TY - JOUR
T1 - Angiotensin-(1-7)-induced Mas receptor activation attenuates atherosclerosis through a nitric oxide-dependent mechanism in apolipoproteinE-KO mice
AU - Yang, Guang
AU - Istas, Geoffrey
AU - Höges, Sascha
AU - Yakoub, Mina
AU - Hendgen-Cotta, Ulrike
AU - Rassaf, Tienush
AU - Rodriguez-Mateos, Ana
AU - Hering, Lydia
AU - Grandoch, Maria
AU - Mergia, Evanthia
AU - Rump, Lars Christian
AU - Stegbauer, Johannes
PY - 2018/1/20
Y1 - 2018/1/20
N2 - Angiotensin (Ang)-(1-7) ameliorates vascular injury by increasing nitric oxide (NO) bioavailability. Evidence that Ang-(1-7) attenuates the development of atherosclerosis through a NO-dependent mechanism is still missing. Moreover, it has been postulated that Ang-(1-7) may mediate its effects by other mechanisms than Mas receptor activation. To investigate Ang-(1-7)-dependent Mas receptor function, we treated apoE-KO and apoE/Mas-KO mice chronically with Ang-(1-7) (82 μg/kg per hour) or saline for 6 weeks. Flow-mediated dilation (FMD), a measure for NO-dependent vasodilation and the most accepted prognostic marker for the development of atherosclerosis, was measured in vivo. Chronic Ang-(1-7) treatment improved FMD and attenuated the development of atherosclerosis in apolipoproteinE (apoE)-KO but not in apoE/Mas-KO mice. These effects were accompanied by increased aortic nitrite and cGMP levels. To test whether Ang-(1-7) modulates atherosclerosis through a NO-dependent mechanism, apoE-KO mice were treated with the NO synthase inhibitor L-NAME (20 mg/kg/day) in the presence or absence of Ang-(1-7). L-NAME treatment reduced aortic nitrite content and increased blood pressure and exaggerated atherosclerosis compared to untreated apoE-KO mice. In L-NAME-treated apoE-KO mice, chronic Ang-(1-7) treatment did not increase aortic nitrite content and consequently showed no effect on blood pressure and the development of atherosclerosis. The present study proves that Ang-(1-7) mediates its protective vascular effects through Mas receptor activation. Moreover, Ang-(1-7)-mediated NO generation is essential for improving vascular function and prevents atherosclerosis in apoE-KO mice.
AB - Angiotensin (Ang)-(1-7) ameliorates vascular injury by increasing nitric oxide (NO) bioavailability. Evidence that Ang-(1-7) attenuates the development of atherosclerosis through a NO-dependent mechanism is still missing. Moreover, it has been postulated that Ang-(1-7) may mediate its effects by other mechanisms than Mas receptor activation. To investigate Ang-(1-7)-dependent Mas receptor function, we treated apoE-KO and apoE/Mas-KO mice chronically with Ang-(1-7) (82 μg/kg per hour) or saline for 6 weeks. Flow-mediated dilation (FMD), a measure for NO-dependent vasodilation and the most accepted prognostic marker for the development of atherosclerosis, was measured in vivo. Chronic Ang-(1-7) treatment improved FMD and attenuated the development of atherosclerosis in apolipoproteinE (apoE)-KO but not in apoE/Mas-KO mice. These effects were accompanied by increased aortic nitrite and cGMP levels. To test whether Ang-(1-7) modulates atherosclerosis through a NO-dependent mechanism, apoE-KO mice were treated with the NO synthase inhibitor L-NAME (20 mg/kg/day) in the presence or absence of Ang-(1-7). L-NAME treatment reduced aortic nitrite content and increased blood pressure and exaggerated atherosclerosis compared to untreated apoE-KO mice. In L-NAME-treated apoE-KO mice, chronic Ang-(1-7) treatment did not increase aortic nitrite content and consequently showed no effect on blood pressure and the development of atherosclerosis. The present study proves that Ang-(1-7) mediates its protective vascular effects through Mas receptor activation. Moreover, Ang-(1-7)-mediated NO generation is essential for improving vascular function and prevents atherosclerosis in apoE-KO mice.
KW - Journal Article
U2 - 10.1007/s00424-018-2108-1
DO - 10.1007/s00424-018-2108-1
M3 - Article
C2 - 29352340
SN - 0031-6768
JO - Pfl�s Archiv / European Journal of Physiology
JF - Pfl�s Archiv / European Journal of Physiology
ER -