A5088799836- Cardiac Valve Diseases and Treatments
- Aortic Disease and Treatment Approaches
- Atherosclerosis and Cardiovascular Diseases
- Nitric Oxide and Endothelin Effects
- Mitochondrial Function and Pathology
- Cardiac tumors and thrombi
- Connective tissue disorders research
- Aortic aneurysm repair treatments
- Sirtuins and Resveratrol in Medicine
- Biomarkers in Disease Mechanisms
- Cancer-related molecular mechanisms research
- Protease and Inhibitor Mechanisms
- RNA regulation and disease
- Cardiomyopathy and Myosin Studies
- Lipid metabolism and disorders
- Cerebrovascular and Carotid Artery Diseases
- Cell Adhesion Molecules Research
- Adipose Tissue and Metabolism
- Infective Endocarditis Diagnosis and Management
- Peroxisome Proliferator-Activated Receptors
- Biochemical effects in animals
- Cardiovascular Health and Disease Prevention
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Congenital Heart Disease Studies
- Cancer, Hypoxia, and Metabolism
Mayo Clinic
2013-2025
Mayo Clinic in Arizona
2013-2024
While reports suggest a single dose of senolytics may improve vasomotor function, the structural and functional impact long-term senolytic treatment is unknown. To determine whether improves vascular stiffness, intimal plaque size composition in aged or hypercholesterolemic mice with established disease. Senolytic (intermittent Dasatinib + Quercetin via oral gavage) resulted significant reductions senescent cell markers (TAF+ cells) medial layer aorta from mice, but not atherosclerotic...
Myxomatous mitral valve disease (MMVD) is associated with leaflet thickening, fibrosis, matrix remodelling, and prolapse. Molecular mechanisms contributing to MMVD, however, remain poorly understood. We tested the hypothesis that increased transforming growth factor-β (TGF-β) signalling reactive oxygen species (ROS) are major contributors pro-fibrotic gene expression in human mouse valves. Using qRT–PCR, we found of TGF-β1 valves from humans MMVD (n = 24) was connective tissue factor (CTGF)...
BACKGROUND: Pharmacological treatments for fibrocalcific aortic valve stenosis (FCAVS) have been elusive >50 years. Here, we tested the hypothesis that reactivation of oxidized sGC (soluble guanylate cyclase), primary receptor nitric oxide, with ataciguat is a safe and efficacious strategy to slow progression FCAVS. METHODS: We used quantitative real-time reverse transcription polymerase chain reaction, Western blotting, immunohistochemistry characterize signaling biological effects on...
The purpose of this study was to characterize changes in antioxidant and age-related gene expression aorta aortic valve with aging, test the hypothesis that increased mitochondrial oxidative stress accelerates endothelial dysfunction. Wild-type (MnSOD +/+ ) manganese SOD heterozygous haploinsufficient +/− mice were studied at 3 18 mo age. In from wild-type mice, preserved, although there age-associated increases Nox2 expression. Haploinsufficiency MnSOD did not alter aorta, but Nox2. When...
Background— Pathological processes underlying myxomatous mitral valve degeneration (MMVD) remain poorly understood. We sought to identify novel mechanisms contributing the development of this condition. Methods and Results— Microarrays were used measure gene expression in 11 nonmyxomatous human valves. Differential (thresholds P <0.05; fold-change >1.5) pathway activation (Ingenuity) confirmed using quantitative reverse transcriptase polymerase chain reaction immunohistochemistry....
Objective: Sirtuin deacetylases are major regulators of organismal aging, and while depletion sirtuin 6 (SIRT6) in mice results a profound progeroid phenotype, the role SIRT6 regulation vasomotor function is unknown. Thus, our objective was to test hypothesis that reductions elicit endothelial dysfunction young, genetically altered mice. Results Approach: We used young (3 month old), littermate-matched, wild-type (WT), heterozygous (HET) expression (qRT-PCR) reduced by 50% HET Carotid vessel...
Aging is a major risk factor for calcific aortic valve disease (CAVD). While recent work suggests that DNA methylation patterns are dramatically altered with aging, changes in age‐related cardiovascular diseases remain largely uncharacterized. Thus, we tested the working hypothesis de novo methyltransferase levels (DNMT3b particular) significantly increased stenotic human valves and would serve to repress expression of protective genes. We used were either normal (NORM) or (STEN). qRT‐PCR...
As part of an upper level undergraduate developmental biology course at the University Minnesota Duluth, we developed a unit in which students carried out original research as cooperative class project. Students had opportunity to gain experience scientific method from experimental design all way through preparation publication on their that included text, figures, and tables. This kind inquiry-based learning has been shown have many benefits for students, including increased long-term...
Excess mitochondrial reactive oxygen species can drive endothelial dysfunction and vascular calcification in atherosclerosis. Recently, SIRT3 has been linked to the activity of ROS‐degrading enzyme MnSOD through regulation protein acetylation levels. It remains unclear, however, whether protects against osteogenic signaling hypercholesterolemia. We hypothesized, that reduction will impair function, decrease antioxidant capacity, increase hypercholesterolemic mice. used Ldlr −/− /ApoB 100/100...
Increasing age is a major risk factor for calcific aortic valve disease (CAVD). Interestingly, SIRT6 knockout mice have marked progeroid phenotype, and we recently reported that sirtuin enzyme expression dramatically reduced with aging further in valves from patients end-stage CAVD. It unknown, however, whether experimentally reducing promotes osteogenic signaling the ultimately accelerates progression of Thus, used cultured mouse interstitial cells ldlr-deficient, apolipoprotein B100-only...
Introduction: Myxomatous mitral valve disease (MMVD) is a degenerative condition characterized by tissue fibrosis and matrix remodeling which ultimately progresses to leaflet prolapse. While recent work has shown that transforming growth factor beta (TGF-β) signaling contributes the pathogenesis of MMVD, upstream regulators this other pathways remain poorly understood. Hypothesis: We sought use high-throughput RNA sequencing coupled with microRNA (miRNA) identify novel molecular targets as...
Activation of soluble guanylate cyclase (sGC), a key downstream target nitric oxide (NO) signaling, is reduced in valve tissue from patients with fibrocalcific aortic stenosis (FCAVS). We hypothesized that restoring NO signaling pathway using Ataciguat (ATA)—an activator oxidized sGC—would slow progression calcification. To determine whether attenuates bone morphogenetic protein (BMP2) vitro, we treated mouse interstitial cells exogenous BMP2(200ng/ml) or without ATA(10nm), and demonstrated...
Background: While a small number of studies suggest that oxidative stress has an influential role in fibrocalcific aortic valve disease (FCAVD), the roles specific antioxidant enzymes progression this remain poorly understood. Here, we focused on selectively altering mitochondrial-derived stress-which been shown to alter myriad age-associated diseases-on molecular and phenotypic drivers FCAVD. Methods: We generated low-density lipoprotein receptor-deficient, Apolipoprotein B100-only mice...
Objective: We recently discovered that activation of oxidized soluble guanylate cyclase with ataciguat (ATA) slows valve calcification and dysfunction in mice humans moderate aortic stenosis (AVS). examined if ATA would attenuate multiple mechanisms contributing to AVS end organ associated AVS, hypothesized: 1) attenuates osteogenic signaling tissue from thereby attenuating dysfunction, 2) increases rates sudden cardiac death our model, 3) treatment prevents QT prolongation deleterious...
Background While recent work from our laboratory showed that DNA (cytosine‐5)‐methyltransferase 3 beta (DNMT3b) is significantly increased in tissue humans with calcific aortic valve stenosis and associated increases global genomic methylation, it unknown whether the net effects of these changes are protective or deleterious. The objective this study was to test hypothesis genetic reduction DNMT3b allows for anti‐osteogenic gene expression, consequently results suppression osteogenic...
Background: Plaque fibrosis and re-differentiation of vascular smooth muscle cells (VSMCs) from a contractile to “synthetic” phenotype are hallmarks advanced atherosclerosis. While in vitro studies demonstrated clear role oxidative stress the loss VSMC phenotypes, roles specific antioxidant mechanisms their therapeutic utility remain unclear. Here we test hypothesis that overexpression catalase protects against excess plaque losses phenotypes vivo . Methods: We used littermate-matched,...
Activation of angiotensin II (AngII) signaling has been implicated in the pathogenesis human myxomatous mitral valve prolapse (MVP). To determine whether chronic AngII infusion can elicit molecular and phenotypic manifestations MVP, we implanted C57BL/6J mice with osmotic minipumps delivering (1000ng/kg/min) or saline for 2 4 weeks. We probed changes mRNA (qRT-PCR) protein (immunohistochemistry) levels valves, assessed function by echocardiography. In line previous findings from 2-week was...
Increased BMP signaling and markers of osteogenic differentiation are strongly associated with regions valvular calcification in aortic valves from humans end-stage calcific valve stenosis. While oxidative stress is also markedly elevated these regions, it unknown whether increasing antioxidant capacity can reduce pro-osteogenic calcification. Therefore, we hypothesized that overexpression manganese superoxide dismutase (MnSOD) the hypercholesterolemic mice, ultimately resulting reduced...
Myxomatous mitral valve disease (MMVD) is associated with increases in valvular fibrosis, matrix remodeling, and transforming growth factor beta (TGF β) signaling. While interleukin 10 (IL‐10) can suppress tissue fibrosis metalloproteinase (MMP) expression, its role MMVD unknown. We tested the hypotheses that reduced IL‐10 expression contributes to increased MMVD, tonically suppresses TGF‐β signaling normal valves. used qRT‐PCR measure of IL10, TGF‐β1, MMP 2 9, connective (CTGF) myxomatous...
Increasing age is the greatest risk factor for development and progression of calcific aortic valve disease (CAVD), mitochondrial dysfunction has been implicated in pathogenesis cardiovascular calcification. Previous findings by our group suggested a significant reduction expression multiple sirtuin (SIRT) isoforms normocholesterolemic aged mouse valves, however, it unclear if losses SIRT3—a major SIRT isoform—modulates Therefore, we hypothesized that loss SIRT3 hypercholesterolemic model...
Marfan syndrome is a connective tissue disorder frequently driven by mutations in the fibrillin-1 gene (Fbn1). This results multiple aberrant cardiovascular phenotypes, including aortic aneurysm and mitral valve prolapse. While molecular changes underlying formation have been extensively studied, underpinnings of prolapse this remain poorly understood. Therefore, we hypothesized that smad2/3 phosphorylation would be significantly increased both aorta from Fbn1 +/1037G mice with associated...
Increased oxidative stress is associated with initiation and progression of atherosclerosis. While catalase catalyzes the breakdown hydrogen peroxide (H 2 O ) to water, it unclear whether overexpression sufficient protect against cardiovascular dysfunction advanced plaque formation. Therefore, we hypothesized in hypercholesterolemic mice following 3 months or 12 Western diet feeding will have preserved endothelial function, reduced H levels, levels osteogenic markers, calcium burden...
In angiotensin II‐induced hypertension, activation of NADPH oxidase is a major contributor to reactive oxygen species generation and endothelial dysfunction. As exercise has been associated with the augmentation antioxidant enzyme expression in cells, we hypothesized that would improve function mice hypertension. Three‐month old received either saline or pressor dose II (1000 ng/kg/min) using subcutaneous osmotic minipumps, were housed cages without running wheel. Endothelium‐dependent...
We previously reported that MnSOD‐deficiency does not cause overt vasomotor dysfunction in aged or hypercholesterolemic mice. To determine whether increasing MnSOD protects against and deleterious molecular changes atherosclerosis, we crossed mice with overexpressing to test the hypothesis lifelong increases protect dysfunction. used Ldlr ‐/‐ /ApoB 100/100 were wild‐type (MnSOD 0/0 ) transgenic Tg/0 fed a western diet for 6 months. organ bath chambers measure aortic endothelium‐dependent...