Endothelium Dysfunction and Inflammatory Mediators

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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


Rayat institute of pharmacy, railmajra,

Distt Nawanshahar (Punjab),India.

pin code 144514


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 Rayat Institute of Pharmacy Rail Majra,              Distt-
     Nawanshahar, India (Punjab)
         2 PCTE institute of Pharmacy, Ludhiana, Punjab

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

             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,



         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 [11-

12] 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) platelet-

derived 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-κB 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-κB 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            . 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 P-

selectin ICAM-1 and E-selectin which in turn persuade process of leucocyte adhesion and
subsequently their migration leading to formation of fatty streak formation              . 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 C-

reactive 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


        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.


       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 activity of                  Increased
     Increased                  Cycloxygenase                      expression of
   expression of                    enzyme                          chemokines

                                 Inflammation                                  Activation of
                                                                             C-reactive protein

 of AT-II receptor       Increased expression of             Activation of
                         adhesion molecules                   Rho-kinase

                   ROS                                eNOS


                               Further damage
                               of endothelium

                                  Heart failure
                              Rheumatoid arthritis
                           Diabetes and renal disorder

Fig 1. Various signalling pathways involved in the pathogenesis of inflammation-

   induced VED

                        Inflammation –
                        induced VED

                                    Activation of
                                   RAAS pathway

                                                                  Direct vasoconstriction
                                                                  ↑Sympathetic outflow
                                                                  ↑Aldosterone release

                                  ↑ROS             Increase expression of
                                                     ICAM and VCAM


Fig 2. Pathogenesis of Inflammation induced cardiovascular disorders


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