angiotensin-i and Aortic-Aneurysm--Abdominal

To test the hypothesis that angiotensin-(1-7) [Ang-(1-7)] may attenuate abdominal aortic aneurysm (AAA) via inhibiting vascular inflammation, extracellular matrix degradation, and smooth muscle cell (SMC) apoptosis, an animal model of AAA was established by angiotensin II (Ang II) infusion to apolipoprotein E-knockout (ApoE. All mice and cultured SMCs or macrophages were divided into control, Ang II-treated, Ang II + Ang-(1-7)-treated, Ang II + Ang-(1-7) + A779-treated and Ang II + Ang-(1-7) + PD123319-treated groups respectively. In vivo, aortic mechanics and serum lipids were assessed. Ex vivo, AAA were examined by histology, immunohistochemistry and zymography. Cultured cells were analysed by RT-PCR, western blots and TUNEL assays.. In vivo, Ang-(1-7) reduced the incidence and severity of AAA induced by Ang II infusion, by inhibiting macrophage infiltration, attenuating expression of IL-6, TNF-α, CCL2 and MMP2, and decreasing SMC apoptosis in abdominal aortic tissues. Addition of A779 or PD123319 reversed Ang-(1-7)-mediated beneficial effects on AAA. In vitro, Ang-(1-7) decreased expression of mRNA for IL-6, TNF-α, and CCL2 induced by Ang II in macrophages. In addition, Ang-(1-7) suppressed apoptosis and MMP2 expression and activity in Ang II-treated SMCs. These effects were accompanied by inhibition of the ERK1/2 signalling pathways via Ang-(1-7) stimulation of Mas and AT. Ang-(1-7) treatment attenuated Ang II-induced AAA via inhibiting vascular inflammation, extracellular matrix degradation, and SMC apoptosis. Ang-(1-7) may provide a novel and promising approach to the prevention and treatment of AAA.

Topics: Angiotensin I; Angiotensin II; Animals; Aortic Aneurysm, Abdominal; Disease Models, Animal; Mice; Mice, Inbred C57BL; Mice, Knockout, ApoE; Peptide Fragments

Topics: Angiotensin I; Angiotensin II; Animals; Aortic Aneurysm, Abdominal; Apolipoproteins E; Blood Pressure; Disease Models, Animal; Humans; Imidazoles; Immunohistochemistry; Lipids; Male; MAP Kinase Signaling System; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, Knockout; Molecular Mimicry; Myocytes, Smooth Muscle; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Peptide Fragments

Angiotensin (Ang)I is cleaved by angiotensin-converting enzyme (ACE) to generate AngII. The purpose of this study was to determine the roles of ACE in endothelial and smooth muscle cells in aortic aneurysms.Methods and Results:AngI infusion led to thoracic and abdominal aortic aneurysms in low-density lipoprotein receptor-deficient mice, which were ablated by ACE inhibition. Endothelial or smooth muscle cell-specific ACE deletion resulted in reduction of AngI-induced thoracic, but not abdominal, aortic dilatation.. AngI infusion causes thoracic and abdominal aortic aneurysms in mice. ACE in aortic resident cells has differential effects on AngI-induced thoracic and abdominal aortic aneurysms.

Topics: Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta, Abdominal; Aorta, Thoracic; Aortic Aneurysm, Abdominal; Aortic Aneurysm, Thoracic; Dilatation, Pathologic; Disease Models, Animal; Endothelial Cells; Mice, Knockout; Myocytes, Smooth Muscle; Peptidyl-Dipeptidase A; Receptors, LDL

Hyperhomocysteinemia (HHcy) is a risk factor for various cardiovascular diseases. However, the mechanism underlying HHcy-aggravated vascular injury remains unclear. Here we show that the aggravation of abdominal aortic aneurysm by HHcy is abolished in mice with genetic deletion of the angiotensin II type 1 (AT1) receptor and in mice treated with an AT1 blocker. We find that homocysteine directly activates AT1 receptor signalling. Homocysteine displaces angiotensin II and limits its binding to AT1 receptor. Bioluminescence resonance energy transfer analysis reveals distinct conformational changes of AT1 receptor upon binding to angiotensin II and homocysteine. Molecular dynamics and site-directed mutagenesis experiments suggest that homocysteine regulates the conformation of the AT1 receptor both orthosterically and allosterically by forming a salt bridge and a disulfide bond with its Arg

Topics: Allosteric Regulation; Angiotensin I; Angiotensin II; Animals; Aortic Aneurysm, Abdominal; HEK293 Cells; Homocysteine; Humans; Male; Mice, Inbred C57BL; Molecular Dynamics Simulation; Mutagenesis, Site-Directed; Protein Conformation; Receptor, Angiotensin, Type 1; Vascular System Injuries

Angiotensin-converting enzyme (ACE) inhibitors have proven their ability to affect vascular wall remodelling, in addition to their anti-hypertensive effects. The aim of this study was to assess the impact of perindopril on the development of abdominal aortic aneurysm (AAA) in a rat model, and its correlation to enzyme activities involved in vascular wall remodelling.. The model of the decellularised aortic xenograft in Lewis rat was chosen. Rats were randomised to two groups: group P fed with 3 mg kg(-1) of perindopril daily during 30 days, or control group C (n = 15 per group)). Rats were euthanised at 30 days for analysis. AAA growth and histological changes in the aortic wall were measured by histomorphometry. Proteolytic activities were measured by gelatin zymography of conditioned medium for activematrix metalloproteinase 9/pro-matrix metalloproteinase 9 (MMP9/pro-MMP9) and activeMMP2/pro-MMP2, and by quantitative immunofluorescence tissue for elastase and plasmin.. The mean maximal diameter of AAAs at 30 days was significantly lower in the treated group P compared with the control group C (2.5 ± 1.0 vs. 4.9 ± 2.1 mm; P < 0.01). The expansion rate of AAAs after 30 days was significantly reduced in group P compared with group C (36 ± 14% vs. 67 ± 23%; P < 0.01). Pro-MMP9 and MMP9 activities were significantly decreased in relative intensity (RI) in group P compared with group C (0.43 ± 0.64 RI vs. 1.02 ± 0.61 RI, P = 0.01; 0.18 ± 0.57 RI vs. 0.66 ± 1.19 RI, P = 0.004). The activation rate of MMP2 was also significantly lower in group P compared with group C (1.27 ± 0.42 vs. 1.67 ± 0.44; P = 0.002). Elastase and plasmin tissue activities were significantly lower in group P compared with group C, respectively (3.9 ± 3.3 vs. 5.8 ± 3.7 IF min(-1) g(-1),and 25.9 ± 23.9 vs. 49.1 ± 38.7 IF min(-1) g(-1); P < 0.05).. After 30 days of treatment by perindopril, a significant decrease in aneurysmal degeneration of the decellularised aortic xenograft AAA model was observed. This phenomenon appears to be induced by a downregulation of enzymes involved in the aortic wall remodelling during aneurysmal degeneration.

Topics: Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Aortic Rupture; Blood Pressure; Disease Models, Animal; Down-Regulation; Enzyme Precursors; Fibrinolysin; Gelatinases; Guinea Pigs; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Pancreatic Elastase; Peptide Hydrolases; Perindopril; Rats; Rats, Inbred Lew; Renin; Time Factors; Transplantation, Heterologous