Angiotensin II-induced Aortic Aneurysm Formation Research Articles

Loss of myeloid Tsc2 predisposes to angiotensin II-induced aortic aneurysm formation in mice

RationaleGenetic studies have proved the involvement of Tuberous sclerosis complex subunit 2 (Tsc2) in aortic aneurysm. However, the exact role of macrophage Tsc2 in the vascular system remains unclear. Here, we examined the potential function of macrophage Tsc2 in the development of aortic remodeling and aortic aneurysms.Methods and resultsConditional gene knockout strategy combined with histology and whole-transcriptomic analysis showed that Tsc2 deficiency in macrophages aggravated the progression of aortic aneurysms along with an upregulation of proinflammatory cytokines and matrix metallopeptidase-9 in the angiotensin II-induced mouse model. G protein-coupled receptor 68 (Gpr68), a proton-sensing receptor for detecting the extracellular acidic pH, was identified as the most up-regulated gene in Tsc2 deficient macrophages compared with control macrophages. Additionally, Tsc2 deficient macrophages displayed higher glycolysis and glycolytic inhibitor 2-deoxy-D-glucose treatment partially attenuated the level of Gpr68. We further demonstrated an Tsc2-Gpr68-CREB network in macrophages that regulates the inflammatory response, proteolytic degradation and vascular homeostasis. Gpr68 inhibition largely abrogated the progression of aortic aneurysms caused by Tsc2 deficiency in macrophages.ConclusionsThe findings reveal that Tsc2 deficiency in macrophages contributes to aortic aneurysm formation, at least in part, by upregulating Gpr68 expression, which subsequently drives proinflammatory processes and matrix metallopeptidase activation. The data also provide a novel therapeutic strategy to limit the progression of the aneurysm resulting from Tsc2 mutations.

The C57Bl/6J mouse strain is more susceptible to angiotensin II-induced aortic aneurysm formation than C57Bl/6N

Background and aimsGenetic variations between C57Bl/6 mouse substrains are highly relevant to the investigation of cardiovascular disease. We here assessed whether these variations have an impact on the incidence of abdominal aortic aneurysms (AAA) in C57Bl/6J and 6 N mice. MethodsAAA were induced by subcutaneous infusion of 1500 ng/kg*min Angiotensin-II for four weeks in six-month-old male CB57Bl/6J and 6N mice. Aortic smooth muscle cells (VSMC) were isolated from untreated animals for in vitro analysis. ResultsC57Bl/6J mice are more susceptible to AAA formation (76.5% vs. 7.1%, p = 0.0002). C57Bl/6J VSMC expressed more pro-inflammatory molecules such as Nlrp3, Aim2 and NF-κB. Additionally, these cells presented significantly higher levels of NADP/NADPH and oxidative DNA modifications, as indicated by 8-OHdG-staining, compared to C57Bl/6N VSMC. ConclusionsIn contrast to previous reports, we present evidence that six-month-old C57BL/6J, but not C57BL/6N mice develop AAA. In accordance with the deficiency of nicotinamide-nucleotide-transhydrogenase (Nnt), C57BL/6J VSMC displayed increased oxidative stress, oxidative DNA damage and a stronger inflammatory phenotype than C57BL/6N VSMC.

The protective effect of puerarin on angiotensin II-induced aortic aneurysm formation by the inhibition of NADPH oxidase activation and oxidative stress-triggered AP-1 signaling pathways.

Puerarin, an active ingredient of Pueraria lobata, has a range of pharmacological effects and excellent pharmacodynamic properties. In the present study, the effect of puerarin on angiotensin II-induced aortic aneurysm formation and the potential underlying molecular mechanisms were examined. The results revealed that puerarin significantly suppressed the viability, and induced the apoptosis, of aneurysm-inducing cells in a time- and dose-dependent manner. Furthermore, treatment with puerarin significantly suppressed the production of reactive oxygen species (ROS) and the expression of matrix metalloproteinase-2 (MMP-2) protein in aneurysm cells. Puerarin treatment significantly increased caspase-9 and -3 activity, induced the protein expression of phosphorylated (p)-Jun and inhibited the protein expression of activator protein 1 (AP-1) in aneurysm cells. It was also demonstrated that Puerarin significantly suppressed the reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase activity in aneurysm cells. Therefore, it was demonstrated that puerarin on suppressed the cell growth of angiotensin II-induced aortic aneurysm formation by affecting the rate of apoptosis, the generation of ROS, MMP-2, AP-1 and p-Jun protein expression and NADPH oxidase.

Oxidised low-density lipoproteins induce platelet adhesion, activation and spreading through novel CD36-tyrosine kinase/Rho kinase dependent signalling pathways

Oxidised low-density lipoproteins induce platelet adhesion, activation and spreading through novel CD36-tyrosine kinase/Rho kinase dependent signalling pathways

A new role for the regulator of g-protein signalling-1 in inflammatory cell function in angiotensin II-induced aortic aneurysm formation

A new role for the regulator of g-protein signalling-1 in inflammatory cell function in angiotensin II-induced aortic aneurysm formation

Combination Therapy with Atorvastatin and Amlodipine Suppresses Angiotensin II-Induced Aortic Aneurysm Formation

BackgroundAbdominal aortic aneurysm (AAA) is a life-threatening vascular disease. It is controversial whether statin and calcium channel blockers (CCBs) has an inhibitory effect on the expansion of AAA. Some studies reported that CCBs have an inhibitory effect on Rho-kinase activity. Rho-kinase plays an important role in the pathogenesis of various cardiovascular diseases. However, there is no study reporting of the association between Rho-kinase and human AAAs.Methods and ResultsExperimental AAA was induced in Apolipoprotein E-deficient (ApoE-/-) mice infused with angiotensin II (AngII) for 28 days. They were randomly divided into the following 5 groups; saline infusion alone (sham), AngII infusion alone, AngII infusion plus atorvastatin (10 mg/kg/day), AngII infusion plus amlodipine (1 mg/kg/day), and AngII infusion plus combination therapy with atorvastatin (10 mg/kg/day) and amlodipine (1 mg/kg/day). The combination therapy significantly suppressed AngII-induced increase in maximal aortic diameter as compared with sham, whereas each monotherapy had no inhibitory effects. The combination therapy significantly reduced AngII-induced apoptosis and elastin degradation at the AAA lesion, whereas each monotherapy did not. Moreover, Rho-kinase activity, as evaluated by the extent of phosphorylation of myosin-binding subunit (a substrate of Rho-kinase) and matrix metalloproteinase activity were significantly increased in the AngII-induced AAA lesion as compared with sham, both of which were again significantly suppressed by the combination therapy. In human aortic samples, immunohistochemistory revealed that the activity and expression of Rho-kinase was up-regulated in AAA lesion as compared with abdominal aorta from control subjects.ConclusionsRho-kinase is up-regulated in the aortic wall of human AAA. The combination therapy with amlodipine and Atorvastatin, but not each monotherapy, suppresses AngII-induced AAA formation in mice in vivo, for which Rho-kinase inhibition may be involved.