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- Balboa Ramilo, Amanda
(författare)
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Exploring Preclinical Targets in Abdominal Aortic Aneurysm
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Abdominal Aortic Aneurysm (AAA) is a vascular disease characterised by the progressive and permanent dilation of the aorta, culminating in rupture and death, if not intervened. It affects 5% of men over the age of 65 years with a history of smoking. No pharmacological options are available to treat this disease. This thesis aims to investigate the role of glucose metabolism and mitochondrial function (Studies I-III) and microRNAs (Study IV) in experimental AAA and evaluate their potential as treatment targets.In Study I, angiotensin II (angII)-infused Apolipoprotein E (ApoE) deficient mice received intraperitoneal injections of the glycolysis inhibitor PFK15, for three weeks, starting one week after disease induction. Treatment with PFK15 reduced aneurysm formation compared with the control group and prevented the decrease in α-smooth cell actin/vimentin gene expression ratio caused by angII. Glycolysis inhibition with PFK15 prevents AAA growth by favouring the maintenance of a contractile phenotype of vascular smooth muscle cells.In Study II, angII-infused ApoE deficient mice received daily subcutaneous injections of the glucagon-like peptide 1 receptor analogue semaglutide, for four weeks, starting simultaneously with disease induction. Treatment with semaglutide prevented death by aortic rupture in the first seven days of disease development and the loss of collagen in the aortic wall. Semaglutide thereby prevents aortic dissection and rupture likely by promoting the maintenance of collagen in the aortic wall. In Study III, mice received angII or saline infusion for four weeks. Mitochondrial function was evaluated ex vivo in whole aortic tissue, by high-resolution respirometry. Aortas of angII-infused mice had a reduced capacity to increase oxygen consumption, in response to ADP and succinate, compared to control. These results demonstrate that it is possible to measure mitochondrial function in whole aneurysmal tissue ex vivo, and, importantly, that mitochondrial function is impaired in AAA. In Study IV, angII-infused ApoE deficient mice received four intraperitoneal injections of miR-10b, starting three days before disease induction and continuing for four weeks. Treatment with miR-10b promoted AAA development, growth and rupture, associated with an increased elastin degradation. miR-10b has an active role in promoting experimental AAA progression by boosting aortic wall degradation. In conclusion, glucose metabolism, mitochondrial function and microRNA are important pathways in the pathophysiology of AAA and promising targets for pharmacological modulation.
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| 5. |
- Gabel, Gabor, et al.
(författare)
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Parallel Murine and Human Aortic Wall Genomics Reveals Metabolic Reprogramming as Key Driver of Abdominal Aortic Aneurysm Progression
- 2021
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Ingår i: Journal of the American Heart Association. - : John Wiley & Sons. - 2047-9980. ; 10:17
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Tidskriftsartikel (refereegranskat)abstract
- Background: While numerous interventions effectively interfered with abdominal aortic aneurysm (AAA) formation/progression in preclinical models, none of the successes translated into clinical success. Hence, a systematic exploration of parallel and divergent processes in clinical AAA disease and its 2 primary models (the porcine pancreatic elastase and angiotensin-II infusion [AngII] murine model) was performed to identify mechanisms relevant for aneurysm disease.Methods and Results: This study combines Movat staining and pathway analysis for histological and genomic comparisons between clinical disease and its models. The impact of a notable genomic signal for metabolic reprogramming was tested in a rescue trial (AngII model) evaluating the impact of 1-(4-pyridinyl)-3-(2-quinolinyl)-2-propen-1-one (PFK15)-mediated interference with main glycolytic switch PFKFB3. Histological evaluation characterized the AngII model as a dissection model that is accompanied by adventitial fibrosis. The porcine pancreatic elastase model showed a transient inflammatory response and aortic dilatation, followed by stabilization and fibrosis. Normalization of the genomic responses at day 14 confirmed the self-limiting nature of the porcine pancreatic elastase model. Clear parallel genomic responses with activated adaptive immune responses, and particularly strong signals for metabolic switching were observed in human AAA and the AngII model. Rescue intervention with the glycolysis inhibitor PFK15 in the AngII model showed that interference with the glycolytic switching quenches aneurysm formation.Conclusions: Despite clear morphological contrasts, remarkable genomic parallels exist for clinical AAA disease and the AngII model. The metabolic response appears causatively involved in AAA progression and provides a novel therapeutic target. The clear transient genomic response classifies the porcine pancreatic elastase model as a disease initiation model.
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| 6. |
- Shamoun, Levar, et al.
(författare)
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Association of gene and protein expression and genetic polymorphism of CC chemokine ligand 4 in colorectal cancer
- 2021
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Ingår i: World Journal of Gastroenterology. - : Baishideng Publishing Group. - 1007-9327 .- 2219-2840. ; 27:30, s. 5076-5087
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND Leukocytes, such as T cells and macrophages, play an important role in tumorigenesis. CC chemokine ligand (CCL) 4, which is produced by lymphocytes and macrophages, has been found to be expressed in the mucosa of the gastrointestinal tract and is a potent chemoattractant for various leukocytes. AIM To examine CCL4 expression and its genetic polymorphism rs10491121 in patients with colorectal cancer (CRC) and evaluate their prognostic significance. METHODS Luminex technology was used to determine CCL4 Levels in CRC tissue (n = 98), compared with paired normal tissue, and in plasma from patients with CRC (n = 103), compared with healthy controls (n = 97). Included patients had undergone surgical resection for primary colorectal adenocarcinomas between 1996 and 2019 at the Department of Surgery, Ryhov County Hospital, Jönköping, Sweden. Reverse transcription quantitative PCR was used to investigate the CCL4 gene expression in CRC tissue (n = 101). Paired normal tissue and TaqMan single nucleotide polymorphism assays were used for the CCL4 rs10491121 polymorphism in 610 CRC patients and 409 healthy controls. RESULTS The CCL4 protein and messenger RNA expression levels were higher in CRC tissue than in normal paired tissue (90%, P < 0.001 and 45%, P < 0.05, respectively). CRC tissue from patients with localized disease had 2.8-fold higher protein expression levels than that from patients with disseminated disease. Low CCL4 protein expression levels in CRC tissue were associated with a 30% lower cancer-specific survival rate in patients (P < 0.01). The level of plasma CCL4 was 11% higher in CRC patients than in healthy controls (P < 0.05) and was positively correlated (r = 0.56, P < 0.01) with the CCL4 protein level in CRC tissue. The analysis of CCL4 gene polymorphism rs10491121 showed a difference (P < 0.05) between localized disease and disseminated disease in the right colon, with a dominance of allele A in localized disease. Moreover, the rate of the A allele was higher among CRC patients with mucinous cancer than among those with nonmucinous cancer. CONCLUSION The present study indicates that the CRC tissue levels of CCL4 and CCL4 gene polymorphism rs10491121, particularly in the right colon, are associated with clinical outcome in CRC patients.
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| 7. |
- Sivertsson, Ebba, et al.
(författare)
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Dose-dependent regulation of kidney mitochondrial function by angiotensin II
- 2023
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Ingår i: Upsala Journal of Medical Sciences. - : Uppsala Medical Society. - 0300-9734 .- 2000-1967. ; 128:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Intrarenal hypoxia has been suggested a unifying pathway to chronic kidney disease (CKD) and increased mitochondria leak respiration, which increases mitochondrial oxygen usage and is one important mechanism contributing to the development of the hypoxia. Previous studies indicate that angiotensin II (Ang II) effects on mitochondria function could be dose dependent. We investigated how moderate and high levels of Ang II affect kidney mitochondria function and pathways of leak respiration. Methods: C57 black 6 mice were treated with either vehicle or Ang II in low dose (400 ng/kg/min) or high dose (1,000 ng/kg/min) for 4 weeks. The function of kidney cortex mitochondria was measured by high-resolution respirometry. Ang II effects on gene expression in kidney tissue were measured by quantitative real-time PCR. Thiobarbituric acids reactive substances were determined as a marker of oxidative stress, and urinary protein excretion was measured as a maker of kidney injury. Results: Low-dose Ang II induced overall mitochondria respiration, without compromising capacity of ATP production. Mitochondrial leak respiration was increased, and levels of oxidative stress were unchanged. However, high-dose Ang II decreased overall mitochondria respiration and reduced mitochondrial capacity for ATP production. Mitochondrial leak respiration was decreased, and oxidative stress increased in kidney tissue. Furthermore, gene expression of mediators that stimulate vasoconstriction and ROS production was increased, while components of counteracting pathways were decreased. Conclusions: In conclusion, Ang II dose-dependently affects mitochondrial function and leak respiration. Thus, Ang II has the potential to directly affect cellular metabolism during conditions of altered Ang II signaling.
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- Wågsäter, Dick, Professor, et al.
(författare)
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miR-10b promotes aortic aneurysm formation and aortic rupture in angiotensin II-induced ApoE-deficient mice
- 2021
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Ingår i: Vascular pharmacology. - : Elsevier. - 1537-1891 .- 1879-3649. ; 141
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Tidskriftsartikel (refereegranskat)abstract
- Abdominal aortic aneurysm (AAA) is associated with increased plasma levels of microRNA (miR) -10b. 5 nmols of miR-10b or miR control was administrated to Apolipoprotein E-deficient mice three days prior implantation of osmotic mini-pumps containing angiotensin II, and for three additional times once a week, which increased expression of miR-10b in plasma. Animals receiving miR-10b had a mortality rate due to aortic rupture of 61% compared to 11% in the miR controls (p < 0.05). Further, miR- 10b resulted in an increased aneurysm formation and growth (p < 0.05), which was accompanied by increased elastin degradation, neutrophil and mast cell markers (p < 0.05). In conclusion, miR-10b is functionally affecting aneurysm development and rupture and not only a marker of AAA. More mechanistic studies are required to better understand miR-10b's role in AAA formation.
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