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Angiotensin (Ang)-(1-7), a metabolite of AngI and AngII, is a counter-regulatory mediator of AngII. In the present study, we investigated the effects of Ang-(1-7) on AngII-induced apoptosis in human umbilical vein endothelial cells (HUVEC). To this end, HUVEC were pretreated with 10(-9), 10(-8), 10(-7) or 10(-6) mol/L Ang-(1-7) at for 30 min before being stimulated with 10(-6) mol/L Ang-II for another 24 h. Acridine orange/ethidium bromide and propidium iodide staining were used to analyse the effects of Ang-(1-7) on AngII-induced apoptosis. Alone, 10(-6) mol/L Ang-(1-7) had no effect on the apoptosis of HUVEC following exposure of cells for 30 min, whereas AngII (10(-6) mol/L, 24 h) significantly enhanced the number of apoptotic cells (P < 0.01). The AngII-induced apoptosis of HUVEC was suppressed by 10(-9)-10(-6) mol/L Ang-(1-7). The anti-apoptotic effects of Ang-(1-7) were almost completely abolished by A-779 (10(-6) mol/L, 30 min), a specific Mas receptor antagonist. In addition, Ang-(1-7) inhibited AngII-induced accumulation of cleaved caspase 3 and enhanced the expression of the anti-apoptotic factor Bcl-2 at both the mRNA and protein levels. Angiotensin II upregulated the expression of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), which is involved in endothelial apoptosis, at both the mRNA and protein levels. This effect was blocked by Ang-(1-7) in a concentration-dependent manner, although A-779 almost completely reversed Ang-(1-7)-mediated inhibition of AngII-induced upregulation of LOX-1. Silencing of LOX-1 using short interference RNA enhanced the protective effects of Ang-(1-7) against AngII-induced apoptosis in HUVEC. Together, the results suggest that Ang-(1-7) ameliorates AngII-induced apoptosis of HUVEC at least in part by suppressing LOX-1 expression., (© 2012 The Authors Clinical and Experimental Pharmacology and Physiology © 2012 Blackwell Publishing Asia Pty Ltd.)

Background and Aims: Amlodipine, a long-acting dihydropyridine calcium channel blocker, is able to improve angiotensin II-mediated vascular endothelial dysfunction. However, the underlying mechanism remains not fully understood. In the present study we attempted to determine whether the protective effect of amlodipine against Ang II-induced endothelial impairment was mediated through blockage of endothelial cell apoptosis., Methods: We pretreated human umbilical venous endothelial cells with increasing doses of amlodipine (10(-8)-10(-6) M) followed by the addition of Ang II. Cell apoptosis was assessed by acridine orange/ethidium bromide staining and by annexin-V/propidium iodide double-labeled cytometry. The involvement of the apoptosis regulators, Bcl-2, Bax, and lectin-like oxidized low-density lipoprotein receptor-1, was determined., Results: Pretreatment with amlodipine resulted in a dose-dependent suppression of Ang II-induced HUVEC apoptosis. Moreover, the Bcl-2/Bax ratio was found to be increased in cells pretreated with amlodipine, indicating an enhanced anti-apoptosis potential. Additionally, the induction of LOX-1 by Ang II was remarkably counteracted by the pre-exposure to amlodipine., Conclusions: Our data demonstrate that amlodipine ameliorates Ang II-induced endothelial apoptosis, which is likely associated with the elevation of Bcl-2/Bax ratio and reduction of the LOX-1 expression., (Copyright © 2011 IMSS. Published by Elsevier Inc. All rights reserved.)

Aims: Angiotensin II (ANG II)-induced inflammatory and oxidative stress responses contribute to the pathogenesis of hypertension. In this study, we determined whether nuclear factor-kappa B (NF-kappaB) activation in the hypothalamic paraventricular nucleus (PVN) increases oxidative stress and contributes to the ANG II-induced hypertensive response., Methods and Results: Rats were infused intravenously with ANG II (10 ng/kg per min) or saline for 4 weeks. These rats received either vehicle or losartan (LOS, 20 microg/h), an angiotensin II type 1 receptor (AT1-R) antagonist; pyrrolidine dithiocarbamate (PDTC, 5 microg/h), a NF-kappaB inhibitor; tempol (TEMP, 80 microg/h), a superoxide scavenger; LOS (20 microg/h), and PDTC (5 microg/h); or TEMP (80 microg/h) and PDTC (5 microg/h), given intracerebroventricularly (ICV) via osmotic minipump. ANG II infusion resulted in increased mean arterial pressure, renal sympathetic nerve activity, plasma proinflammatory cytokines (PIC), norepinephrine, and aldosterone. These rats also had higher levels of Fra-LI (an indicator of chronic neuronal activation), PIC, phosphorylated IKKbeta, NF-kappaB subunits, AT1-R, superoxide, and gp91phox (a subunit of NADP(H) oxidase) and lower levels of IkappaBalpha in the PVN than control animals. ICV treatment with LOS, PDTC, or TEMP attenuated these changes, and combined treatment with ICV LOS and PDTC, or ICV TEMP and PDTC prevented these ANG II-induced hypertensive responses., Conclusion: These findings suggest that an ANG II-induced increase in the brain renin-angiotensin system activates NF-kappaB in the PVN and contributes to sympathoexcitation in hypertension. The increased superoxide in the PVN contributes to NF-kappaB activation and neurohumoral excitation in hypertension.