A REVIEW ARTICLE ON ENDOTHELIAL DYSFUNCTION IN PATIENT WITH TYPE 2 DIABETES MELLITUS

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The endothelial cells involved in modulating vascular tone and structure. Endothelial cells produce a vast range of causes that also regulate cellular adhesion, smooth muscle proliferations and vessel wall inflammation. Endothelial function is important for homeostasis of the body and its dysfunction is associated with several pathophysiology conditions like diabetes, atherosclerosis. Sufferers with diabetes at all times exhibit an impairment of endotheliumdependent vasodilation. Therefore, working out and treating endothelial dysfunction is the principle focus within the prevention of vascular problems associated with all types of diabetes mellitus. This review will focus on the pathophysiology, assessment and therapeutics that exceptionally target endothelial dysfunction within the context of diabetic setting. Pathophysiology including nitric oxide, oxidative stress, angII, diabetes will be discussed. Pharmacological approaches that upregulate endothelium derives nitric oxide synthase and treatment that might prevent the development of diabetes associated vascular complications will be discussed. Keywords: endothelial dysfunction, nitric oxide, nitric oxide synthase ,vascular smooth muscle cells, endothelialderived hyperpolarizing factors.
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  IAJPS 2018, 05 (02), 1102-1114 Sandhya Badoni et al  ISSN 2349-7750 www.iajps.com   Page 1102 CODEN [USA]: IAJPBB ISSN: 2349-7750 INDO AMERICAN JOURNAL OF PHARMACEUTICAL SCIENCES   http://doi.org/10.5281/zenodo.1188219 Available online at: http://www.iajps.com  Review Article    A REVIEW ARTICLE ON   ENDOTHELIAL DYSFUNCTION IN PATIENT WITH TYPE 2 DIABETES MELLITUS Sandhya Badoni *, Arun Kumar, Aarti Sati *Division of Pharmaceutical Sciences, Shri Guru Ram Rai Institute of Technology and Science, Dehradun, Uttarakhand, India Abstract: The endothelial cells involved in modulating vascular tone and structure. Endothelial cells produce a vast range of causes that also regulate cellular adhesion, smooth muscle proliferations and vessel wall inflammation. Endothelial  function is important for homeostasis of the body and its dysfunction is associated with several pathophysiology conditions like diabetes, atherosclerosis. Sufferers with diabetes at all times exhibit an impairment of endothelium-dependent vasodilation. Therefore, working out and treating endothelial dysfunction is the principle focus within the  prevention of vascular problems associated with all types of diabetes mellitus. This review will focus on the  pathophysiology, assessment and therapeutics that exceptionally target endothelial dysfunction within the context of diabetic setting. Pathophysiology including nitric oxide, oxidative stress, angII, diabetes will be discussed.  Pharmacological approaches that upregulate endothelium derives nitric oxide synthase and treatment that might  prevent the development of diabetes associated vascular complications will be discussed. Keywords:  endothelial dysfunction, nitric oxide, nitric oxide synthase ,vascular smooth muscle cells, endothelial-derived hyperpolarizing factors. Corresponding author: Sandhya Badoni,  Division of Pharmaceutical Sciences, Shri Guru Ram Rai Institute of Technology and Science,  Dehradun, Uttarakhand, India  Please cite this article in press as Sandhya Badoni et al   ,    A Review Article on   Endothelial Dysfunction in Patient with Type 2 Diabetes Mellitus  , Indo Am. J. P. Sci, 2018; 05(02).   QR   code  IAJPS 2018, 05 (02), 1102-1114 Sandhya Badoni et al  ISSN 2349-7750 www.iajps.com   Page 1103 1. INTRODUCTION Diabetes mellitus is a metabolic disorder which affects millions of inhabit worldwide. Numbers compiled by WHO reveal that approximately 150 million people comprise diabetes mellitus & this number may be double by the year of 2050. This may be direct to generously proportioned population, obesity, transform in dietetic practice etc   [1][2][3].   Type 2 Diabetes Mellitus multiply the danger of cardiovascular disease. Hyperglycaemia is the key aspect which develops the endothelial dysfunction in diabetes mellitus. The mechanism underlying for this is however unpredictable. A number of studies suggested that NO-mediated vasodilation is abnormal in a patient suffering from type 2 diabetes mellitus [93].. Obese  patients without type 2 Diabetes mellitus have been shown also to have an abnormal endothelial function (Steinberg et al 1996; Perticone et al 2001 ). Vascular endothelial provides a substantial barrier  between the vessel wall and the lumen & also secrets several mediators like endothelin 1, thromboxane 2 (for vasoconstriction), nitric oxide (NO)/endothelial-derived hyperpolarizing factors (EDHF) for vasodilation. [5] Patients suffering from diabetes, can leads to an impairment of NO production and activity. Endothelium impairs due to diabetes mellitus, can cause endothelial dysfunction & which can be considered as the earliest tread of the cardiovascular disease (CVD)[4].Due to diabetes-induced endothelial dysfunction, it may cause various complications such as vascular ischemia, coronary artery disease (CAD),  peripheral vascular disease (PVD) etc[1]. Up to 75%  patient with diabetes dies due to dysfunction of endothelium. 1.1 Endothelial cell Endothelial cell acts as a barrier which provides a  physiological protection. Endothelial cell serves as  pool between circulating blood and vascular smooth muscle cells (VSMC)[8][6][7] .The main function of the endothelium is coagulation, platelet adhesion,thrombosis,regulation of vascular tone, control volume & electrolyte content of intravascular and extravascular spaces   [6][7]. Fig 1: Functions performed by endothelium Endothelium is enclosed by a glycocalyx that serves to the selectivity of its barrier function (van Haaren et al. 2003). Moreover, the endothelium assures the fluidity of blood by its contribution to hemostasis. Blood coagulation limit, the formation of a platelet thrombus and production of fibrinolysis regulators are prevented  by living endothelial cells(van Hinsbergh 2001)[2].The endothelium, not individual responds to vasoactive agents but is also involved in the catabolism, metabolism, and synthesis of various vasoactive agents, particularly in the lung (Shaul 1999)[2].Endothelium-derived factors having a Vasodilating and antiproliferative property include endothelium-derived hyperpolarization factor (EDHF) , nitric oxide (NO) and prostacyclin (PGI2) . Ang II & ROS exerts vasoconstrictor effects [9]. Because endothelium is the central monitor of vascular homeostasis, it maintains the equilibrium between vasodilation and vasoconstriction. THROMBOSIS PLATELET ADHESION VSMC PROLIFERATION FIBRINOLYSIS VASCULAR PERMEABILITY ENDOTHELIUM    IAJPS 2018, 05 (02), 1102-1114 Sandhya Badoni et al  ISSN 2349-7750 www.iajps.com   Page 1104 (Acetylcholine ) O 2 Arginine nitric oxide EC  NOS GUANYLATE CYCLASE GTP c-GMP VSMC Produces Relaxation Fig.2: Endothelial cell as a regulator of the smooth muscle cells [8]. As shown in figure 2 the endothelial cell (EC) produces nitric oxide (NO), gas that diffuses into the vascular smooth muscle cells (VSMC) and activates the enzyme guanylate cyclase which produces recurring GMP. The latter induces muscle relaxation, which is  physiologically translated into vasodilation. The direct srcinator of NO is the amino acid arginine and the  basis enzyme in its creation is nitric oxide synthase (NOS) [8].Endothelial cells are as well reliable for the maintenance of blood fluidity and restoration of vessel  partition integrity (when injured) to avoid bleeding [8].Endothelial cell-derived factors additionally are critical mediators of VSMC development and inflammation [6][10]. 1.2 Nitric oxide  NO plays an essential role in vascular homeostasis. In endothelial cells, L-arginine converts in the presence of endothelial nitric oxide synthase (eNOS) to L-citrulline and furthermore synthesized nitric oxide. Circulating  blood & receptor-operated substances such as acetylcholine; bradykinin derived a shear stress due to which NO released from endothelial cells [9][11][12].  Nitric oxide Diffuses Vascular smooth muscle cells (VSMC) Activates Soluble guanylate cyclase (sGC) Increased level of Cyclic guanosine -3, 5-monophosphate (cGMP) Causes Relaxation of VSMC Fig 3. Nitric oxide function pathway [9]  IAJPS 2018, 05 (02), 1102-1114 Sandhya Badoni et al  ISSN 2349-7750 www.iajps.com   Page 1105  Nitric oxide performs numerous functions such as vasodilation (maintains B.P.), decrease oxidation of LDL, reduces platelet aggregation, prevents leukocyte adhesion, decrease endothelin production [9][13][14]. Mechanism of action of NO :  Nitric oxide is unconfined by the endothelial cells through assorted stimuli, such as 5-OH-tryptamine, acetylcholine, thrombin, arachidonic acid, changes in arterial  pressure, etc., either as NO or bound to a -SH group-containing carrier molecule (e.g. L-cys) that stabilizes  NO release[15][16][17]. In the smooth muscle cells,  NO released and it activates the guanylate cyclase and mounting the intensity of intracellular messenger cGMP. This make happens relaxation of smooth muscle, inhibition of platelet aggregation [17][18].    NO is not as much stable than other endothelial vasodilators, such as prostacyclin. Mutually, endothelial agent’s  causes platelet aggregation & relaxation of vessels, but through different mechanism [16], that is the rise in cGMP flatten in platelet and central nervous system & increases in intracellular cGMP level respectively. In addition, NO free by neutrophills and other white cells enhance the platelet antiaggregant effect of PGI 2  [16]. NO be able to require to oxi-Hb & Fc-SH complexes of other proteins, thus modulating the movement of many hepatic enzyme [19][20] Studies on isolated hepatocytes showed that [21], phosphorilation of IP 3  (cGMP dependent protein kinase receptor) increases its sensitivity to P-inositol by the emit of free intracellular calcium ion. An additional hypothesis suggests that hyperpolarizing factor  produces by endothelium may induce vasodilation. In the smooth muscles, it is demonstrated that NO induces hyperpolarization through the opening of K  +  channels [22][23]. 1.3 Decreased level of NO eNOS (endothelial nitric oxide synthase) is depending upon various factors for its multiple activity and functions.BH 4  (tetrahydrobiopterin) sustain the diamer structure & bioavailability of eNOS. Synthesis of BH 4  is completed by the enzyme called Guanosine-5-triphosphate cyclohydrolase 1 (GTPCH 1). GTPCH 1 is playing an important role to maintain BH 4  level &  NO production [9] A decreased activity of eNOS is mainly responsible for the decrease level of NO production. Oxidative stress causes eNOS uncoupling, in which activity of eNOS decreased and it will generate reactive oxygen species (ROS) as an alternative of nitric oxide. The mechanism through which eNOS uncoupled is  –   oxidation of BH4, depletion of enzyme L-arginine, and accumulation of endogenous methylarginine [9][25]. The activity of eNOS is also regulated by insulin inside the endothelial cells. By increasing BH4 synthesis, insulin can regulate the eNOS activity. Due to insulin resistance, insulin mediated endothelial vasodilation is impaired. Contrarily, because of the function of NO in  peripheral tissues, eNOS plays an important role in the regulation of insulin sensitivity. Endogenous products of arginine metabolism (ADMA = asymmetric dimethyl-L-arginine) inhibited the eNOS [24]. After oxidative stress, there are changes in ADMA level & they cause a reduction in NO formation which causes endothelial dysfunction [9][24]. 2. ENDOTHELIAL DYSFUNCTION AND DIABETES MELLITUS Diabetes is besides measured as a vascular disease for the reason that it produces effects on macro and microcirculation of numerous vascular cells/beds [9]. As soon as endothelium loses its physiological  properties such as affinity to promote vasodilation, fibrinolysis and anti-aggregation. In that case this is called endothelial dysfunction. Prolong exposure to hyperglycemia is the key culprit in the pathogenesis of diabetic complications, concerning augmented ROS and RNS production. Oxidative stress leads to an imbalance in the vascular homeostasis due to increased vasoconstriction and impaired vasorelaxtion that finally  bring up diabetic endothelial dysfunction. Table 1: Difference between a healthy and dysfunctional endothelium HEALTHY ENDOTHELIUM DYSFUNCTIONAL ENDOTHELIUM    Vasodilatory ( NO, PGI 2 )    impaired vasodilation ( NO, PGI 2 )    Oxidative stress, low uric acid    Oxidative stress, uric acid      Repair (EPCs), damage (CECs,MPs)    Repair(EPCs), damage (CECs,MPs)      Anti-coagulant    Pro-coagulant   *NO- niric oxide *PGI 2 -prostacyclin *EPCs-endothelial progenitor cells *CECs-circulating endothelial cells *MPs-microparticles
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