Background-Angiotensin II (ATII), a potent vasoconstrictor, causes hypertension, promotes infiltration of myelomonocytic cells into the vessel wall, and stimulates both vascular and inflammatory cell NADPH oxidases.
Clinical Perspective on p 1381Primary sources of ROS in the cardiovascular system are the Nox-based, multisubunit enzymes NADPH oxidases. 3 Several Nox isoforms are expressed and functional in phagocytic cells like monocytes, macrophages, and neutrophils (myelomonocytic cells); T cells; endothelial cells; vascular smooth muscle cells; and adventitial fibroblasts. All of these have been suggested to contribute to cardiovascular pathology, 3,4 although the importance of individual cell types and their relative impact on the development of cardiovascular disease remain unclear.The phagocytic NADPH oxidase is a major source of ROS elicited by angiotensin II (ATII). 5 In ApoE Ϫ/Ϫ mice fed a high-fat diet, the extent of atherosclerotic lesions is attenuated by limiting the burden of superoxide generated by myelomonocytes. 6 Leukocyte activation by ATII involving the phagocyte-type NADPH oxidase had been demonstrated in
The correlation between mtROS formation and acetylcholine-dependent relaxation revealed that mitochondrial radical formation significantly contributes to age-dependent endothelial dysfunction.
Chronic nitroglycerin treatment results in development of nitrate tolerance associated with endothelial dysfunction (ED). We sought to clarify how mitochondria- and NADPH oxidase (Nox)-derived reactive oxygen species (ROS) contribute to nitrate tolerance and nitroglycerin-induced ED. Nitrate tolerance was induced by nitroglycerin infusion in male Wistar rats (100 microg/h/4 day) and in C57/Bl6, p47(phox/) and gp91(phox/) mice (50 microg/h/4 day). Protein and mRNA expression of Nox subunits were unaltered by chronic nitroglycerin treatment. Oxidative stress was determined in vascular rings and mitochondrial fractions of nitroglycerin-treated animals by L-012 enhanced chemiluminescence, revealing a dominant role of mitochondria for nitrate tolerance development. Isometric tension studies revealed that genetic deletion or inhibition (apocynin, 0.35 mg/h/4 day) of Nox improved ED, whereas nitrate tolerance was unaltered. Vice versa, nitrate tolerance was attenuated by co-treatment with the respiratory chain complex I inhibitor rotenone (100 microg/h/4 day) or the mitochondrial permeability transition pore blocker cyclosporine A (50 microg/h/4 day). Both compounds improved ED, suggesting a link between mitochondrial and Nox-derived ROS. Mitochondrial respiratory chain-derived ROS are critical for the development of nitrate tolerance, whereas Nox-derived ROS mediate nitrate tolerance-associated ED. This suggests a crosstalk between mitochondrial and Nox-derived ROS with distinct mechanistic effects and sites for pharmacological intervention.
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