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  • 1
    In: Experimental Gerontology, Elsevier BV, Vol. 90 ( 2017-04), p. 83-89
    Type of Medium: Online Resource
    ISSN: 0531-5565
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2017
    detail.hit.zdb_id: 2005397-6
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  • 2
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 41, No. 10 ( 2021-10), p. 2538-2550
    Abstract: A cardinal feature of Marfan syndrome is thoracic aortic aneurysm. The contribution of the renin-angiotensin system via AT1aR (Ang II [angiotensin II] receptor type 1a) to thoracic aortic aneurysm progression remains controversial because the beneficial effects of angiotensin receptor blockers have been ascribed to off-target effects. This study used genetic and pharmacological modes of attenuating angiotensin receptor and ligand, respectively, to determine their roles on thoracic aortic aneurysm in mice with fibrillin-1 haploinsufficiency ( Fbn1 C1041G/+ ). Approach and Results: Thoracic aortic aneurysm in Fbn1 C1041G/+ mice was found to be strikingly sexual dimorphic. Males displayed aortic dilation over 12 months while aortic dilation in Fbn1 C1041G/+ females did not differ significantly from wild-type mice. To determine the role of AT1aR, Fbn1 C1041G/+ mice that were either +/+ or −/− for AT1aR were generated. AT1aR deletion reduced expansion of ascending aorta and aortic root diameter from 1 to 12 months of age in males. Medial thickening and elastin fragmentation were attenuated. An antisense oligonucleotide against angiotensinogen was administered to male Fbn1 C1041G/+ mice to determine the effects of Ang II depletion. Antisense oligonucleotide against angiotensinogen administration attenuated dilation of the ascending aorta and aortic root and reduced extracellular remodeling. Aortic transcriptome analyses identified potential targets by which inhibition of the renin-angiotensin system reduced aortic dilation in Fbn1 C1041G/+ mice. Conclusions: Deletion of AT1aR or inhibition of Ang II production exerted similar effects in attenuating pathologies in the proximal thoracic aorta of male Fbn1 C1041G/+ mice. Inhibition of the renin-angiotensin system attenuated dysregulation of genes within the aorta related to pathology of Fbn1 C1041G/+ mice.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
    detail.hit.zdb_id: 1494427-3
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  • 3
    In: Global Translational Medicine, AccScience Publishing, Vol. 2, No. 1 ( 2023-02-24), p. 288-
    Abstract: Hepatocyte-derived angiotensinogen (AGT) is the precursor of angiotensin II (AngII). We determined the effects of hepatocyte-specific (N-acetylgalactosamine-conjugated) antisense oligonucleotides targeting AGT (GalNAc AGT ASO) on AngII-mediated blood pressure (BP) regulation and atherosclerosis and compared its effects with losartan, an AngII type 1 (AT1) receptor blocker, in hypercholesterolemic mice. Eight-week-old male low-density lipoprotein (LDL) receptor deficient mice were administered vehicle or GalNAc AGT ASO (1, 2.5, or 5 mg/kg) subcutaneously beginning 2 weeks before the initiation of Western diet feeding. All mice were fed Western diet for 12 weeks. Their systolic BP was monitored by the tail-cuff technique, and the atherosclerotic lesion area was measured by an en face method. Although the effects of all 3 doses of GalNAc AGT ASO on plasma AGT concentrations were similar, GalNAc AGT ASO reduced BP and atherosclerotic lesion size in a dose-dependent manner. Subsequently, we compared the effects of GalNAc AGT ASO (5 mg/kg) with losartan (15 mg/kg/day). Compared to losartan, GalNAc AGT ASO led to more profound increases in plasma renin and reduction in BP but had similar effects on atherosclerosis. Remarkably, GalNAc AGT ASO also reduced liver steatosis, which was not observed in losartan-treated mice. In conclusion, the BP increase and atherosclerosis development in hypercholesterolemic mice are dependent on AngII generated from hepatic AGT. Deleting hepatic AGT improves diet-induced liver steatosis, and this occurs in an AT1 receptor-independent manner.
    Type of Medium: Online Resource
    ISSN: 2811-0021
    URL: Issue
    Language: Unknown
    Publisher: AccScience Publishing
    Publication Date: 2023
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  • 4
    In: Frontiers in Cardiovascular Medicine, Frontiers Media SA, Vol. 10 ( 2023-8-16)
    Abstract: Whole body manipulation of the renin-angiotensin system (RAS) consistently exerts profound effects on experimental atherosclerosis development. A deficit in the literature has been a lack of attention to the effects of sex. Also, based on data with gene-deleted mice, the site of RAS activity that influences lesion formation is at an unknown distant location. Since angiotensin (AngII) concentrations are high in kidney and the major components of the RAS are present in renal proximal tubule cells (PTCs), this study evaluated the role of the RAS in PTCs in atherosclerosis development. Methods and results Mice with an LDL receptor −/− background were fed Western diet to induce hypercholesterolemia and atherosclerosis. We first demonstrated the role of AT1 receptor antagonism on atherosclerosis in both sexes. Losartan, an AngII type 1 (AT1) receptor blocker, had greater blood pressure-lowering effects in females than males, but equivalent effects between sexes in reducing atherosclerotic lesion size. To determine the roles of renal AT1a receptor and angiotensin-converting enzyme (ACE), either component was deleted in PTCs after weaning using a tamoxifen-inducible Cre expressed under the control of an Ndrg1 promoter. Despite profound deletion of AT1a receptor or ACE in PTCs, the absence of either protein did not influence development of atherosclerosis in either sex. Conversely, mice expressing human angiotensinogen and renin in PTCs or expressing human angiotensinogen in liver but human renin in PTCs did not change atherosclerotic lesion size in male mice. Conclusion Whole-body AT1R inhibition reduced atherosclerosis equivalently in both male and female mice; however, PTC-specific manipulation of the RAS components had no effects on hypercholesterolemia-induced atherosclerosis.
    Type of Medium: Online Resource
    ISSN: 2297-055X
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2023
    detail.hit.zdb_id: 2781496-8
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  • 5
    In: Alzheimer Disease & Associated Disorders, Ovid Technologies (Wolters Kluwer Health), Vol. 34, No. 2 ( 2020-04), p. 105-111
    Abstract: The field of dementia research is rapidly evolving, especially with regards to our understanding of the diversity of neuropathologic changes that underlie cognitive decline. Definitions and criteria for known conditions are being periodically revised and refined, and new findings are being made about neuropathologic features associated with dementia status. The database maintained by the National Alzheimer’s Coordinating Center (NACC) offer researchers a robust, rapid, and statistically well-powered method to evaluate the implications of newly identified neuropathologic conditions with regards to comorbidities, demographic associations, cognitive status, neuropsychologic tests, radiographic findings, and genetics. NACC data derive from dozens of excellent US Alzheimer disease research centers, which collectively follow thousands of research volunteers longitudinally. Many of the research participants are autopsied using state-of-the-art methods. In this article, we describe the NACC database and give examples of its use in evaluating recently revised neuropathologic diagnoses, including primary age-related tauopathy (PART), limbic predominant age-related TDP-43 encephalopathy (LATE), and the preclinical stage of Alzheimer disease neuropathologic change, based on the National Institute on Aging—Alzheimer’s Association consensus guidelines. The dementia research community is encouraged to make use of this readily available database as new neuropathologic changes are recognized and defined in this rapidly evolving field.
    Type of Medium: Online Resource
    ISSN: 0893-0341
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2020
    detail.hit.zdb_id: 2048789-7
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  • 6
    In: Alzheimer's & Dementia, Wiley, Vol. 15, No. 7S_Part_21 ( 2019-07)
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    Language: English
    Publisher: Wiley
    Publication Date: 2019
    detail.hit.zdb_id: 2201940-6
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  • 7
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S3 ( 2022-12)
    Abstract: Genome‐wide association studies (GWAS) have identified more than 70 genetic loci significantly associated with Alzheimer’s disease (AD). AD‐associated genetic variants have been mapped to biological pathways including endocytosis, oxidative stress, immune response, synaptic plasticity, lipid metabolic, apoptotic process, and amyloid‐beta formation. These diverse biological pathways may be differentially responsible for brain pathologies and combinations of proteinopathies. Pathway‐specific polygenic risk scores (PRSs) are useful to estimate an individual’s genetic liability according to well‐characterized biologic pathways. In this study, we investigated differences in AD‐PRSs calculated by biological pathways in different brain proteinopathies. Method Participant data comprised autopsied volunteers from the National Alzheimer’s Coordinating Center (NACC) database linked to Alzheimer’s Disease Genetics Consortium (ADGC) genotype data. We obtained Gene Ontology (GO) terms listed for Homo sapiens and mapped genes to each of the GO terms. Of 18,826 GO terms, 7,300 biological processes were extracted among those constructed of 3 or more genes. We also obtained AD‐related GWAS summary statistics from Kunkle et al. (2019; PMID 30820047). We then extracted single nucleotide polymorphisms (SNPs) with p 〈 0.5 that were not located near the APOE loci. We examined the associations between biological pathway‐specific PRSs and proteinopathies using the Kruskal Wallis non‐parametric test. Result ADGC genotype data were available for 1,610 NACC participants. There were 4,866 biological processes that had GWAS summary statistics from at least five SNPs. The distributions of “negative regulation of amyloid‐beta formation” PRSs were significantly different between A scores (Thal phase ratings for Aβ distribution: A0 = Phase 0, A1 = Phase 1 or 2, A2 = Phase 3, and A3 = Phase 4 or 5). The top three biological processes for B score (Braak NFT stage: B0 = Stage 0, B1 = Stage I or II, B2 = Stage III or IV, and B3 = Stage V or VI) were “cell differentiation”, “signal transduction”, and “protein transport”. There was no significant biological pathway associated with TDP‐43 or Lewy body pathologies. Conclusion Distinct brain proteinopatholies are likely caused by disruption of unique, albeit correlated, biological pathways. Further studies that integrate genetic information with PRSs may elucidate the mechanisms underlying brain proteinopathies.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2201940-6
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  • 8
    In: Alzheimer's & Dementia, Wiley
    Abstract: Research‐oriented autopsy cohorts provide critical insights into dementia pathobiology. However, different studies sometimes report disparate findings, partially because each study has its own recruitment biases. We hypothesized that a straightforward metric, related to the percentage of research volunteers cognitively normal at recruitment, would predict other inter‐cohort differences. METHODS The National Alzheimer's Coordinating Center (NACC) provided data on N  = 7178 autopsied participants from 28 individual research centers. Research cohorts were grouped based on the proportion of participants with normal cognition at initial clinical visit. RESULTS Cohorts with more participants who were cognitively normal at recruitment contained more individuals who were older, female, had lower frequencies of apolipoprotein E ε4, Lewy body disease, and frontotemporal dementia, but higher rates of cerebrovascular disease. Alzheimer's disease (AD) pathology was little different between groups. DISCUSSION The percentage of participants recruited while cognitively normal predicted differences in findings in autopsy research cohorts. Most differences were in non‐AD pathologies. HIGHLIGHTS Systematic differences exist between autopsy cohorts that serve dementia research. We propose a metric to use for gauging a research‐oriented autopsy cohort. It is essential to consider the characteristics of autopsy cohorts.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 2201940-6
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  • 9
    Online Resource
    Online Resource
    Wiley ; 2019
    In:  Alzheimer's & Dementia Vol. 15, No. 7S_Part_19 ( 2019-07)
    In: Alzheimer's & Dementia, Wiley, Vol. 15, No. 7S_Part_19 ( 2019-07)
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    Language: English
    Publisher: Wiley
    Publication Date: 2019
    detail.hit.zdb_id: 2201940-6
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  • 10
    In: Alzheimer's & Dementia, Wiley, Vol. 16, No. S6 ( 2020-12)
    Abstract: Metabolic syndrome (MetS) is defined by the presence of five cardiovascular risk factors: diabetes, hypertension, high body weight, and hypercholesterolemia. Each factor has been reported to associate with cognition, but the association of MetS with cognitive function is not well understood. The current study explored the association of MetS with cognition in a nationally representative sample of elderly adults in the United States. Method Cross‐sectional data from the National Health and Nutrition Examination Survey (NHANES 2011‐2014) were obtained for participants age ≥60 years. MetS was defined per American Heart Association criteria (≥ 3/5 factors). Cognitive performance was based on components of the Consortium to Establish a Registry in Alzheimer’s disease (CERAD) neurocognitive battery. A composite z‐score was calculated for each CERAD component; z‐scores were then averaged to estimate global cognition (Figure 1). Memory complaint was based on self‐report. Linear regression models were fit to evaluate the association between global cognition and MetS, and logistic regression was used to evaluate the association of memory complaint with MetS; we used survey statistics to account for the complex NHANES sampling design. Result Included participants (n=2593) were mean 69.4 years old; 54.8% (n=1318) were female. MetS was present in 60.9% (n=1633) of participants. After adjustment for age, sex, race/ethnicity, education, alcohol use, poverty, marital status, and memory complain, MetS was associated with almost 1/3 standard deviation lower mean global cognition compared to participants with no MetS factors (β= ‐0.28; 95%CI ‐0.46,‐0.10), while participants with 1‐2 MetS conditions had similarly lower cognitive scores relative to participants with none (β= ‐0.23; 95%CI ‐0.42,‐0.04) (Table 1). After adjustment for age, sex, race/ethnicity, education, alcohol use, poverty, marital status, and z‐score, MetS was not significantly associated with memory complaint (OR=0.90; 95%CI 0.33, 2.45). Conclusion Our findings suggest that MetS was associated with lower cognitive performance in older adults, but this association may be modified by participant characteristics. Participants who did not meet criteria for MetS but had 1‐2 risk factors showed similar cognitive performance to those with MetS, so focusing on dichotomous MetS classifications may obscure cognitive risks for those individuals who don’t fully meet the MetS criteria.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 2201940-6
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