Pharmacological Interventions to Prevent Vascular Endothelial by ert634


									    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
  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,
  Department of Biochemistry, School of Biological Sciences, Madurai Kamaraj University, Madurai–625 021, Tamilnadu, India, and
  Department of Cardio-Thoracic Surgery, Madurai Medical College and Government Rajaji Hospital, Madurai–525 021, Tamilnadu,

                                        (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.                                                    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
     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-
     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
  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-
  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
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