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      Heterogeneity in the Acute Control of Vascular Protein Synthesis in vivo


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          In response to both hemodynamic and neurohumoral changes, the cardiovascular system remodels and this process could contribute to end organ damage. The aim of this study was to determine the early in vivo interactions between 3 systems known to contribute to vascular hypertrophic remodeling, in conduit and resistance arteries. Exogenous angiotensin II, norepinephrine and endothelin 1 administration elevated protein synthesis in the aorta and in small mesenteric arteries. In small arteries, the effect of angiotensin II was blocked by angiotensin II type 1, α-adrenergic and endothelin receptor antagonists, while only the α-adrenergic and endothelin receptor antagonists inhibited the effect of norepinephrine. Moreover, only the endothelin receptor antagonist significantly blunted the effect of exogenous endothelin on protein synthesis. In the aorta, the stimulation of angiotensin II on protein synthesis was also inhibited by the 3 antagonists. However, only the α-adrenoceptor antagonist blunted the response to norepinephrine, and the 3 antagonists prevented the endothelin-induced elevation of protein synthesis. The blood pressure effects of the drugs did not correlate with their capacity to stimulate or inhibit vascular protein synthesis. In conclusion, interactions in the control of protein synthesis are heterogeneous along the vascular tree. In small arteries, the interaction is linear with endothelin as the downstream effector. In the aorta, the local sympathetic nervous system appears to control protein synthesis. The heterogeneity in downstream effectors should be considered in studies investigating signaling events related to protein synthesis, which is used as an early marker of hypertrophy.

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          Most cited references 9

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          Cardiac and vascular fibrosis and hypertrophy in aldosterone-infused rats: role of endothelin-1.

          Increased endothelin-1 (ET-1) or aldosterone may be associated with promotion of cardiovascular hypertrophy and fibrosis. We evaluated whether the selective ETA receptor-antagonist BMS 182874 (BMS) prevents cardiac and vascular collagen deposition and hypertrophy in aldosterone-infused rats. Rats received subcutaneous aldosterone (0.75 microg/h) and 1% sodium chloride in drinking water +/- BMS (40 mg/kg per day in food) for 6 weeks. Heart and aorta were cross-sectioned and stained with Sirius red. Heart weight did not change with either aldosterone infusion or BMS treatment. Cardiac and aortic interstitial and perivascular collagen were quantified with videomorphometry. Aortic collagen and media cross-sectional area were significantly increased 3.5-fold (P .05 and P < .05, respectively). BMS prevented collagen deposition except for interstitial collagen in the right ventricle. Cardiac and aortic fibrosis were significantly increased in aldosterone-infused hypertensive rats. The ETA receptor antagonist prevented cardiac and aortic collagen deposition and aortic hypertrophy. This suggests a role for ET-1 in fibrosis of heart and large vessels in conditions associated with mineralocorticoid excess.
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            Apoptosis in aorta of deoxycorticosterone acetate-salt hypertensive rats: effect of endothelin receptor antagonism

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              Mildly oxidized low-density lipoprotein acts synergistically with angiotensin II in inducing vascular smooth muscle cell proliferation.

              Considerable attention has been focused on both mildly oxidized low-density lipoprotein (mox-LDL) and highly oxidized LDL (ox-LDL) as important risk factors for cardiovascular disease. Further, angiotensin II (Ang II) appears to play a crucial role in the development of hypertension and atherosclerosis. We assessed the effect of oxidatively modified LDL and its major oxidative components, i.e., hydrogen peroxide (H2O2), lysophosphatidylcholine (LPC), and 4-hydroxy-2-nonenal (HNE) and their interaction with Ang II on vascular smooth muscle cell (VSMC) DNA synthesis. Growth-arrested rabbit VSMCs were incubated in serum-free medium with different concentrations of native LDL, mox-LDL, ox-LDL, H2O2, LPC, or HNE with or without Ang II. DNA synthesis in VSMCs was measured by [3H]thymidine incorporation. Ang II stimulated DNA synthesis in a dose-dependent manner with a maximal effect at a concentration of 1 micromol/l (173%). Ang II (0.5 micromol/l) amplified the effect of native LDL at 500 ng/ml, ox-LDL at 100 ng/ml, and mox-LDL at 50 ng/ml on DNA synthesis (108 to 234%, 124 to 399%, 129 to 433%, respectively). H2O2 had a maximal effect at a concentration of 5 micromol/l (177%), LPC at 15 micromol/l (156%), and HNE at 0.5 micromol/l (137%). Low concentrations of H2O2 (1 micromol/l), LPC (5 micromol/l), or HNE (0.1 micromol/l) also acted synergisitically with Ang II (0.5 micromol/l) in inducing DNA synthesis to 308, 304, or 238%, respectively. Synergistic interactions of Ang II (0.5 micromol/l) with mox-LDL, ox-LDL (both 50 ng/ml), H2O2 (1 micromol/l), LPC (5 micromol/l), or HNE (0.1 micromol/l) on DNA synthesis were completely reversed by the combined use of probucol (10 micromol/l), a potent antioxidant and candesartan (0.1 micromol/l), an AT1 receptor antagonist. Our results suggest that mox-LDL, ox-LDL, and their major components H2O2, LPC, and HNE act synergistically with Ang II in inducing VSMC DNA synthesis. A combination of antioxidants with AT1 receptor blockade may be effective in the treatment of VSMC proliferative disorders associated with hypertension and atherosclerosis.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                April 2003
                19 June 2003
                : 40
                : 2
                : 123-131
                aFaculté de pharmacie, Université de Montréal, Montréal, et bCentre de recherche de l’Hôtel-Dieu de Québec, Université Laval, Québec, Canada
                70709 J Vasc Res 2003;40:123–131
                © 2003 S. Karger AG, Basel

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                Page count
                Figures: 2, Tables: 2, References: 40, Pages: 9
                Research Paper


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