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- Nallapalli, Rajesh K, et al.
(författare)
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Targeting filamin A reduces K-RAS-induced lung adenocarcinomas and endothelial response to tumor growth in mice
- 2012
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Ingår i: Molecular Cancer. - : BioMed Central. - 1476-4598. ; 11:50
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Tidskriftsartikel (refereegranskat)abstract
- Background: Many human cancer cells express filamin A (FLNA), an actin-binding structural protein that interacts with a diverse set of cell signaling proteins, but little is known about the biological importance of FLNA in tumor development. FLNA is also expressed in endothelial cells, which may be important for tumor angiogenesis. In this study, we defined the impact of targeting Flna in cancer and endothelial cells on the development of tumors in vivo and on the proliferation of fibroblasts in vitro. less thanbrgreater than less thanbrgreater thanMethods: First, we used a Cre-adenovirus to simultaneously activate the expression of oncogenic K-RAS and inactivate the expression of Flna in the lung and in fibroblasts. Second, we subcutaneously injected mouse fibrosarcoma cells into mice lacking Flna in endothelial cells. less thanbrgreater than less thanbrgreater thanResults: Knockout of Flna significantly reduced K-RAS-induced lung tumor formation and the proliferation of oncogenic K-RAS-expressing fibroblasts, and attenuated the activation of the downstream signaling molecules ERK and AKT. Genetic deletion of endothelial FLNA in mice did not impact cardiovascular development; however, knockout of Flna in endothelial cells reduced subcutaneous fibrosarcoma growth and vascularity within tumors. less thanbrgreater than less thanbrgreater thanConclusions: We conclude that FLNA is important for lung tumor growth and that endothelial Flna impacts local tumor growth. The data shed new light on the biological importance of FLNA and suggest that targeting this protein might be useful in cancer therapeutics.
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| 3. |
- Redfors, Björn, et al.
(författare)
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Are the different patterns of stress-induced (Takotsubo) cardiomyopathy explained by regional mechanical overload and demand: Supply mismatch in selected ventricular regions?
- 2013
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Ingår i: Medical hypotheses. - : Elsevier BV. - 1532-2777 .- 0306-9877. ; 81:5, s. 954-960
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Tidskriftsartikel (refereegranskat)abstract
- Takotsubo cardiomyopathy (TCM) or stress-induced cardiomyopathy is an increasingly recognized syndrome characterized by severe regional left ventricular dysfunction in the absence of an explanatory coronary lesion. TCM may lead to lethal complications but is completely reversible if the patient survives the acute phase. The pathogenesis of TCM and the mechanism behind this remarkable recovery are unknown. Plasma levels of catecholamine are elevated in many TCM patients and exogenously administered catecholamine induces TCM-like cardiac dysfunction in both humans and rats. A catecholamine excess increases myocardial metabolic demand by increasing the force of contraction as well as the heart rate, and also alters cardiac depolarization patterns. We propose that an altered spatiotemporal pattern of cardiac contraction and excessive force of contraction may lead to a redistribution of wall stresses in the left ventricle. This redistribution of wall stress causes regional mechanical overload of regions where wall tension becomes disproportionately great and renders these cardiomyocytes "metabolically insufficient". In other words, these cardiomyocytes experience a demand: supply mismatch on the basis of excessive metabolic demand. In order to prevent the death of these cardiomyocytes and to prevent excessive wall tension from developing in neighboring regions, a protective metabolic shutdown occurs in the affected cardiomyocytes. This metabolic shutdown, i.e., acute down regulation of non-vital cellular functions, serves to protect the affected regions from necrosis and explains the apparently complete recovery observed in TCM. We propose that this phenomenon may share important characteristics with phenomena such as ischemic conditioning, stunning and hibernation. In this manuscript, we discuss our hypothesis in the context of available knowledge and discuss important experiments that would help to corroborate or refute the hypothesis.
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| 4. |
- Redfors, Björn, et al.
(författare)
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Cardioprotective effects of isoflurane in a rat model of stress-induced cardiomyopathy (takotsubo).
- 2014
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Ingår i: International journal of cardiology. - : Elsevier BV. - 1874-1754 .- 0167-5273. ; 176:3, s. 815-821
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Tidskriftsartikel (refereegranskat)abstract
- Stress-induced cardiomyopathy (SIC) is a common syndrome with substantial morbidity and mortality. SIC is common in intensive care units' patients. No therapeutic intervention for SIC has been evaluated in randomized clinical trial so far. Our aim was to investigate whether isoflurane is cardioprotective in an experimental SIC model.
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| 5. |
- Redfors, Björn, et al.
(författare)
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Contrast echocardiography reveals apparently normal coronary perfusion in a rat model of stress-induced (Takotsubo) cardiomyopathy.
- 2014
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Ingår i: European heart journal cardiovascular Imaging. - : Oxford University Press (OUP). - 2047-2412 .- 2047-2404. ; 15:2, s. 152-157
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Tidskriftsartikel (refereegranskat)abstract
- Stress-induced cardiomyopathy (SIC) is an important differential diagnosis to acute myocardial infarction (AMI) that is associated with significant morbidity and mortality. The typical hallmark of SIC is left-ventricular apical akinesia but preserved function in basal segments. Catecholamines are postulated to play an important role in SIC but the precise pathophysiology is incompletely understood. Whether myocardial perfusion of the affected segments is impaired in SIC has been debated and remains unknown.
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| 6. |
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| 7. |
- Redfors, Björn, et al.
(författare)
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Effects of doxorubicin on myocardial expression of apolipoprotein-B.
- 2012
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Ingår i: Scandinavian Cardiovascular Journal. - : Informa UK Limited. - 1651-2006 .- 1401-7431. ; 46:2
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Doxorubicin (DOX) is an effective antitumor agent against a variety of human malignancies but is associated with deleterious side effects, including myocardial damage and heart failure. Myocardial apoB-containing lipoprotein (apoB) is upregulated post myocardial infarction and has been shown to be cardioprotective in this setting by unloading excessive lipid. The aim of this study was to investigate whether apoB expression is increased also in DOX-induced heart failure and whether apoB overexpression protects the heart in DOX-induced myocardial injury. Design: Cardiac function and energy metabolism was studied in mice and rats 24 hours after intraperitoneally administered DOX. Results: We found that the content of apoB was decreased in rat myocardium 24 hours after DOX injection. In contrast, apoB content was increased in the infarcted myocardium of rats 24 hours post ischemia-reperfusion. Moreover, transgenic mice overexpressing apoB had better cardiac function and lower intracellular lipid accumulation compared to wild type mice 24h post DOX. Conclusions: Our findings indicate that depression of the myocardial apoB system may contribute to DOX-induced cardiac injury and that overexpression of apoB is protective, not only in ischemically damaged myocardium, but also in DOX-induced heart failure.
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| 8. |
- Redfors, Björn, et al.
(författare)
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Effects of doxorubicin on myocardial expression of apolipoprotein-B.
- 2012
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Ingår i: Scandinavian Cardiovascular Journal. - : Informa UK Limited. - 1401-7431 .- 1651-2006. ; 46:2, s. 93-98
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Tidskriftsartikel (refereegranskat)abstract
- Abstract OBJECTIVE: Doxorubicin (DOX) is an effective antitumour agent against a variety of human malignancies but is associated with deleterious side effects, including myocardial damage and heart failure. Myocardial apoB-containing lipoprotein (apoB) is upregulated post myocardial infarction and has been shown to be cardioprotective in this setting by unloading excessive lipid. The aim of this study was to investigate whether apoB expression is increased also in DOX-induced heart failure and whether apoB overexpression protects the heart in DOX-induced myocardial injury. DESIGN: Cardiac function and energy metabolism was studied in mice and rats 24 hours after intraperitoneally administered DOX. RESULTS: We found that the content of apoB was decreased in rat myocardium 24 hours after DOX injection. In contrast, apoB content was increased in the infarcted myocardium of rats 24 hours post ischemia-reperfusion. Moreover, transgenic mice overexpressing apoB had better cardiac function and lower intracellular lipid accumulation compared to wild type mice 24 hours post DOX.
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| 9. |
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| 10. |
- Redfors, Björn, et al.
(författare)
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Influence of anesthetic agent, depth of anesthesia and body temperature on cardiovascular functional parameters in the rat.
- 2014
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Ingår i: Laboratory animals. - : SAGE Publications. - 1758-1117 .- 0023-6772. ; 48:1, s. 6-14
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Tidskriftsartikel (refereegranskat)abstract
- Sedating animals is sometimes necessary in experimental research. This paper presents and discusses the influence of four of the most common anesthetic agents on cardiovascular parameters in rats. We also studied the influence of body temperature. Ten-week-old Sprague-Dawley rats were anesthetized with either isoflurane, pentobarbital, ketamine/xylazine or tiletamine/zolazepam (n=12 in each group). A pressure-sensing catheter was placed in the right carotid artery for the continuous measurement of arterial pressure, and echocardiography was performed. Indices of cardiac function were significantly higher in the tiletamine/zolazepam rats compared with the other groups. Heart rate was highest but stroke volume lowest with pentobarbital. Left ventricular diastolic dimension was lower in the pentobarbital and tiletamine/zolazepam rats compared with the isoflurane or ketamine/xylazine rats. Intraventricular diastolic pressure was similar in all groups whereas intraventricular systolic pressure, as well as both systolic and diastolic aortic pressures, was significantly higher in the tiletamine/zolazepam rats compared with the other groups. No hemodynamic indices differed significantly among the isoflurane, pentobarbital and ketamine/xylazine rats. Lowering body temperature significantly reduced heart rate and cardiac output but had no apparent effect on hemodynamic parameters. In conclusion, although cardiac functional parameters differed between the different anesthetic agents in ways that could be of relevance to the researcher, they may all have a role in experimental cardiology. Importantly, tiletamine/zolazepam anesthesia resulted in significantly higher indices of cardiac function and elevated blood pressures compared with the other anesthetic agents, a finding that should be kept in mind when interpreting data obtained in rats sedated on this regimen.
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