardio- DYSFUNCTION vascular disease and thrombotic complications.117) The exact mechanism by which homocysteine pro- Short and long term black tea consump- motes vascular disease remains unclear. How- tion reverses endothelial dysfunction in patients ever, there is signiﬁcant support that hyperhomo- with coronary artery diseases due to antioxidant cysteinemia impairs endothelial function via oxida- and anti-atherosclerotic properties of catechins.132) tive inactivation of NO.118) Early clinical trials sug- Genisten, a phytoestogen derived from soyabeans, gested that lowering tHcy using folic acid may re- binds to estrogen receptors and produces estro- tard the progression of atherosclerosis.119) However, gen like cardiovascular protective effect. Genis- treatment with high-dose folic acid improves en- tein enhances NO mediated relaxation in arotic dothelial function in post-acute myocardial infarc- rings isolated from overiectomized rats.133) The tion patients, independent from homocysteine sta- vasorelaxant response to acetylcholine has been tus.120) On the other hand, folic acid therapy has noted to be enhanced in animals supplemented been noted to effectively lower plasma homocys- with garlic and turmeric.134) Concord grape juice teine level and improve total plasma antioxidant ca- (CGJ), a non-alcoholic rich source of grape-derived pacity in hemodialysis patients.121) The folic acid polyphenols enhanced endothelial formation of supplementation has reduced plasma tHcy level and NO and endothelium-derived hyperpolarizing factor produced a signiﬁcantly greater reversal of the en- (EDHF) through redox-sensitive activation of Src dothelial dysfunction.122) kinase with subsequent PI3-kinase/Akt-dependent phosphorylation of eNOS.135) Astragalus mem- branaceus and astragalus saponin potently protected ANTIOXIDANTS ON ENDOTHELIAL endothelium-dependent relaxation against acute in- DYSFUNCTION jury induced by Hcy through nitric oxide regulatory pathways.136) Pterospartum tridentatum has been The statement of oxidative stress mediates shown to reduce the development of diabetic vas- atherosclerotic endothelial dysfunction implicates a cular complications against oxidative injury.137) potential for antioxidant therapies to prevent vascu- lar pathology. Several antioxidants such as ascor- bic acid (vitamin C), α-tocopherol (vitamin E), FUTURE DIRECTIONS glutathione, BH4, and N-acetylcysteine have been shown to improve endothelial function.39, 123–126) Rho-kinase, a serine threonine kinase is ex- Vitamin C, a potent water-soluble scavenger of free pressed in vascular smooth muscle cells and en- radicals, reduces monocyte adhesion to endothe- dothelial cells.138) Activation of Rho-kinase inhibits lial cells, inhibits LDL oxidation, decreases inacti- myosin light chain phosphatase and consequently vation of NO and stimulates eNOS activity.125, 127) increases vascular tone that involves in the patho- Vitamin C has been shown to improve the func- genesis of hypertension and coronary/cerebral va- tion of endothelium in patients with cardiovas- sospasms.139) Our laboratory has recently shown cular diseases.128) Moreover, vitamin C has been the ameliorative effect of fasudil, a selective in- noted to prevent homocysteine-induced impairment hibitor of Rho-kinase in hypertension, diabetes mel- of vascular endothelial function. This result sup- litus and hyperhomocysteinemia-induced VED.140) ported the adverse effect of homocysteine on vas- The oxidant mediated activation of poly (ADP- cular endothelial cells are mediated through oxida- ribose) polymerase (PARP) plays a pivotal role tive stress mechanisms.129) Furthermore, vitamin C in the development of endothelial dysfunction.141) blocks vascular dysfunction and release of IL-6 in- The PARP overactivation results in rapid deple- duced by ET-1.126) Vitamin E, a fat-soluble inhibitor tion of intracellular NAD and ATP pools, slows of lipid peroxidation, inhibits leukocyte adhesion the rate of glycolysis and mitochondrial respira- and oxidation of LDL cholesterol.130) Oral supple- tion and eventually leads to endothelial dysfunc- mentation of vitamin E attenuates transient impair- tion.142) PARP inhibitors such as PJ-34 and INO ment of endothelial function in smokers.131) 1001 exert beneﬁcial effects against diabetes, hy- perhomocysteinemia, hypertension, aging and en- 8 Vol. 54 (2008) dotoxic shock-induced VED.141, 143–146) Activation blockers, L-arginine and BH4 have been shown of Akt stimulates phosphorylation of eNOS, in- to prevent endothelial dysfunction and reduce the creases the production of NO and reduces ox- risk of cardiovascular complications. The protec- idative stress.147–149) Demethylasterriquinone B1 tive role of insulin sensitizers and antioxidant ther- (DAQ B1), an activator of Akt has reduced ox- apy in endothelial dysfunction remains to be fur- idative stress and prevented hypertension, dia- ther explored. Various experimental studies have betes mellitus and hyperhomocyteinemia associ- demonstrated the endothelial protective role of in- ated VED.149, 150) The inhibition of protein tyro- hibitors of Rho-kinase, PARP, PTPase, geranyl ger- sine phosphatase (PTPase) has been documented to anyl transferase and transketolase, and activators of activate Akt.151, 152) We have recently shown that Akt and PKA, which would be novel future candi- bis(maltolato)oxovanadium (BMOV), a PTPase in- dates for treating cardiovascular disorders. How- hibitor activates eNOS by opening of ATP-sensitive ever, further studies are warranted to explore the K+ channels and consequently decreases oxidative novel role of these signaling systems in the mod- stress to prevent VED.22, 153) GGTI-298, an in- ulation of cardiovascular functions. hibitor of geranylgeranyltransferase-I, inhibits the activation of certain Rho family GTPase such as Acknowledgement We wish to express our grate- Rho A and Rac 1, which in turn results in in- fulness to Shri. Parveen Garg Ji, Honorable Chair- creased eNOS activity and hence NO production man, I.S.F. Institute of Pharmaceutical Sciences and with diminished release of ROS.154) Benfotiamine, Drug Research, Moga, Punjab for his praiseworthy a lipophilic derivative of thiamine is a transketo- inspiration and support for this study. lase activator, which prevents vascular accumula- tion of advanced glycation end products (AGE) and induction of pro-apoptotic caspase-3.155) Moreover, REFERENCES benfotiamine has been shown to reduce endoge- nous AGE production and oxidative stress and pre- 1) Nedeljkovic, Z. S., Gokce, N. and Loscalzo, J. vent micro and macrovascular dysfunction induced (2003) Mechanisms of oxidative stress and vascu- by an AGE-rich meal in patients with type 2 di- lar dysfunction. Postgrad. Med. J., 79, 195–200. abetes.156) Activation of protein kinase A (PKA) 2) Davignon, J. and Ganz, P. (2004) Role of Endothe- stimulates eNOS phosphorylation and increases the lial Dysfunction in Atherosclerosis. 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