In established lesions, resident macrophages secrete metal- loproteinases and cathepsins, destabilizing the fibrous cap of the plaque, which may result in plaque rupture and the release of tissue factor to cause thrombosis, coronary occlu- sion, and acute MI. Endothelial dysfunction and decreased nitric oxide avail- ability related to mechanical and inflammatory injury of arter- ies are also associated with increased arterial stiffness and the development of isolated systolic hypertension.75 A decline in flow-mediated vasodilator capacity attributable to decreased endothelium-derived nitric oxide occurs in aging and subclini- cal vascular disease.76 Impaired endothelium-mediated vaso- dilation is responsible for the exaggerated exercise-induced increases in BP seen in these population groups.77 1.2.4. Oxidative Stress Oxidative stress is a critical feature of both hypertension and In vascular tissue, the principal effectors of oxidative injury are the NAD(P)H oxidases, which are acti- vated by mechanical forces (eg, hypertension), hormones (particularly angiotensin II), oxidized cholesterol, and cyto- kines. Several NAD(P)H oxidase isoforms expressed in endo- thelial and vascular smooth muscle cells are upregulated in the setting of atherosclerosis and arterial injury. Angiotensin II receptor dependent activation of NAD(P)H oxidase stim- ulates formation of oxidant superoxide anion (O2 ), which reacts with nitric oxide to form the powerful oxidant per- oxynitrite (ONOO ). The resultant reduction in nitric oxide bioactivity contributes to the vasoconstrictor response to angiotensin II and elevates BP. Angiotensin II induced activa- tion of NAD(P)H oxidase also stimulates oxidation of low- density lipoprotein cholesterol and increases the expression of monocyte chemoattractant protein-1 and vascular cell adhe- sion molecule-1, thus linking activation of the RAAS to the atherosclerotic process. 1.2.5. Humoral and Metabolic Factors Many of the mechanisms that initiate and maintain hyper- tension also damage target organs, including the coronary arteries and the myocardium. 