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
1
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
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
2
Distt-
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
3
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.
4
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
5
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
6
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.
7
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.
8
Increased activity of
Cycloxygenase
enzyme
Increased
expression of
NF-kB
Increased
expression of
chemokines
Activation of
C-reactive protein
Inflammation
Overactivation
of AT-II receptor
Increased expression of
adhesion molecules
ROS
Activation of
Rho-kinase
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
9
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
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