Abdominal aortic aneurysm (AAA) is a life-threatening situation affecting almost 10% of elders. There has been no effective medication for AAA other than surgical intervention. Dipeptidyl peptidase-4 (DPP-4) inhibitors have been shown to have a protective effect on cardiovascular disease. Whether DPP-4 inhibitors may be beneficial in the treatment of AAA is unclear. We investigated the effects of DPP-4 inhibitor sitagliptin on the angiotensin II (Ang II)-infused AAA formation in apoE-deficient (apoE-/-) mice. Mice with induced AAA were treated with placebo or 2.5, 5 or 10 mg/kg/day sitagliptin. Ang II-infused apoE-/- mice exhibited a 55.6% incidence of AAA formation, but treatment with sitagliptin decreased AAA formation. Specifically, administered sitagliptin in Ang II-infused mice exhibited decreased expansion of the suprarenal aorta, reduced elastin lamina degradation of the aorta, and diminished vascular inflammation by macrophage infiltration. Treatment with sitagliptin decreased gelatinolytic activity and apoptotic cells in aorta tissues. Sitaglipitn, additionally, was associated with increased levels of plasma active glucagon-like peptide-1 (GLP-1). In vitro studies, GLP-1 decreased reactive oxygen species (ROS) production, cell migration, and MMP-2 as well as MMP-9 activity in Ang II-stimulated monocytic cells. The results conclude that oral administration of sitagliptin can prevent abdominal aortic aneurysm formation in Ang II-infused apoE-/-mice, at least in part, by increasing of GLP-1 activity, decreasing MMP-2 and MMP-9 production from macrophage infiltration. The results indicate that sitagliptin may have therapeutic potential in preventing the development of AAA.
Increased plasma DPP-4 activity may correlate with aneurysmal development. CD26 on monocytes plays a critical role in cell differentiation, possibly mediated by extracellular signal-regulated protein kinase 1/2-p21 axis signaling pathways and cytoskeletal proteins reassembly. Exploring the role of DPP-4 further may yield potential therapeutic insights.
Aortic dissection (AD) is a highly lethal vascular disease characterized by separation of the constituent layers of the aortic wall. An increasing body of research indicates that inflammatory response and oxidative stress are implicated in vascular remodeling, which plays a key role in the development of AD. Hydrogen sulfide (H2S) has been found to protect against various types of cardiovascular disease, including myocardial infarction, arthrosclerosis, and hypertension. However, research on the effect of H2S on AD is insufficient. This study therefore elucidated the effect of H2S on the development and progression of AD, and the potential mechanism involved. Using β-aminopropionitrile fumarate (BAPN) and angiotensin II (Ang-II)-induced AD animal models, the administration of NaHS (as H2S donor, 56 μmol/kg body weight/day) was found to retard the development of AD. Murine VSMCs (Movas) exposed to interleukin-6 (IL-6) (20 ng/mL) to induce phenotypic switch. Histological analyses indicated that H2S administration inhibited the accumulation of inflammatory cells in the aortic wall and the related expression of inflammatory genes. Additionally, H2S treatment elevated aortic superoxide dismutase (SOD) activity and ablated malonaldehyde (MDA) and nitric oxide (NO) levels. In mechanistic terms, H2S attenuated IL-6 induced a pathological VSMC phenotypical switch through NO modulation by N(G)-monomethyl-L-arginine acetate salt (L-NMMA) stimulation. H2S inhibits AD formation by decreasing the inflammatory response, and oxidative stress, and by positively participating in vascular remodeling. These findings suggest a role for H2S as a novel and promising therapeutic strategy to prevent AD development.
Galectin-3 (Gal-3) is a 26-kDa lectin that regulates many aspects of inflammatory cell behavior. We assessed the hypothesis that increased levels of Gal-3 contribute to abdominal aortic aneurysm (AAA) progression by enhancing monocyte chemoattraction through macrophage activation. We analyzed the plasma levels of Gal-3 in 76 patients with AAA (AAA group) and 97 controls (CTL group) as well as in angiotensin II (Ang-II)-infused ApoE knockout mice. Additionally, conditioned media (CM) were used to polarize THP-1 monocyte to M1 macrophages with or without Gal-3 inhibition through small interfering RNA targeted deletion to investigate whether Gal-3 inhibition could attenuate macrophage-induced inflammation and smooth muscle cell (SMC) apoptosis. Our results showed a markedly increased expression of Gal-3 in the plasma and aorta in the AAA patients and experimental mice compared with the CTL group. An in vitro study demonstrated that the M1 cells exhibited increased Gal-3 expression. Gal-3 inhibition markedly decreased the quantity of macrophage-induced inflammatory regulators, including IL-8, TNF-α, and IL-1β, as well as messenger RNA expression and MMP-9 activity. Moreover, Gal-3-deficient CM weakened SMC apoptosis through Fas activation. These findings prove that Gal-3 may contribute to AAA progression by the activation of inflammatory macrophages, thereby promoting SMC apoptosis.
OBJECTIVES Although commercial iliac branch devices offer a new and valid endovascular approach to treating iliac aneurysm and effectively preserve antegrade flow of the internal iliac artery, their use may not be suited for all types of challenging anatomy, especially isolated common iliac artery aneurysm. Our custom-made iliac bifurcation device has a unique design and excludes both combined and isolated iliac branch aneurysm. This study validated the efficacy and safety of the custom device by comparing clinical outcomes between groups receiving commercial and custom devices. METHODS Data of consecutive patients receiving iliac bifurcation device implantation for iliac aneurysm with or without concomitant endovascular repair for abdominal aortic aneurysm from January 2010 to May 2019 were reviewed. RESULTS Iliac bifurcation device implantation with or without concomitant abdominal aortic aneurysm stent grafting was completed in 46 patients (commercial, n = 35; custom, n = 11). No significant differences were observed regarding postoperative complications, occlusion or endoleak. Comparisons of primary (80.8% vs 85.7%, P = 0.88) and secondary (86.5% vs 85.7%, P = 0.85) patency and freedom from reintervention (88.2% vs 100%, P = 0.33), all-cause mortality (78.6% vs 100%, P = 0.25) and aneurysm-related mortality (100% vs 100%, P = 1.00) also indicated no differences at a 5-year surveillance point. Furthermore, the iliac aneurysms of the groups displayed similar shrinkage 1 year after procedures. CONCLUSIONS For iliac aneurysm, the novel custom-made iliac bifurcation device is an adaptable design not inferior to commercial devices with regard to postoperative complications, bridge occlusion, endoleak and short-term aneurysm remodelling. It provides an alternative for treatment, particularly when certain anatomic challenges are present. Clinical trial registration 2018-07-050BC, 2017-01-023ACF.
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