Matthias R Meyer1, Matthias Barton2, Eric R Prossnitz3. 1. Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States. 2. Molecular Internal Medicine, University of Zürich, Zürich, Switzerland. 3. Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States. Electronic address: eprossnitz@salud.unm.edu.
Abstract
AIMS: Aging, a physiological process and main risk factor for cardiovascular and renal diseases, is associated with endothelial cell dysfunction partly resulting from NADPH oxidase-dependent oxidative stress. Because increased formation of endothelium-derived endothelin-1 (ET-1) may contribute to vascular aging, we studied the role of NADPH oxidase function in age-dependent contractions to ET-1. MAIN METHODS: Renal arteries and abdominal aortas from young and old C57BL6 mice (4 and 24 months of age) were prepared for isometric force measurements. Contractions to ET-1 (0.1-100 nmol/L) were determined in the presence and absence of the NADPH oxidase-selective inhibitor gp91ds-tat (3 μmol/L). To exclude age-dependent differential effects of NO bioactivity between vascular beds, all experiments were conducted in the presence of the NO synthase inhibitor L-NAME (300 μmol/L). KEY FINDINGS: In young animals, ET-1-induced contractions were 6-fold stronger in the renal artery than in the aorta (p<0.001); inhibition of NADPH oxidase by gp91ds-tat reduced the responses to ET-1 by 50% and 72% in the renal artery and aorta, respectively (p<0.05). Aging had no effect on NADPH oxidase-dependent and -independent contractions to ET-1 in the renal artery. In contrast, contractions to ET-1 were markedly reduced in the aged aorta (5-fold, p<0.01 vs. young) and no longer sensitive to gp91ds-tat. SIGNIFICANCE: The results suggest an age-dependent heterogeneity of NADPH oxidase-mediated vascular contractions to ET-1, demonstrating an inherent resistance to functional changes in the renal artery but not in the aorta with aging. Thus, local activity of NADPH oxidase differentially modulates responses to ET-1 with aging in distinct vascular beds.
AIMS: Aging, a physiological process and main risk factor for cardiovascular and renal diseases, is associated with endothelial cell dysfunction partly resulting from NADPH oxidase-dependent oxidative stress. Because increased formation of endothelium-derived endothelin-1 (ET-1) may contribute to vascular aging, we studied the role of NADPH oxidase function in age-dependent contractions to ET-1. MAIN METHODS: Renal arteries and abdominal aortas from young and old C57BL6 mice (4 and 24 months of age) were prepared for isometric force measurements. Contractions to ET-1 (0.1-100 nmol/L) were determined in the presence and absence of the NADPH oxidase-selective inhibitor gp91ds-tat (3 μmol/L). To exclude age-dependent differential effects of NO bioactivity between vascular beds, all experiments were conducted in the presence of the NO synthase inhibitor L-NAME (300 μmol/L). KEY FINDINGS: In young animals, ET-1-induced contractions were 6-fold stronger in the renal artery than in the aorta (p<0.001); inhibition of NADPH oxidase by gp91ds-tat reduced the responses to ET-1 by 50% and 72% in the renal artery and aorta, respectively (p<0.05). Aging had no effect on NADPH oxidase-dependent and -independent contractions to ET-1 in the renal artery. In contrast, contractions to ET-1 were markedly reduced in the aged aorta (5-fold, p<0.01 vs. young) and no longer sensitive to gp91ds-tat. SIGNIFICANCE: The results suggest an age-dependent heterogeneity of NADPH oxidase-mediated vascular contractions to ET-1, demonstrating an inherent resistance to functional changes in the renal artery but not in the aorta with aging. Thus, local activity of NADPH oxidase differentially modulates responses to ET-1 with aging in distinct vascular beds.
Authors: Mary L Modrick; Dale A Kinzenbaw; Yi Chu; Curt D Sigmund; Frank M Faraci Journal: Am J Physiol Regul Integr Comp Physiol Date: 2012-03-28 Impact factor: 3.619
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