scholarly journals Tropoelastin: an in vivo imaging marker of dysfunctional matrix turnover during abdominal aortic dilation

2019 ◽  
Author(s):  
Begoña Lavin ◽  
Sara Lacerda ◽  
Marcelo E Andia ◽  
Silvia Lorrio ◽  
Robert Bakewell ◽  
...  
Keyword(s):  
Magnetic Resonance ◽  
Aortic Aneurysm ◽  
Murine Model ◽  
In Vivo Imaging ◽  
Gene Knockout ◽  
Aortic Dilation ◽  
Luminal Diameter ◽  
Enhanced Mri ◽  
Abdominal Aortic

Abstract Aims Dysfunctional matrix turnover is present at sites of abdominal aortic aneurysm (AAA) and leads to the accumulation of monomeric tropoelastin rather than cross-linked elastin. We used a gadolinium-based tropoelastin-specific magnetic resonance contrast agent (Gd-TESMA) to test whether quantifying regional tropoelastin turnover correlates with aortic expansion in a murine model. The binding of Gd-TESMA to excised human AAA was also assessed. Methods and results We utilized the angiotensin II (Ang II)-infused apolipoprotein E gene knockout (ApoE−/−) murine model of aortic dilation and performed in vivo imaging of tropoelastin by administering Gd-TESMA followed by late gadolinium enhancement (LGE) magnetic resonance imaging (MRI) and T1 mapping at 3 T, with subsequent ex vivo validation. In a cross-sectional study (n = 66; control = 11, infused = 55) we found that Gd-TESMA enhanced MRI was elevated and confined to dilated aortic segments (control: LGE=0.13 ± 0.04 mm2, control R1= 1.1 ± 0.05 s−1 vs. dilated LGE =1.0 ± 0.4 mm2, dilated R1 =2.4 ± 0.9 s−1) and was greater in segments with medium (8.0 ± 3.8 mm3) and large (10.4 ± 4.1 mm3) compared to small (3.6 ± 2.1 mm3) vessel volume. Furthermore, a proof-of-principle longitudinal study (n = 19) using Gd-TESMA enhanced MRI demonstrated a greater proportion of tropoelastin: elastin expression in dilating compared to non-dilating aortas, which correlated with the rate of aortic expansion. Treatment with pravastatin and aspirin (n = 10) did not reduce tropoelastin turnover (0.87 ± 0.3 mm2 vs. 1.0 ± 0.44 mm2) or aortic dilation (4.86 ± 2.44 mm3 vs. 4.0 ± 3.6 mm3). Importantly, Gd-TESMA-enhanced MRI identified accumulation of tropoelastin in excised human aneurysmal tissue (n = 4), which was confirmed histologically. Conclusion Tropoelastin MRI identifies dysfunctional matrix remodelling that is specifically expressed in regions of aortic aneurysm or dissection and correlates with the development and rate of aortic expansion. Thus, it may provide an additive imaging marker to the serial assessment of luminal diameter for surveillance of patients at risk of or with established aortopathy.

scholarly journals In Vivo Aortic Magnetic Resonance Elastography in Abdominal Aortic Aneurysm

2020 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Huiming Dong ◽  
Duncan S. Russell ◽  
Alan S. Litsky ◽  
Matthew E. Joseph ◽  
Xiaokui Mo ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Magnetic Resonance ◽  
Aortic Aneurysm ◽  
Magnetic Resonance Elastography ◽  
Abdominal Aortic

scholarly journals One amino acid change of Angiotensin II diminishes its effects on abdominal aortic aneurysm

2019 ◽  
Vol 39 (5) ◽  
Author(s):  
Ya Wang ◽  
Yinchuan Xu ◽  
Congqing Wu ◽  
Hongguang Xia ◽  
Yingchao Wang ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Amino Acid ◽  
Aortic Aneurysm ◽  
Infusion Rate ◽  
Amino Acid Change ◽  
Aortic Rupture ◽  
Mouse Strains ◽  
Aortic Dilation ◽  
Abdominal Aortic

Abstract Angiotensin (Ang) A is formed by the decarboxylation of the N terminal residue of AngII. The present study determined whether this one amino acid change impacted effects of AngII on abdominal aortic aneurysm (AAA) formation in mice. Computational analyses implicated that AngA had comparable binding affinity to both AngII type 1 and 2 receptors as AngII. To compare effects of these two octapeptides in vivo, male low-density lipoprotein receptor (Ldlr) or apolipoprotein E (Apoe) deficient mice were infused with either AngII or AngA (1 μg/kg/min) for 4 weeks. While AngII infusion induced AAA consistently in both mouse strains, the equivalent infusion rate of AngA did not lead to AAA formation. We also determined whether co-infusion of AngA would influence AngII-induced aortic aneurysm formation in male Apoe−/− mice. Co-infusion of the same infusion rate of AngII and AngA did not change AngII-induced AAA formation. Since it was reported that a 10-fold higher concentration of AngA elicited comparable vasoconstrictive responses as AngII, we compared a 10-fold higher rate (10 μg/kg/min) of AngA infusion into male Apoe−/− mice with AngII (1 μg/kg/min). This rate of AngA led to abdominal aortic dilation in three of ten mice, but no aortic rupture, whereas the 10-fold lower rate of AngII infusion led to abdominal aortic dilation or rupture in eight of ten mice. In conclusion, AngA, despite only being one amino acid different from AngII, has diminished effects on aortic aneurysmal formation, implicating that the first amino acid of AngII has important pathophysiological functions.

scholarly journals Allosteric Activation of PP2A Inhibits Experimental Abdominal Aortic Aneurysm

2021 ◽  
Author(s):  
Xianming Zhou ◽  
Chao Zhang ◽  
Fei Xie ◽  
Wei Wei ◽  
Rui Li ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Murine Model ◽  
Molecular Mechanisms ◽  
Aortic Aneurysms ◽  
Abdominal Aortic ◽  
Phosphatase 2A ◽  
Novel Strategy ◽  
Species Production

Although extremely important, the molecular mechanisms that govern aortic aneurysm (AA) formation and progression are still poorly understood. This deficit represents a critical roadblock toward the development of effective pharmaceutical therapies for the treatment of AA. While dysregulation of Protein Phosphatase 2A (PP2A) is thought to play a role in cardiovascular disease, its role in aortic aneurysm is unknown. The objective of this study is to test the hypothesis that PP2A regulates abdominal aortic aneurysm (AAA) progression in a murine model. In an angiotensin II-induced AAA murine model, the PP2A inhibitor, LB-100, markedly accelerated AAA progression as demonstrated by increased abdominal aortic dilation and mortality. AAA progression was associated with elevated inflammation and extracellular matrix fragmentation, concomitant with increases in both metalloproteinase activity and reactive oxygen species production. Conversely, administration of a novel class of small molecule activators of PP2A (SMAPs) resulted in an antithetical effect. SMAPs effectively reduced AAA incidence along with the corresponding pathologies that were increased with LB-100 treatment. Mechanistically, modulation of PP2A activities in vivo functioned in part via alteration of the ERK1/2 and NFkB signaling pathways, known regulators of AAA progression. These studies, for the first time, demonstrate a role of PP2A in AAA etiology and demonstrate that PP2A activation may represent a novel strategy for the treatment of abdominal aortic aneurysms.

scholarly journals In-Vivo Imaging of Changes in Abdominal Aortic Aneurysm Thrombus Volume During the Cardiac Cycle

2009 ◽  
Vol 16 (3) ◽  
pp. 314-319 ◽  
Author(s):  
Maarten Truijers ◽  
Mark F. Fillinger ◽  
Klaas Jan W. Renema ◽  
Steven P. Marra ◽  
Luuk J. Oostveen ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
In Vivo Imaging ◽  
Cardiac Cycle ◽  
Abdominal Aortic

Influence of preoperative statins and aspirin administration on biological and magnetic resonance imaging properties in patients with abdominal aortic aneurysm

VASA ◽  
2020 ◽  
pp. 1-9
Author(s):  
Milos Sladojevic ◽  
Petar Zlatanovic ◽  
Zeljka Stanojevic ◽  
Igor Koncar ◽  
Sasenka Vidicevic ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Abdominal Aortic Aneurysm ◽  
Magnetic Resonance ◽  
Aortic Aneurysm ◽  
Signal Intensity ◽  
Psoas Muscle ◽  
Resonance Imaging ◽  
Maximal Diameter ◽  
Aneurysm Wall ◽  
Abdominal Aortic

Summary: Background: Main objective of this study was to evaluate the influence of statins and/or acetylsalicylic acid on biochemical characteristics of abdominal aortic aneurysm (AAA) wall and intraluminal thrombus (ILT). Patients and methods: Fifty patients with asymptomatic infrarenal AAA were analyzed using magnetic resonance imaging on T1w sequence. Relative ILT signal intensity (SI) was determined as a ratio between ILT and psoas muscle SI. Samples containing the full ILT thickness and aneurysm wall were harvested from the anterior surface at the level of the maximal diameter. The concentration of enzymes such as matrix metalloproteinase (MMP) 9, MMP2 and neutrophil elastase (NE/ELA) were analyzed in ILT and AAA wall; while collagen type III, elastin and proteoglycan 4 were analyzed in harvested AAA wall. Oxidative stress in the AAA wall was assessed by catalase and malondialdehyde activity in tissue samples. Results: Relative ILT signal intensity (1.09 ± 0.41 vs 0.89 ± 0.21, p = 0.013) were higher in non-statin than in statin group. Patients who were taking aspirin had lower relative ILT area (0.89 ± 0.19 vs 1.13. ± 0.44, p = 0.016), and lower relative ILT signal intensity (0.85 [0.73–1.07] vs 1.01 [0.84–1.19], p = 0.021) compared to non-aspirin group. There were higher concentrations of elastin in AAA wall among patients taking both of aspirin and statins (1.21 [0.77–3.02] vs 0.78 (0.49–1.05) ng/ml, p = 0.044) than in patients who did not take both of these drugs. Conclusions: Relative ILT SI was lower in patients taking statin and aspirin. Combination of antiplatelet therapy and statins was associated with higher elastin concentrations in AAA wall.

In vivo imaging reveals prostate pathology in the PTEN knockout murine model of prostate cancer

2016 ◽  
Author(s):  
Alysha Bhatti ◽  
Almeida Gilberto Serrano de ◽  
Serena Tommasini Ghelfi ◽  
Alwyn Dart ◽  
Anabel Varela-Carver ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Murine Model ◽  
In Vivo Imaging

scholarly journals BIMG-08. DEUTERIUM MAGNETIC RESONANCE SPECTROSCOPY USING 2H-PYRUVATE ALLOWS NON-INVASIVE IN VIVO IMAGING OF TERT EXPRESSION IN BRAIN TUMORS

2021 ◽  
Vol 3 (Supplement_1) ◽  
pp. i2-i2
Author(s):  
Georgios Batsios ◽  
Celine Taglang ◽  
Meryssa Tran ◽  
Anne Marie Gillespie ◽  
Joseph Costello ◽  
...  
Keyword(s):  
Magnetic Resonance ◽  
Magnetic Resonance Spectroscopy ◽  
In Vivo Imaging ◽  
Lactate Production ◽  
Telomere Maintenance ◽  
Resonance Spectroscopy ◽  
Low Grade ◽  
Non Invasive ◽  
Tert Expression

Abstract Telomere shortening constitutes a natural barrier to uncontrolled proliferation and all tumors must find a mechanism of maintaining telomere length. Most human tumors, including high-grade primary glioblastomas (GBMs) and low-grade oligodendrogliomas (LGOGs) achieve telomere maintenance via reactivation of the expression of telomerase reverse transcriptase (TERT), which is silenced in normal somatic cells. TERT expression is, therefore, a driver of tumor proliferation and, due to this essential role, TERT is also a therapeutic target. However, non-invasive methods of imaging TERT are lacking. The goal of this study was to identify magnetic resonance spectroscopy (MRS)-detectable metabolic biomarkers of TERT expression that will enable non-invasive visualization of tumor burden in LGOGs and GBMs. First, we silenced TERT expression by RNA interference in patient-derived LGOG (SF10417, BT88) and GBM (GS2) models. Our results linked TERT silencing to significant reductions in steady-state levels of NADH in all models. NADH is essential for the conversion of pyruvate to lactate, suggesting that measuring pyruvate flux to lactate could be useful for imaging TERT status. Recently, deuterium (2H)-MRS has emerged as a novel, clinically translatable method of monitoring metabolic fluxes in vivo. However, to date, studies have solely examined 2H-glucose and the use of [U-2H]pyruvate for non-invasive 2H-MRS has not been tested. Following intravenous injection of a bolus of [U-2H]pyruvate, lactate production was higher in mice bearing orthotopic LGOG (BT88 and SF10417) and GBM (GS2) tumor xenografts relative to tumor-free mice, suggesting that [U-2H]pyruvate has the potential to monitor TERT expression in vivo. In summary, our study, for the first time, shows the feasibility and utility of [U-2H]pyruvate for in vivo imaging. Importantly, since 2H-MRS can be implemented on clinical scanners, our results provide a novel, non-invasive method of integrating information regarding a fundamental cancer hallmark, i.e. TERT, into glioma patient management.

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