Angiotensin-(1-7)-induced Mas receptor activation attenuates atherosclerosis through a nitric oxide-dependent mechanism in apolipoproteinE-KO mice

Abstract

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.

Increased Reactive Oxygen Species Generation Contributes to the Atherogenic Activity of the B2 Bradykinin Receptor

“…Pathomechanisms identified in this study could act in concert with already established B2 and/or AT1 receptor-dependent atherogenic activities. Notably, the following mechanisms mediated by the B2 and/or AT1 receptor could play a direct or indirect role in B2 bradykinin receptor-enhanced atherosclerosis: (I) The B2 bradykinin receptor could promote atherosclerosis by the reduced activation of atheroprotective AT1-inhibitory receptors, AGTR2 and MAS1 (34, 50–52), which are directly down-regulated by the B2 bradykinin receptor and angiotensin II AT1 receptor (34, 53) and indirectly dampened via angiotensin II AT1-mediated ACE2 down-regulation (54). (II) In addition, the B2 bradykinin receptor could enhance atherogenesis by decreasing the expression of the vasculoprotective endothelial Kruppel-like factor 4, KLF4 (55), which is directly downregulated by angiotensin II AT1 stimulation [(56); NCBI GEO dataset GSE19286 in Abd Alla et al (7)], and indirectly down-regulated by reduced Mas receptor activation (57).…”

The potential actions of angiotensin‐converting enzyme II (ACE2) activator diminazene aceturate (DIZE) in various diseases

“…The non‐classical axis consists of ACE2 converting Ang II into Ang (1‐7), a heptapeptide that stimulates the Mas oncogene receptor (MasR) expressed on blood vessels . Numerous experimental studies have shown that Ang (1‐7) exerts a vasoprotective role by increasing NO bioavailability possibly through the MasR resulting in improved vasodilation . Additionally, ACE2 produces alamandine through the conversion of Ang A .…”

Pathobiological Interactions of Local Bone Marrow Renin-Angiotensin System and Central Nervous System in Systemic Arterial Hypertension

“…This results in decreased circulation levels of a subtype of T cells, neutrophils and macrophages ( 93 ). To research Ang-(1-7)-dependent Mas receptor function, Yang et al used apoE-KO and apoE/Mas-KO mice with Ang-(1-7) or saline for 6 weeks ( 94 ). To check whether Ang-(1-7) regulates atherosclerosis through a NO-dependent pathway, apoE-KO mice were used with the NO synthase inhibitor in the presence or lack of Ang-(1-7) ( 94 ).…”

“…To research Ang-(1-7)-dependent Mas receptor function, Yang et al used apoE-KO and apoE/Mas-KO mice with Ang-(1-7) or saline for 6 weeks ( 94 ). To check whether Ang-(1-7) regulates atherosclerosis through a NO-dependent pathway, apoE-KO mice were used with the NO synthase inhibitor in the presence or lack of Ang-(1-7) ( 94 ). Ang-(1-7) has been shown to have protective vascular effects through Mas receptor activation ( 94 ).…”

“…To check whether Ang-(1-7) regulates atherosclerosis through a NO-dependent pathway, apoE-KO mice were used with the NO synthase inhibitor in the presence or lack of Ang-(1-7) ( 94 ). Ang-(1-7) has been shown to have protective vascular effects through Mas receptor activation ( 94 ).…”