To The Editorial Manager, Pharmacological Review Subject.

Submission of manuscript Dear Sir/Mam, I am submiiting my manuscript of my review article entitled as Endothelium Dysfunction, Inflammation and Cardiovascular disorder. This review article deals with the relationship between inflammation and cardiovascular disorders. I am pleased if you will accept my article only if you find it suitable. Thanking you with anticipation Ramica Sharma Mpharmacy(Pharmacology). Rayat institute of pharmacy, railmajra, Distt Nawanshahar (Punjab),India. pin code 144514 ramicasharma@yahoo.com

Endothelium Dysfunction, Inflammation and Cardiovascular disorder Ramica Sharma1 (Master in pharmacology), Chetan Kumar1 (Bachelor in Pharmacy), Seema Thakur2 (Master in pharmacology), Dr. AC Rana 1 (Ph.d) 1 Rayat Institute of Pharmacy Rail Majra, Nawanshahar, India (Punjab) 2 PCTE institute of Pharmacy, Ludhiana, Punjab Distt-

Corresponding Author Ramica Sharma, Master in Pharmacy Rayat Institute of Pharmacy, Rail Majra Distt. Nawanshahr (Punjab). Postal Code.144514 Email. ramicasharma@yahoocom Contact Number. 8146556929 Fax. 01881270501

Abstract.
Vascular endothelium maintains tone and free flow of blood in vessels Several studies indicate that the impairment in the maintenance of vascular tone results in vascular endothelial dysfunction (VED) results from reduced activation of endothelial nitric oxide synthase (eNOS) Various inflammatory mediators are also upregulated during VED Inflammation is a trait of several diseases including rheumatoid arthritis, Alzheimer's disease, asthma and various cardiovascular disorders Interestingly few recent studies demonstrated the role of various inflammatory mediators in the progression of VED and vascular disease associated with this Hence the present review has been designed to delineate the role of various inflammatory mediators in the pathogenesis of inflammation-induced VED

Key Words. Vascular endothelial dysfunction (VED) endothelial nitric oxide synthase (eNOS) Inflammatory Mediators, Rheumatoid Arthritis, cardiovascular disordes, asthma, alzheimer

Introduction
Vascular endothelium plays a detrimental role in maintenance of vascular homeostasis by stimulating the synthesis and release of numerous vasodilating factors such as prostacyclin nitric oxide (NO) [1-3]. Endothelium is the starting place for the synthesis of endothelium derived relaxing factor (EDRF) that is nothing but NO [4-6]. VED is generally characterized by containment in the endothelium dependent vasorelaxation caused by attenuated generation and bioavailability of nitric oxide (NO) which results from reduced activity of eNOS and increased oxidative stress in the vessel wall which blight the regulation of vascular homeostasis [1,2,7]. VED has been implicated in the progression of various cardiovascular disorders like atherosclerosis[1,8,9], hypertension[10] , diabetes mellitus [1112] coronary artery diseases [13] and stroke [14]. Various inflammatory mediators such as intracellular adhesion molecule-1 (ICAM-1) vascular cell adhesion molecule-1 (VCAM-1) vonWillebrand factor nuclear factor kappa-B (NF-kB) and various growth factors like vascular endothelial growth factors (VEGF) basic fibroblast growth factors (bFGF) plateletderived growth factors (PDGF) and transforming growth factor-b (TGF-b) are also upregulated during VED due to the formation of reactive oxygen species(ROS) [7, 15, 16] . Recent research has shown that inflammation and its mediator plays a key role in various vascular disorders Thus the present review has been designed with an idea to find out the correlation between VED and inflammatory mediators.

Vascular endothelium and Inflammation

The word inflammation comes from the Latin word inflammare (to set on fire) Celsus was the first person to record the cardinal signs of inflammation and considered inflammation as a beneficial response to injury [17]. Various studies indicate that during VED there is decreased generation and bioavailability of NO [18]. It has been noted that NO inhibits the adhesion cascade by interfering with rolling of leucocytes and diminishing the cytokine-induced expression of vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemotactic protein-1 (MCP-1) [2 11] .Various signaling pathway are responsible for inflammation-induced VED Rho proteins are involved in the regulation of several cellular functions [2,19,20] . Rho kinase a serine theronine small G-protein activates nuclear transcriptional factors like NF-kB and I-B kinase responsible for mediating inflammation [21] .Further the activation of Rho-kinase increases the generation of ROS22 reduces the biosynthesis and generation of NO23 and stimulates the proliferation of VSMC Moreover during inflammation there is increased expression of monocyte chemoattractant protein-1 and transforming growth factor-1 leading to VED [24, 25]. Further CCL2 plays an important role in vascular inflammation by inducing leukocyte recruitment and activation [26]. Angiotensin II (Ang II) increases the expression of adhesion molecules cytokines and chemokines and exerts a proinflammatory effect on leucocytes endothelial cells and VSMC [27]. Ang II initiates an inflammatory cascade of reduced nicotinamide-adenine dinucleotide phosphate oxidase (NADPH) ROS and NF-B which mediates transcription and gene expression and increases adhesion molecules and chemokines [28]. An excess of ROS decreases

generation and bioavailability of NO [18]. Moreover inflammation is associated with elevated level of C-reactive protein (CRP) [29] .The signaling mechanism involved in the pathogenesis of inflammation-VED and its associated disorders have been summarized in figure 1

Inflammation and Cardiovascular Disorders

Recent studies indicate that inflammatory mediators are implicated in the pathogenesis of various cardiovascular and inflammatory disorders that occur due to VED and their role has burgeoned It has been reported that in United States Atherosclerosis a major inflammatory cardiovascular disorder is one of the leading causes of mortality and disability [30-31]. Atherosclerosis is a multifactorial multistep disease that involves chronic inflammation and plaque rupture [32]. In atherosclerosis the normal functions of the endothelium are distorted that results in aggagerating an inflammatory response
[33]

. These

lipoprotein particles can undergo oxidative modification like that of LDL and activate inflammatory functions of vascular endothelial cells [34]. Further cytokines peroxides and other substances released in response to injury may hassle endothelial cells to express Pselectin ICAM-1 and E-selectin which in turn persuade process of leucocyte adhesion and subsequently their migration leading to formation of fatty streak formation
[35]

. Further

Urotensin II (U-II) basically a cyclic undecapeptide is found in high concentration in atheromatous lesions [36,37] . U-II accelerates foam cell formation and proliferation of VSMC suggesting development of atherosclerotic plaque [38-40]. Beside this inflammation was also implicated in pathogenesis of hypertension [41-42]. and various cardiovascular disorder by increasing the expression of C-RP [43-44] and activating Rennin Angiotensin

Aldosterone System (RAAS) and elevates the blood pressure [45-46]. Plasma CRP concentrations also predicts the risk of myocardial infarction (MI) and ischemic stroke [47]. Angiotensin II is the main culprit responsible for triggering vascular inflammation by inducing oxidative stress resulting in up-regulation of pro-inflammatory transcription factors such as NF-kB [27,48-50]. These in turn regulate the production of various inflammatory mediators that lead to endothelial dysfunction and vascular injury [41,46-47]. Elevated plasma levels of proinflammatory cytokines and chemokines such as interleukin (IL)-1 IL-6 fractalkine and monocyte chemoattractant protein-1 (MCP-1) currently known as CC chemokine ligand 2 (CCL2) has been elicted in the pathogenesis of pulmonary hypertension [26]. Further various studies elict the importance of IL-6 in both acute and chronic inflammation as it act as the main inducer of acute phase reactants such as Creactive protein fibrinogen and serum amyloid A protein [51] .In addition to this there is inhibition of caveolin that causes proliferation of VSMC [52]. Neopterin is secreted by macrophages following stimulation by the cytokine interferon-g and is a susceptible marker for the activation of the cell-mediated immune system [53-54] .The serum level of neopetrin is found to be elevated in patients with unstable angina and acute MI compared [55] Fig 2 shows the pathogenesis of inflammation-induced cardiovascular disorders

Conclusion
Inflammation induce-VED has been revealed to be involved in pathogenesis of various vascular disorders by inducing C-RP urotensin and increasing the expression of various inflammatory mediators. Rho-kinase was also found to be upregulated and actively involved in Inflammation and vascular pathogenesis.

Acknowledgement We wish to express our gratitude to Prof AC Rana (Director) Sh Nirmal Singh Rayat and S Gurwinder Bahara (Chairman) Rayat institute of Pharmacy Railmajra for his praise worthy suggestion and constant support for this study.

Increased expression of NF-kB

Increased activity of Cycloxygenase enzyme

Increased expression of chemokines

Inflammation

Activation of C-reactive protein

Overactivation of AT-II receptor

Increased expression of adhesion molecules

Activation of Rho-kinase

ROS

eNOS

NO

Further damage of endothelium

Atherosclerosis Hypertension Heart failure Rheumatoid arthritis Diabetes and renal disorder Fig 1. Various signalling pathways involved in the pathogenesis of inflammationinduced VED

Inflammation induced VED

Activation of RAAS pathway Urotensin-II
AT-II

Direct vasoconstriction Sympathetic outflow Aldosterone release

ROS

Increase expression of ICAM and VCAM CRP

Lipid peroxidation

Atherosclerosis Hypertension Angina

Fig 2. Pathogenesis of Inflammation induced cardiovascular disorders

10

References

1. Feletou M, Vanhoutte PM. Endothelial dysfunction a multifaceted disorder. Am J Physiol, 2006,291,H985-1002. 2. Balakumar P, Sharma R and Singh M. Benfotiamine attenuate nicotine and uric acid-induced vascular endothelial dysfunction in rats. Pharmacological Res, 2008,58,356 363. 3. Satttar N. Inflammation and endothelial dysfunction. intimate companions in the pathogenesis of vascular disease? Clin Sci, 2004,106,. 443445. 4. Shimokawa H, Matoba T. Hydrogen peroxide as an endothelium-derived hyperpolarizing factor. Pharmacol Res, 2004,49,543549. 5. Ignarro LJ, Byrn RE, Buga GM , Wood KS, Chaudhuri G. Pharmacological evidence that endothelium-derived relaxing factor is nitric oxide. use of pyrogallol and superoxide dismutase to study endothelium-dependent and nitric oxide-elicited vascular smooth muscle relaxation. J Pharmacol Exp Therap. 1988, 181-189. 6. Ignarro LJ. Nitric oxide in the regulation of vascular function. an historical overview. J Cardiol, 2002,17,301-306. 7. Balakumar P, Chakkarwar VA, Krishan P, Singh and M. Vascular endothelial dysfunction. A tug of war in diabetic nephropathy. Biomed Pharmacotherapy, 2009,63, 171-179.

11

8. Davignon J, Ganz P.Role of endothelial dysfunction in atherosclerosis. Circulation 2004,109,27-32. 9. Nakagami H, Kaneda Y, Ogihara T, Morishita R.Endothelial dysfunction in hyperglycemia as a trigger of atherosclerosis. Curr Diabetes Rev, 2005,1, 59-63.

10. Quyyumi A, Patel S. Endothelial Dysfunction and Hypertension. Cause or Effect? Hypertension,2010, 55,1092-1094. 11. Khan F, Cohen RA, Rudermann NB, Chipkin SR, Coffman JD. Vasodilator response in forearm skin of patient with Insulin-dependent diabetes mellitus. Vasc Med, 1996,1,187-193. 12. U Hink, LiH Mollnau, M Oelze, E Matheis, M Hartmann. Mechanisms underlying endothelial dysfunction in diabetes mellitus. Circ Res, 2001,88,14-22. 13. Heitzer T, Schlinzig T, Krohn K, Meinertz T, Munzel T.Endothelial dysfunction oxidative stress and risk of cardiovascular events in patients with coronary artery disease. Circulation, 2001,104,2673-2703. 14. Roquer J, Segura T, Serena J, Castillo J.Endothelial dysfunction, vascular disease and stroke. the ARTICO study. Cerebrovasc Dis, 2009,27,25-37. 15. Endemann DH and Schiffrin EL. Endothelial dysfunction. J Am Society Nephrology, 2004,15,1983-1992. 16. Pennathur S and Heinecke JW. Oxidative stress and endothelial dysfunction in vascular disease. Curr Diabetes Rep, 2007,10,257-264.

12

17. Ferrero-Miliani L, Nielsen OH, Andersen PS, Girardin SE. Chronic inflammation. importance of NOD2 and NALP3 in interleukin-1b generation. Clin Exp Imm, 2006,147,227235. 18. Verma S, Reddy K, Balakumar P.The Defensive Effect of Benfotiamine in Sodium Arsenite-Induced Experimental Vascular Endothelial Dysfunction. Biol Trace Elem Res, 2010, 101007/s12011-009-8567-7. 19. Balakumar P, Singh M. Different role of rho-kinase in pathological and physiological cardiac hypertrophy in rats. Pharmacol, 2006,78,91-97. 20. Koyanagi M, Kitamoto S, Usui M, Kaibuchi K, Kataoka HC, Egashira K et al. Important Role of Rho-kinase in the Pathogenesis of Cardiovascular Inflammation and Remodeling Induced by Long-Term Blockade of Nitric Oxide Synthesis in Rats. Hypertension, 2002,39,245-250. 21. Segain JP, Raingeard D, Bletiere de la, Sauzeau V, Bourreille A, Hilaret G et al . Rho-kinase blockade prevents inflammation via nuclear factor kappa B inhibition. evidence in Crohn's disease and experimental colitis. Gastroenterology, 124; 2003.1180-1187. 22. Brown JH, Del Re DP, Susssman MA.The Rac and Rho hall of fame. a decade of hypertrophy signalling hits. Circ Res, 2006,98,730-742. 23. Nohria A, Grunert ME, Rikitake Y, Noma K, Prsic A, Ganz P et al. Rho kinase inhibition improves endothelial functions in human subjects with coronary artery disease. Circ Res, 2006,99,14261432.

13

24. Feinberg MW, Shimizu K, Lebedeva M, Haspel R, Takayama K, Chen Z et al.Essential role for Smad3 in regulating MCP-1 expression and vascular inflammation. Circ Res, 2004,19,601-608. 25. Shireman PK, Contreras-Shannon V, Ochoa O, Karia BP, Michalel JE, McManus LM. MCP-1 deficiency causes altered inflammation with impaired skeletal muscle regeneration. J Leukoc Biol, 2007, 81,doi. 101189/jlb0506356. 26. Zhang W, Rojas M, Lilly B, Tsai NT, Lemtalsi T, Liou GI et al. NAD(P)H oxidase dependent regulation of CCL2 production during retinal inflammation. Invest Ophthalmol Vis Sci, 209, 50, 3033-3040. 27. Dhindsa S, Garg R, Bandyopathyay A, Dandona PN. Angiotensin II and Inflammation. The Effect of ACE Inhibition and Angiotensin II Receptor Blockade. Metabolic Syndrome and Related Disorders, 2003,4, 255-259. 28. Ferder L, Inserra F, Martnez-Maldonado M. Inflammation and the metabolic syndrome. role of angiotensin II and oxidative stress. Curr Hypertens Rep, 2006, 8, 191-198. 29. Ridker PM, Hennekens CH, Buring JE. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med, 2000,342,836843. 30. Shear CL, Pouleur HG, Ryder SW, Orloff DG. Biomarkers in the Prevention and Treatment of Atherosclerosis. Need Validation and Future. Pharmacol. Reviews, 2007,59,40-53.

14

31. Hansson GK. Inflammation Atherosclerosis and Coronary Artery Disease. NEJM, 2005,352,1685-1695. 32. Libby P, Ridker PM, Maseri A. Inflammation and Atherosclerosis. Circulation, 2002,105,1135-1143. 33. Paoletti R, Gotto AM, Hajjar Jr DP. Inflammation in Atherosclerosis and Implications for Therapy. Circulation, 2004,109,III-20 III-26. 34. Kaperonisa EA, Liapisa CD, Kakisisb JD, Dimitroulisa D, Papavassiliouc VG. Inflammation and Atherosclerosis. Eur. J. Vasc. Endo. Vasc. Surg, 2006,31,386393. 35. Schauer IE, Knaub LA, Lloyd M, Watson PA, Gliwa C, Lewis KE et al. CREB. Downregulation in Vascular Disease. A Common Response to Cardiovascular Risk. Arterioscl Thromb Vasc Bio,2010, 30,733-741. 36. Watanabe T, Suguro T, Kanome T, Sakamoto Y, Kodate S, Hagiwara T et al .Human Urotensin-II Accelerates Foam Cell Formation in Human MonocyteDerived Macrophages. Hypertension, 2005,46,738-744. 37. Mallamaci F, Cutrupi, S, Pizzini P, Tripepi G, Zoccali C. Urotensin II and Biomarkers of Endothelial Activation and Atherosclerosis in End-Stage Renal Disease. Am J Hyp, 2006,19,505510. 38. Suguro T, Watanabe T, Ban Y, Kodate S, Misaki A, Hirano T, Miyazaki A, Adachi M. Increased Human Urotensin II Levels Are Correlated With Carotid Atherosclerosis in Essential Hypertension. Am J Hyp, 2007,20,211217.

15

39. Cheung BM, Leung R, Man YB, Wong LY. Plasma concentration of urotensin II is raised in hypertension, J Hypertens, 2004, 22, 13411344. 40. Ng LL, Loke I, OBrien RJ, I B Squire, Davies JE. Plasma urotensin in human systolic heart failure. Circulation, 2002,106,28772880. 41. Androulakis E, Tousoulis D, Papageorgiou N, Tsioufis C, Kallikarzaros L, Stefanadis C. Essential Hypertension. Is There a Role for Inflammatory Mechanisms? Cardiol Rev, 2009,17, 216-221. 42. Mathew R. Inflammation and Pulmonary Hypertension. Cardiol in Rev, 2010, 18, 67-72S. 43. Brianna R, Sandra PR, Joseph BM, Benjamin DH, Chloe AA, Chloe M, Tami LB, John FC, Abdallah GK, Jeffery LA. C - reactive protein Predicts Death in Patients with Non-Ischemic Cardiomyopathy. Cardiology, 2005,104,196-201. 44. Bucova M, Bernadic M, Buckingham M. C-reactive protein cytokines and inflammation in cardiovascular disease. Bratisl Lek Listy, 2008,109,333-340. 45. Rompe F, Unger T, Steckelings UM. The angiotensin AT2 receptor in inflammation Drug News Perspect, 2010, 23, 104-111. 46. Savoia C, Schiffrin EL. Vascular inflammation in hypertension and diabetes. molecular mechanisms and therapeutic interventions Clinical Science, 2007, 112, 375384. 47. Savoia C, Schiffrin EL . Inflammation in hypertension. Curr Opin Nephrol Hypertens, 2006, 15, 152-158.

16

48. Clapp BR, Hirschfield GM, Storry C, Gallimore JR, Stidwilll RP, Singer M et al. Inflammation and Endothelial Function Direct Vascular Effects of Human C reactive protein on Nitric Oxide Bioavailability. Circulation, 2005, 111, 15301536. 49. Ruiz-Ortega M, Esteban V, Ruperez M, Sanchez-Lopez E, Rodriguez-Vita J, Carvajal G et al. Renal and vascular hypertension-induced inflammation. Role of angiotensin II. Pathophysiology of hypertension. Current Opinion in Nephrology & Hypertension, 2006, 15, 159-166. 50. Vaziri ND, Bai Y, Ni Z, Quiroz Y, Pandian R, Rodriguez-Iturbe B. Intra-Renal Angiotensin II/AT1 Receptor Oxidative Stress Inflammation and Progressive Injury in Renal Mass Reduction. JPET, 2007, 323, 8593. 51. Silvio D, Bin G. Interleukin-6. a therapeutic Jekyll and Hyde in gastrointestinal and hepatic diseases. Gut, 2010, 59, 149-151. 52. Cohen AW, Hnasko R, Schubert W, Lisanti MP. Role of Caveolae and Caveolins in Health and Disease. Physiol Rev, 2004, 84, 1341-1379. 53. Hatzistilianou KH, Eboriadou M, Papastavrou T, Magnesali C, Pappa S.

Neopterin and circulating adhesion molecules as prognostic markers in childhood asthma. Arch Med Sci, 2007, 3, 123-128. 54. Fuchs D, Weiss G, Wachter H. Neopterin biochemistry and clinical use as a marker for cellular immune reactions Int Arch Allergy Immunol,1993, 101, 1-6. 55. Garcia-Mol X, Cole D, Zouridakis E, Kaski JC. Increased serum neopterin. a marker of coronary artery disease activity in women. Heart, 2000, 83, 346-350.

17