Abstract
Inflammation and oxidative stress play a crucial role in angiotensin (Ang) II-mediated vascular injury. Angiotensin-converting enzyme 2 (ACE2) has recently been identified as a specific Ang II-degrading enzyme but its role in vascular biology remains elusive. We hypothesized that loss of ACE2 would facilitate Ang II-mediated vascular inflammation and peroxynitrite production. 10-week wildtype (WT, Ace2+/y) and ACE2 knockout (ACE2KO, Ace2−/y) mice received with mini-osmotic pumps with Ang II (1.5 mg.kg−1.d−1) or saline for 2 weeks. Aortic ACE2 protein was obviously reduced in WT mice in response to Ang II related to increases in profilin-1 protein and plasma levels of Ang II and Ang-(1–7). Loss of ACE2 resulted in greater increases in Ang II-induced mRNA expressions of inflammatory cytokines monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-1β, and IL-6 without affecting tumor necrosis factor-α in aortas of ACE2KO mice. Furthermore, ACE2 deficiency led to greater increases in Ang II-mediated profilin-1 expression, NADPH oxidase activity, and superoxide and peroxynitrite production in the aortas of ACE2KO mice associated with enhanced phosphorylated levels of Akt, p70S6 kinase, extracellular signal-regulated kinases (ERK1/2) and endothelial nitric oxide synthase (eNOS). Interestingly, daily treatment with AT1 receptor blocker irbesartan (50 mg/kg) significantly prevented Ang II-mediated aortic profilin-1 expression, inflammation, and peroxynitrite production in WT mice with enhanced ACE2 levels and the suppression of the Akt-ERK-eNOS signaling pathways. Our findings reveal that ACE2 deficiency worsens Ang II-mediated aortic inflammation and peroxynitrite production associated with the augmentation of profilin-1 expression and the activation of the Akt-ERK-eNOS signaling, suggesting potential therapeutic approaches by enhancing ACE2 action for patients with vascular diseases.
Highlights
Vascular inflammation and oxidative stress play a crucial role in the pathogenesis of vascular injury mediated by angiotensin (Ang) II, the major effector peptide of the renin-angiotensin system (RAS) [1,2,3]
We demonstrated that Angiotensin-converting enzyme 2 (ACE2) deficiency mice develop impaired cardiac functions, pathological remodeling with enhanced inflammatory cytokines, oxidative stress and ERK1/2 activation in heart [20,22,23] whereas ACE2 overexpression prevents Ang II-induced inflammation, oxidative stress and ERK1/2 activation in association with an attenuation of cardiovascular remodeling and dysfunction [9,23,24], suggesting a critical role ACE2 in regulation of inflammation, oxidative stress and cardiovascular function
We firstly evaluated the effects of Ang II on aortic expressions of ACE2 and profilin-1
Summary
Vascular inflammation and oxidative stress play a crucial role in the pathogenesis of vascular injury mediated by angiotensin (Ang) II, the major effector peptide of the renin-angiotensin system (RAS) [1,2,3]. Ang II has recently been shown to induce vascular injury by modulating release of inflammatory chemokines such as monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-1b, IL-6 [2,3] and promoting the NADPH oxidase activation and superoxide (O2–) production [4,5], contributing to endothelial nitric oxide (NO) synthase (eNOS) uncoupling and impaired NO bioavailability as well as vascular oxidative stress [1,6,7]. Ang II is a well-known activator of profilin-1, extracellular signal-regulated kinases (ERK) and phosphatidylinositol 3-kinase (PI3K)/Akt signaling cascades, leading to increased formation of nitrotyrosine, an index of peroxynitrite damage to vascular tissues [1,9,10,11,12]. Little is known regarding the relationship among profilin-1, inflammation and peroxynitrite production in the vascular diseases
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