21 research outputs found
Bone Response to Cyclooxygenase Inhibition and Mechanical Loading
No full textBone is a dynamic tissue constantly adapting to daily mechanical forces. Suppressing the bone’s ability to adapt to increased forces may lead to insufficient strength and ultimately fracture. Non-steroidal anti-inflammatory drugs (NSAIDs) block the bone formation response to a single load. However, the effect of chronic NSAID use on the bone formation response to multiple loads is unknown. Since Cox-2 inhibitors are used for treating chronic pain, it is essential to investigate their effects on bone. NSAIDs inhibit the cyclooxygenase (Cox) enzyme which is the rate limiting step in prostaglandin E2 (PGE2) production and a key step in the bone response to loading. PGE2 activates downstream signaling molecules of the low-density lipoprotein receptor related protein 5 (Lrp5) pathway independent of Lrp5 receptor activation. The Lrp5 pathway is a primary mediator of mechanical loading in bone. To better understand the interaction of the PGE2 and Lrp5 pathways, Lrp5-/- and gain of function mice (HBM) were used to test the effects of chronic Cox-2 inhibition with loading. |The results confirmed that Cox inhibitors block the bone formation response to a single load; however, chronic Cox-2 inhibition did not suppress the bone formation response to multiple loads. Furthermore there was no interaction between Cox-2 inhibition and varying levels of Lrp5 expression. |Cox-2 is the primary isoform in the bone response to a single mechanical load. To investigate the difference in response to a single versus multiple loads, Cox-1 and Cox-2 gene responses were measured. Cox-2 gene expression in osteocytes increased after loading while Cox-1 gene expression did not. However, immunohistochemistry showed cells expressing Cox-1 increased along the periosteal and endocortical surfaces following multiple loads.|In conclusion, Cox inhibition suppressed the bone formation response to a single load but not to multiple loads. Osteocyte Cox-1 gene expression was not upregulated to compensate for Cox-2 inhibition but Cox-1 activation along the periosteal and endocortical surfaces may play a role in the adaptive response to loading. While Cox-2 is important in the initial response to loading, Cox-1 may play a role in bone adaptation to multiple loading sessions.ProQuest Traditional Publishing Optionxi, 100 pagesxi, 100 page
Exercise Ameliorates High Fat Diet Induced Cardiac Dysfunction by Increasing Interleukin 10
No full textIncreasing evidence suggests that a sedentary lifestyle and a high fat diet (HFD) leads to cardiomyopathy. Moderate exercise ameliorates cardiac dysfunction, however underlying molecular mechanisms are poorly understood. Increased inflammation due to induction of pro-inflammatory cytokine such as tumor necrosis factor-alpha (TNF-α) and attenuation of anti-inflammatory cytokine such as interleukin10 (IL-10) contributes to cardiac dysfunction in obese and diabetics. We hypothesized that exercise training ameliorates HFD- induced cardiac dysfunction by mitigating obesity and inflammation through upregulation of IL-10 and downregulation of TNF-α. To test this hypothesis, eight week old, female C57BL/6J mice were fed with HFD and exercised (swimming 1hr/day for 5 days/week for eight weeks). The four treatment groups: normal diet (ND), HFD, HFD + exercise (HFD + Ex) and ND + Ex were analyzed for mean body weight, blood glucose level, TNF-α, IL-10, cardiac fibrosis by Masson Trichrome, and cardiac dysfunction by echocardiography. Mean body weights were increased in HFD but comparatively less in HFD + Ex. The level of TNF-α was elevated and IL-10 was downregulated in HFD but ameliorated in HFD + Ex. Cardiac fibrosis increased in HFD and was attenuated by exercise in the HFD + Ex group. The percentage ejection fraction and fractional shortening were decreased in HFD but comparatively increased in HFD + Ex. There was no difference between ND and ND + Ex for the above parameters except an increase in IL-10 level following exercise. Based on these results, we conclude that exercise mitigates HFD- induced cardiomyopathy by decreasing obesity, inducing IL-10, and reducing TNF-α in mice
Perfectionism in sport and dance: A double-edged sword
No full textThe author provides comments on the contributions to this special issue on perfectionism in sport and dance focusing on how they provide further support for the view that perfectionism is a "double-edged sword." In addition, the author gives his personal view on using the tripartite model versus the 2 x 2 model of perfectionism as an analytic framework and, in conclusion, outlines future research on perfectionism in sport and dance that he thinks is needed to further advance our knowledge
Restoration of normal blood flow in atherosclerotic arteries promotes plaque stabilization
No full textBlood flow is a key regulator of atherosclerosis. Disturbed blood flow promotes atherosclerotic plaque development, whereas normal blood flow protects against plaque development. We hypothesized that normal blood flow is also therapeutic, if it were able to be restored within atherosclerotic arteries. Apolipoprotein E-deficient (ApoE-/-) mice were initially instrumented with a blood flow-modifying cuff to induce plaque development and then five weeks later the cuffwas removed to allowrestoration of normal blood flow. Plaques in decuffed mice exhibited compositional changes that indicated increased stability compared to plaques in mice with the cuff maintained. The therapeutic benefit of decuffingwas comparable to atorvastatin and the combination had an additive effect. In addition, decuffing allowed restoration of lumen area, blood velocity, and wall shear stress to near baseline values, indicating restoration of normal blood flow. Our findings demonstrate that the mechanical effects of normal blood flow on atherosclerotic plaques promote stabilization
Exercise Training Promotes Cardiac Hydrogen Sulfide Biosynthesis and Mitigates Pyroptosis to Prevent High-Fat Diet-Induced Diabetic Cardiomyopathy
No full textObesity increases the risk of developing diabetes and subsequently, diabetic cardiomyopathy (DMCM). Reduced cardioprotective antioxidant hydrogen sulfide (H2S) and increased inflammatory cell death via pyroptosis contribute to adverse cardiac remodeling and DMCM. Although exercise training (EX) has cardioprotective effects, it is unclear whether EX mitigates obesity-induced DMCM by increasing H₂S biosynthesis and mitigating pyroptosis in the heart. C57BL6 mice were fed a high-fat diet (HFD) while undergoing treadmill EX for 20 weeks. HFD mice developed obesity, hyperglycemia, and insulin resistance, which were reduced by EX. Left ventricle pressure-volume measurement revealed that obese mice developed reduced diastolic function with preserved ejection fraction, which was improved by EX. Cardiac dysfunction was accompanied by increased cardiac pyroptosis signaling, structural remodeling, and metabolic remodeling, indicated by accumulation of lipid droplets in the heart. Notably, EX increased cardiac H₂S concentration and expression of H₂S biosynthesis enzymes. HFD-induced obesity led to features of type 2 diabetes (T2DM), and subsequently DMCM. EX during the HFD regimen prevented the development of DMCM, possibly by promoting H₂S-mediated cardioprotection and alleviating pyroptosis. This is the first report of EX modulating H₂S and pyroptotic signaling in the heart
Diastolic Dysfunction with Vascular Deficits in HIV-1-Infected Female Humanized Mice Treated with Antiretroviral Drugs
No full textEarly-onset heart failure is a major treat to healthy aging individuals with HIV-1 infection. Women with HIV-1 infection (WLWH) are especially vulnerable and develop heart failure with preserved ejection fraction (HFpEF), of which left ventricular diastolic dysfunction, vascular deficits, myocardial infarction, and fibrosis are major components. HIV-infected rodent models that exhibit these pathophysiological features remain under-reported, and this has left a void in our understanding of their molecular causes and therapeutic strategies to blunt its development. Here, we show that female NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ humanized mice (Hu-mice) infected with HIV-1ADA and treated for 13 weeks with dolutegravir (DTG)/tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) develop progressive diastolic dysfunction with preserved ejection fraction (E:A ratio, E:e′, IVRT, left atrial volume and global longitudinal strain increased by 32.1 ± 5.1%, 28.2 ± 5.6%, 100.2 ± 12.6%, 26.6 ± 4.2% and 32.5 ± 4.3%, respectively). In vivo photoacoustic imaging revealed a 30.4 ± 6.8% reduction in saturated oxygenated hemoglobin in the anterior wall of the heart. The ex vivo analysis of hearts showed a reduction in density of perfused microvessels/ischemia (30.6 ± 6.2%) with fibrosis (20.2 ± 1.2%). The HIF-1α level was increased 2.6 ± 0.5-fold, while inflammation-induced serum semicarbazide amine oxidase and glycolysis byproduct methylglyoxal increased 2-fold and 2.1-fold, respectively. Treating H9C2 cardiac myocytes with DTG, FTC and TDF dose-dependently increased expression of HIF-1α. These data show that HIV-infected Hu-mice treated with DTG/TDF/FTC for thirteen weeks develop cardiac diastolic dysfunction, with vascular deficits, ischemia, and fibrosis like those reported in women living with HIV-1 infection (WLWH). They also show that DTG, TDF, and FTC treatment can increase total HIF-1α in H9C2 cells
Restoration of normal blood flow in atherosclerotic arteries promotes plaque stabilization
No full textSummary: Blood flow is a key regulator of atherosclerosis. Disturbed blood flow promotes atherosclerotic plaque development, whereas normal blood flow protects against plaque development. We hypothesized that normal blood flow is also therapeutic, if it were able to be restored within atherosclerotic arteries. Apolipoprotein E-deficient (ApoE−/−) mice were initially instrumented with a blood flow-modifying cuff to induce plaque development and then five weeks later the cuff was removed to allow restoration of normal blood flow. Plaques in decuffed mice exhibited compositional changes that indicated increased stability compared to plaques in mice with the cuff maintained. The therapeutic benefit of decuffing was comparable to atorvastatin and the combination had an additive effect. In addition, decuffing allowed restoration of lumen area, blood velocity, and wall shear stress to near baseline values, indicating restoration of normal blood flow. Our findings demonstrate that the mechanical effects of normal blood flow on atherosclerotic plaques promote stabilization
Sympathoinhibition and vasodilation contribute to the acute hypotensive response of the superoxide dismutase mimic, MnTnBuOE-2-PyP5+, in hypertensive animals
No full textThe pathogenesis of hypertension has been linked to excessive levels of reactive oxygen species (ROS), particularly superoxide (O2•−), in multiple tissues and organ systems. Overexpression of superoxide dismutase (SOD) to scavenge O2•− has been shown to decrease blood pressure in hypertensive animals. We have previously shown that MnTnBuOE-2-PyP5+ (BuOE), a manganese porphyrin SOD mimic currently in clinical trials as a normal tissue protector for cancer patients undergoing radiation therapy, can scavenge O2•− and acutely decrease normotensive blood pressures. Herein, we hypothesized that BuOE decreases hypertensive blood pressures. Using angiotensin II (AngII)-hypertensive mice, we demonstrate that BuOE administered both intraperitoneally and intravenously (IV) acutely decreases elevated blood pressure. Further investigation using renal sympathetic nerve recordings in spontaneously hypertensive rats (SHRs) reveals that immediately following IV injection of BuOE, blood pressure and renal sympathetic nerve activity (RSNA) decrease. BuOE also induces dose-dependent vasodilation of femoral arteries from AngII-hypertensive mice, a response that is mediated, at least in part, by nitric oxide, as demonstrated by ex vivo video myography. We confirmed this vasodilation in vivo using doppler imaging of the superior mesenteric artery in AngII-hypertensive mice. Together, these data demonstrate that BuOE acutely decreases RSNA and induces vasodilation, which likely contribute to its ability to rapidly decrease hypertensive blood pressure
Data_Sheet_1_A Link Between Methylglyoxal and Heart Failure During HIV-1 Infection.PDF
No full textEarly-onset heart failure (HF) continues to be a major cause of morbidity and mortality in people living with human immunodeficiency virus type one (HIV-1) infection (PLWH), yet the molecular causes for this remain poorly understood. Herein NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ humanized mice (Hu-mice), plasma from PLWH, and autopsied cardiac tissues from deceased HIV seropositive individuals were used to assess if there is a link between the glycolysis byproduct methylglyoxal (MG) and HF in the setting of HIV-1 infection. At five weeks post HIV infection, Hu-mice developed grade III-IV diastolic dysfunction (DD) with an associated two-fold increase in plasma MG. At sixteen-seventeen weeks post infection, cardiac ejection fraction and fractional shortening also declined by 26 and 35%, and plasma MG increased to four-fold higher than uninfected controls. Histopathological and biochemical analyses of cardiac tissues from Hu-mice 17 weeks post-infection affirmed MG increase with a concomitant decrease in expression of the MG-degrading enzyme glyoxalase-1 (Glo1). The endothelial cell marker CD31 was found to be lower, and coronary microvascular leakage and myocardial fibrosis were prominent. Increasing expression of Glo1 in Hu-mice five weeks post-infection using a single dose of an engineered AAV2/9 (1.7 × 1012 virion particles/kg), attenuated the increases in plasma and cardiac MG levels. Increasing Glo1 also blunted microvascular leakage, fibrosis, and HF seen at sixteen weeks post-infection, without changes in plasma viral loads. In plasma from virally suppressed PLWH, MG was also 3.7-fold higher. In autopsied cardiac tissues from seropositive, HIV individuals with low viral log, MG was 4.2-fold higher and Glo1 was 50% lower compared to uninfected controls. These data show for the first time a causal link between accumulation of MG and HF in the setting of HIV infection.</p
