Abstract P135: Deletion of the Mas Receptor Aggravates Vascular Dysfunction and the Development of Atherosclerosis Through a NO-dependent Mechanism in Apolipoprotein E-deficient Mice
Recently, we have shown that chronic Ang-(1-7) treatment acting through the Mas receptor improves vascular dysfunction in atherosclerotic apolipoprotein E-deficient (apoE-KO) mice by increasing NO bioavailability. To test whether deletion of the Mas receptor aggravates atherosclerosis and to examine the underlying mechanism, we generated apoE/Mas-KO mice.
12 weeks old ApoE-KO and apoE/Mas-KO mice fed on a lipid-rich Western diet were treated via osmotic minipumps with either saline or Ang-(1-7) (82 μg/kg/h) for 6 weeks. Aortae were stained with red oil and quantified for atherosclerosis. To examine whether Ang-(1-7) modulates the development of atherosclerosis through a NO dependent mechanism, 8 weeks old apoE-KO mice treated with L-NAME (20mg/kg/d) were infused either with Ang-(1-7) or saline for 6 weeks. Tissue nitrite, a marker for NO generation was measured by HPLC.
Endothelial dependent vasodilation and atherosclerosis was significantly impaired in apoE/Mas-KO mice compared to apoE-KO (relative lesion area of the aortic arch: 38.7±3.0 vs. 25.4±2.0%; P<0.01; specific lesion area 11.7±0.9 vs. 8.1±1.0mm2 P<0.01). Moreover, nitrotyrosin and urinary 8-Isoprostane levels, both markers for oxidative stress were significantly increased in apoE/Mas-KO compared to apoE-KO mice. In contrast, chronic Ang-(1-7) treatment attenuated atherosclerotic lesion in apoE-KO (11.1±2.6% vs. 25.4±2.0, P<0.01 and 3.1±0.8mm2 vs. 8.1±1.0, P<0.01) but not in apoE/Mas-KO mice (38.7±3.0 vs. 38.0±14.2% and 11.7±0.9 vs. 11.4±5.0mm2). Additionally, aortic nitrite content was increased in Ang-(1-7) treated apoE-KO compared to untreated apoE-KO mice (180±31 vs. 311±47μM/g, P<0.05). L-NAME treatment increased blood pressure (BP) and reduced aortic nitrite content significantly compared to sham-treated apoE-KO mice. However, Ang-(1-7) treatment did not affect BP (127±3 vs. 128±3mmHg), aortic nitrite (861±16 vs. 1004±174 μM/g) content and the development of atherosclerosis in L-NAME treated apoE-KO mice.
In conclusion, our findings indicate that Ang-(1-7) improves atherosclerosis via Mas receptor activation. Moreover, these effects seems to mediated through a NO-dependent mechanism as Ang-(1-7) failed to affect atherosclerosis in L-NAME treated mice.
Author Disclosures: G. Yang: None. K. Grave: None. M. Thieme: None. U. Hendgen-Cotta: None. L.C. Rump: None. J. Stegbauer: None.
- © 2015 by American Heart Association, Inc.