Endothelial dysfunction

A substrate for the synthesis of NO that has a potential for improving endothelial dysfunction. 

Fig. 2.1 Sequence of events in atherogenesis and role of low-density lipoprotein. Native LDL, in the subendothelial space, undergoes progressive oxidation (mmLDL) and activates the expression of MCP-1 and M-CSF in the endothelium (EC). MCP-1 and M-CSF promote the entry and maturation of monocytes to macrophages, which further oxidise LDL (oxLDL). Ox-LDL is specifically recognised by the scavenger receptor of macrophages and, once internalised, formation of foam cells occurs. Both mmLDL and oxLDL induce endothelial dysfunction, associated with changes of the adhesiveness to leukoc)des or platelets and to wall permeability.

DREXLERH and HORNiG B (1999) Endothelial dysfunction in human disease of Molecular and Cellular Cardiology 31, 51-60. 

Drexler, H., Zeiher, A.M., Meinzer, K. and Just, H. (1991). Correction of endothelial dysfunction in cotronaty microcirculation of hypercholesterolaemic patients by L-arginine. Lancet 338, 1546-1550. 

Patients with HF are at an increased risk of thromboembolic events secondary to a combination of hypercoagulability, relative stasis of blood, and endothelial dysfunction. However, the role of antiplatelets and anticoagulants remains debatable due to a lack of prospective clinical trials. 

Factors that predispose an individual to IHD are listed in Table 4—2. Hypertension, diabetes, dyslipidemia, and cigarette smoking are associated with endothelial dysfunction and potentiate atherosclerosis of the coronary arteries. The risk for IHD increases two-fold for every 20 mm Hg increment in systolic blood pressure and up to eight-fold in the presence of diabetes.5,6 Physical inactivity and obesity independently increase the risk for IHD, in addition to predisposing individuals to other cardiovascular risk factors (e.g., hypertension, dyslipidemia, and diabetes). 

Angiotensin II is a neurohormone produced primarily in the kidney. It is a potent vasoconstrictor and stimulates the production of aldosterone. Together, angiotensin II and aldosterone increase blood pressure and sodium and water retention (increasing ventricular wall tension), cause endothelial dysfunction, promote blood clot formation, and cause myocardial fibrosis. 

Endothelial dysfunction, inflammation, and the formation of fatty streaks contribute to the formation of atherosclerotic coronary artery plaques, the underlying cause of coronary artery disease (CAD). The predominant cause of ACS, in more than 90% of patients, is atheromatous plaque rupture, Assuring, or erosion of an unstable atherosclerotic plaque that occludes less than 50% of the coronary lumen prior to the event, rather than a more stable 70% to 90% stenosis of the coronary artery.3 Stable stenoses are characteristic of stable angina. 

To reduce mortality, administration of an aldosterone antagonist, either eplerenone or spironolactone, should be considered within the first 2 weeks following MI in all patients who are already receiving an ACE inhibitor (or ARB) and have an EF of equal to or less than 40% and either heart failure symptoms or diagnosis of diabetes mellitus.3 Aldosterone plays an important role in heart failure and in MI because it promotes vascular and myocardial fibrosis, endothelial dysfunction, hypertension, left ventricular hypertrophy, sodium retention, potassium and magnesium loss, and arrhythmias. Aldosterone antagonists have been shown in experimental and human studies to attenuate these adverse effects.70 Spironolactone decreases all-cause mortality in patients with stable, severe heart failure.71... 

McDermott DH, Halcox JP, Schenke WH, et al. Association between polymorphism in the chemokine receptor CX3CR1 and coronary vascular endothelial dysfunction and atherosclerosis. Circ Res 2001 89(5) 401—407. 

V3. Vermes, I., Spooren, P. F. M. J., Kalsbeek-Batenburg, E. M., and Haanen, C., In addition to von Willebrand factor and urinary albumin excretion, plasma endothelin is an indicator of endothelial dysfunction in diabetes mellitus. Diabetes 36,472-473 (1993). 

Hozawa, A, Jacobs, DR, Jr., Steffes, MW, Gross, MD, Steffen, LM, and Lee, DH, 2007. Relationships of circulating carotenoid concentrations with several markers of inflammation, oxidative stress, and endothelial dysfunction The Coronary Artery Risk Development in Young Adults (CARDIA)/Young Adult Longitudinal Trends in Antioxidants (YALTA) study. Clin Chem 53,447 455. 

If persistent, these molecules (coding for inflammation, oxidative stress, remodeling, and thrombosis) can cause endothelial dysfunction and acceleration of arthrosclero-sis progression [117]. SWNTs were shown also to alter the cardiac activity by affecting the arterial baroreflex function (BRF) of sinus mode in rats exposed by intratracheal instillation [118]. 

Prasad A, Narayanan S, Husain S, Padder F, Waclawiw M, Epstein N, Quyyumi AA. Insertion-deletion polymorphism of the ACE gene modulates reversibility of endothelial dysfunction with ACE inhibition. Circulation 2000 102 35-41. 

Butler R, Morris AD, Burchell B, Struthers AD. DD angiotensin-converting enzyme gene polymorphism is associated with endothelial dysfunction in normal humans. Hypertension 1999 33 1164-1168. 

Duffy SJ, Keaney JF Jr, Holbrook M, Gokce N, Swerdloff PL, Frei B and Vita JA. 2001. Short- and longterm black tea consumption reverses endothelial dysfunction in patients with coronary artery disease. Circulation 104(2) 151-156. 

Arteel and Sies (1999) examined procyanidin oligomers of different size, isolated from the seeds of Theobroma cacao, for their ability to protect against nitration of tyrosine. Serraino and others (2003) investigated antioxidant activity of the blackberry juice and cyanidin-3-O-glucoside on endothelial dysfunction in cells and in vascular rings exposed to peroxynitrite. However, more work is needed in this area, and the confounding effects of oxidized protein/amino acids in the diet need to be elucidated. 

Serraino I, Dugo L, Dugo P, Mondello L, Mazzon E, Dugo G, Caputi AP and Cuzzocre S. 2003. Protective effects of cyanidin-3-O-glucoside from blackberry extract against peroxynitrite-induced endothelial dysfunction and vascular failure. Life Sci 73(9) 1097-1114. 

In the recent review Carr et al. [54] considered potential antiatherogenic mechanisms of a-tocopherol and ascorbic acid. These authors concluded that these antioxidants are able to inhibit LDL oxidation, leukocyte adhesion to the endothelium, and vascular endothelial dysfunction. They also believe that ascorbic acid is more effective than a-tocopherol in the inhibition of these pathophysiological processes due to its capacity of reacting with a wide spectrum of oxygen and nitrogen free radicals and its ability to regenerate a-tocopherol. 

The formation of atherosclerotic plaques is the underlying cause of coronary artery disease (CAD) and ACS in most patients. Endothelial dysfunction leads to the formation of fatty streaks in the coronary arteries and eventually to atherosclerotic plaques. Factors responsible for development of atherosclerosis include hypertension, age, male gender, tobacco use, diabetes mellitus, obesity, and dyslipidemia. 

The response-to-injury hypothesis states that risk factors such as oxidized LDL, mechanical injury to the endothelium, excessive homocysteine, immunologic attack, or infection-induced changes in endothelial and intimal function lead to endothelial dysfunction and a series of cellular interactions that culminate in atherosclerosis. The eventual clinical outcomes may include angina, myocardial infarction, arrhythmias, stroke, peripheral arterial disease, abdominal aortic aneurysm, and sudden death. 

Vascular changes include thickening of pulmonary vessels that may lead to endothelial dysfunction of the pulmonary arteries. Later, structural changes increase pulmonary pressures, especially during exercise. In severe COPD, secondary pulmonary hypertension leads to right-sided heart failure (cor pulmonale). 

Wassmann S, Laufs U, Stamenkovic D, Linz W, Stasch JP, Ahlbory K, Rosen R, Bohm M, Nickening G (2002) Raloxifene improves endothelial dysfunction in hypertension by reduced oxidative stress and enhanced nitric oxide production. Circulation 105 2083-2091... 

Perrault LP, Malo O, Bidouard JP, Villeneuve N, Vilaine JP, Vanhoutte PM (2003) Inhibiting the NO pathway with intracoronary L-NAME infusion increases endothelial dysfunction and intimal hyperplasia after heart transplantation. J Heart Lung Transplant 22 439-451... 

Dysregulation of the vascular endothelium has emerged as a critical component of most thrombotic disorders [10, 21]. Often without any anatomical sign of atherosclerosis, many cardiovascular diseases express a vasomotor abnormality termed endothelial dysfunction, indexed clinically as impaired endothelium-dependent vasodilation [31]. Although its mechanism is multifactorial, endothelial dysfunction is characterized by diminished vascular NO production and/or bioavailability [32]. The... 

Lefer, D.J., Nakanishi, K., Vinten-Johansen, J., Ma, X.L., and Lefer, A.M., Cardiac venous endothelial dysfunction after myocardial ischemia and reperfusion in dogs, Am. J. Physiol, 263, H850-H856, 1992. 

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