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- Bandaru, Manoj Kumar, 1987-, et al.
(författare)
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Apoc2 mutant zebrafish: a model for hypertriglyceridemia and early-stage atherosclerosis
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Zebrafish larvae in a hypertriglyceridemic background can be useful to identify and characterize causal genes for triglyceride metabolism. A previous, small-scale study suggested that apolipoprotein C-II (apoc2)-mutant zebrafish larvae can be used to model hypertriglyceridemia-induced atherosclerosis. We aimed to replicate these findings in a large-scale study and asses if APOC-II may represent a useful therapeutic target. We generated apoc2 mutant zebrafish using CRISPR-Cas9 and examined cardiometabolomic traits in their offspring (F1 generation). Systematic characterization of 384 larvae using our image and assay-based, high-throughput pipeline showed that compound heterozygous larvae for loss of function mutations in apoc2 (n=35) have higher whole-body levels of triglycerides (0.71±0.16 SD), HDL cholesterol (0.32±0.15 SD) and total cholesterol (0.37±0.18 SD), and a trend for lower whole-body glucose levels (0.23±0.14 SD) compared with larvae without mutations in apoc2 (n=174). Such larvae also tended to have more vascular lipid deposition, however this effect did not reach significance (P=0.12). Interestingly, the trends for lower whole-body glucose levels and more vascular lipid deposition in larvae with anticipated loss of functional apoc2 reached significance when larvae (n=3812) from other screens, in which apoc2 was not experimentally perturbed were included as additional wildtype controls. Thus, our large-scale study confirms the role of apoc2 in hypertriglyceridemia and early-stage atherosclerosis. While apoc2 mutant zebrafish model can be used as a genetic background to identify and characterize causal genes for triglyceride metabolism, independent and opposite effects on triglycerides and glucose suggest that APOC-II is likely not a suitable target for prevention and treatment of coronary artery disease.
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| 2. |
- Bandaru, Manoj Kumar, 1987-, et al.
(författare)
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Image-based, in vivo characterization of cardiometabolic consequences of mutations in pcsk9
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Based on the association of loss-of-function mutations in proprotein convertase subtilisin/kexin type 9 (PCSK9) with low plasma LDL cholesterol levels, inhibition of the PCSK9 protein using monoclonal antibodies have emerged as an effective treatment option to lower LDL cholesterol levels and reduce the risk of coronary artery disease. Despite these beneficial effects, PCSK9 inhibitors may increase the risk of diabetes. In this study, we mimicked the mechanistic action of PCSK9 inhibitors in humans by inducing mutations in pcsk9 in zebrafish and examining their effects on dyslipidemia, early-stage atherosclerosis and diabetes-related traits in data from nearly 5000 zebrafish larvae. At 10 days of age, larvae with mutations in pcsk9 were characterized by lower whole-body LDL cholesterol levels (beta±SE -0.056±0.025 SD units) and protection against early-stage atherosclerosis, with less vascular lipid deposition (-0.133±0.035 SD) and less co-localization of macrophages with lipids (-0.086±0.032 SD). Mutant larvae also had fewer pancreatic β-cells (-0.153±0.055 SD). Thus, our findings in pcsk9 mutant larvae are in line with results from people carrying loss-of-function PCSK9 mutations, and are also in line with the effects of PCSK9 inhibitors in humans. Further, our results suggest that mutations in pcsk9 may increase the risk of diabetes through a direct effect on pancreatic β-cells.
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| 3. |
- Ingelsson, Erik, 1975-
(författare)
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Insulin Resistance and Inflammation as Risk Factors for Congestive Heart Failure
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Congestive heart failure (CHF) is a major cause of morbidity and mortality and the identification of modifiable risk factors is crucial in order to diminish suffering of this common disease. The primary aim of this thesis was to investigate novel metabolic risk factors for CHF, with a focus on insulin resistance and inflammation. The secondary aim was to examine the validity of the CHF diagnosis in the Swedish hospital discharge register.This thesis was based on the Uppsala Longitudinal Study of Adult Men (ULSAM) cohort, a community-based prospective study started in 1970. The participants were examined at age 50 and 70 and the data was completed with annual updates on mortality and in-hospital morbidity using national registers. We showed that insulin resistance predicts CHF incidence independently of established risk factors in both middle-aged and elderly men. The previously described association between obesity and subsequent CHF may be mediated partly by insulin resistance. Moreover, it was established that inflammation, measured as erythrocyte sedimentation rate is a significant predictor of CHF, independent of established risk factors including an interim myocardial infarction. Furthermore, a low beta-carotene level, as well as an increased apolipoprotein B/A-I-ratio was found to predict CHF independently of established risk factors.We also showed that the validity of the CHF diagnosis in the Swedish hospital discharge register appears less precise than for other recently investigated cardiovascular diagnoses. However, when including only cases from selected clinics or cases with a primary diagnosis of CHF, the validity is comparable to the above diagnoses. In conclusion, insulin resistance and inflammation are strong independent risk factors for the development of CHF, and seem to be involved in the early process leading to CHF. If confirmed, our observations could have large clinical implications as they may offer new approaches in the prevention of CHF.
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| 5. |
- Mubanga, Mwenya
(författare)
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Dog Ownership and Cardiovascular Disease
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The relationship between pet ownership and human health has been studied extensively; however, the effect of dog ownership on human health has had conflicting results. The overall aim of this research project was to investigate the impact of dog ownership, and the death of the dog, on human cardiovascular health and all-cause mortality.Study I was a population-based study investigating the association between dog ownership with the risk of cardiovascular disease (CVD) and death. Of 3,432,153 individuals included, dog ownership (13.1%) was associated with a lower risk of CVD- and all-cause death by 23% and 20%, respectively. In single-person households, there was an inverse association between dog ownership and incident CVD, as well as a stronger inverse association with CVD-death and all-cause death.Study II was a population-based study investigating the association between dog ownership and initiation of treatment for cardiovascular risk factors in 2,026,865 adults. Dog ownership (14.6%) was associated with a slightly elevated risk of initiating treatment (2%) for hypertension and dyslipidaemia, but not for diabetes mellitus. However, some evidence for residual confounding was found.Study III investigated the risk of death after hospitalization for a first-ever acute myocardial infarction (n=181,696) or first-ever ischemic stroke (n=157,617) in two population-based cohorts. Dog ownership was associated with a 20% to 24% lower risk of all-cause mortality and CVD-death, respectively.In Study I-III, ownership of hunting breed dogs was associated with the lowest risk of the outcomes, while owning dogs of mixed pedigree was associated with worse cardiovascular health.Study IV found evidence of an increased risk of CVD after the loss of a life-insured pet (dog or cat; n=147,251) during the first week, 3-6 months after and 6-12 months after pet-loss.This thesis has used the Swedish population and health registers to investigate the relationship between various aspects of dog ownership and cardiovascular risk. By using defined, quantifiable end-points and robust statistical methods, this project has made an important contribution to the body of research underlying the positive relationship between dog ownership and cardiovascular health, paving the way for further research into causal mechanisms.
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