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BACKGROUND: Ischemic studies, a known stimulator of intracellular ROS, have suggested that Heat Shock Protein (HSP) 27 may play a role in cardioprotection. We speculate that age-associated increases in ROS may also increase HSPs and that this may be a compensatory mechanism to circumvent the augmented ROS seen in the aging heart. PURPOSE: Here we determine the influence of aging on HSPs in the heart of adult (6-month), aged (30-month) and very aged (36-month) Fischer 344/NNiaHSd X Brown Norway/BiNia (F344/NXBN) rats. METHODS: Immunoblotting and immunohistochemical analyses were performed on hearts samples to examine the expression of HSP and to determine changes in (-O2·) expression and localization. RESULTS: Compared to adults, increases in (-O2·) as determined by oxidation of hydroethidine to ethidium (Et) were increased 168.6 ± 5.2% in 36-month heart and this finding was highly correlated with increases in left ventricular wall thickness (r = 0.669; P < 0.01) and total protein nitration (r = 0.663, P < 0.01). Compared to 6-month animals, cardiac HSP27 content was 76.6 ± 14.0% and 82.5 ± 17.4% higher in the 30- and 36-month hearts, respectively. Similarly, the content of HSP70 in the heart was 47.5 ± 6.1% and 90.2 ± 3.1% higher in the 30- and 36-month hearts. Regression analysis showed that increases in cardiac (-O2·) with aging were significantly correlated with changes in the cardiac HSP content. CONCLUSION: These results suggest that HSP regulation in the aging F344/NXBN heart may be potentiated by increase in ROS. Further, HSPs may be play a pivotal role in unraveling the molecular events that lead to age-associated alterations in cardiac oxidative stress. (Supported by funds from NSF Grant 0314742)
The effects of ageing on the cardiovascular system contribute to substantial alterations in cellular morphology and function. The variables regulating these changes are unknown; however, one set of signalling molecules that may be of particular importance in mediating numerous cellular responses, including control of cell growth, differentiation and adaptation, are the proteins associated with the mitogen-activated protein kinase (MAPK) signalling systems. The MAPKs, in conjunction with the p70 S6k signalling cascade, have emerged as critical components for regulating numerous mechanotransduction-related cellular responses. Here we investigate the ability of uniaxial stretch to activate the MAPK and p70 S6k pathways in adult (6-month-old), aged (30-month-old) and very aged (36-month-old) Fischer 344/NNiaHSd x Brown Norway/BiNia (FBN) rats. Western blotting of the MAPK family proteins extracellular signal-regulated kinase (Erk) 1/2, p38- and c-Jun NH(2)-terminal kinase (Jnk)-MAPKs showed differential expression and activation between these proteins with age. An acute 15 min interval of 20% uniaxial stretch using an ex vivo aortic preparation demonstrated similar regulation of Erk1/2, p38- and Jnk-MAPK. However, ageing altered uniaxial induced p70 S6k pathway signalling. These observations confirm previous data demonstrating that MAPK proteins are mechanically regulated and also suggest that p70 S6k signalling expression and activation are controlled differently with ageing. Taken together, these data may help to explain, in part, the age-related changes in vascular morphology, function and response to injury.
Background: Age associated cardiovascular disease is thought to be caused in part by the gradual oxidative damage to biomolecules. We have previously reported that aging in the Fisher344 X Brown Norway (FBN) rat aorta is characterized by increased levels of ROS and alterations in oxidative stress induced cell signaling. Acetaminophen was found to scavenge free radicals in recent ischemia-reperfusion studies. It remains unknown if chronic acetaminophen administration influences ROS signaling in the aging inferior vena cava (IVC). PURPOSE: Here we examined if chronic treatment with a therapeutic dose of acetaminophen attenuates age-associated alterations in ROS-related signaling in the IVC. METHODS: FBN rats (27 month; n=8) were subjected to 6 months of treatment with a therapeutic dose of acetaminophen (30mg/kg/day), with age-matched untreated FBN rats as controls. Immunoblotting analysis was used to examine the expression and activation of signaling molecules, which were previously shown to be affected by oxidative stress in the IVC. RESULTS: Immunoblotting analysis revealed that when compared to IVC from 6 month control animals, the total levels of NFκB p65 in 33 month-old control and treated IVC were 50.43±11.41% and 26.52±7.94% lower, respectively. Corresponding phospho-Erk1/2 levels were 21.51±7.66%, 94.97±17.16% higher and phospho-AMPK levels were 148.94±17.72% and 88.53±27.40% higher, respectively. CONCLUSION: Chronic acetaminophen treatment altered the age associated expression of ROS related signaling molecules in FBN rat IVC, suggesting that acetaminophen may have a protective effect against oxidative stress. (Supported by NIH Grant 027103-1 to EB, NSF-EPSCoR Grant 0314742 to MU, McNeil Pharmaceuticals Grant 991-546-518 to EB and EW)
Oxidative-nitrosative stress may play a role in age-associated cardiovascular disease as implied by recent studies.However, limited research has been conducted using aged female rodent models. In this study, we examined hearts obtained from 6-, 26-, and 30-month old female Fischer 344/Nnia x Brown Norway/BiNia (F344xBN) rats in order to examine how aging affects levels of cardiac oxidative-nitrosative stress and apoptosis. Oxidative (superoxide anion and 4-HNE) and nitrosative (protein nitrosylation) stress markers were increased 180 ± 17 %, 110 ± 3 %, and 14 ± 2 %, respectively in 30-month hearts compared to the hearts of 6-month female rats. Coincident with these changes in oxidative-nitrosative stress, aging was also found to be associated with increases in the number of Tdt-mediated dUTP nick labeling (TUNEL)-positive cardiomyocytes, alterations in the Bax/Bcl-2 ratio, and elevated cleavage of caspase-3. Regression analysis demonstrates significant correlation in the age-associated changes markers of oxidative-nitrosative stress with changes in apoptotic signaling. The findings from this descriptive study imply that age-associated increases in mitochondrial-mediated apoptosis may be associated with the increase in oxidative-nitrosative stress in the aging F344xBN female heart.
INTRODUCTION Due to having atypical presentations, women with potential cardiac disease may be approached and treated less aggressively than male patients. Differences in care along gender lines have been described at a university affiliated hospital in West Virginia (WV) in the past three decades. The purpose of this study is to determine if differences along gender lines in the care of patients with chest pain persists. METHODS From July-December of 2015, a retrospective chart review was performed at Cabell Huntington Hospital in WV. Data from 375 patients with a diagnosis of chest pain presenting to the emergency department (ED) was compared to data from 25 years prior. Symptoms, risk factors, medical history, medications, physical examination, laboratory, and electrocardiogram results, treatment in the emergency department, and ultimate diagnoses were studied. RESULTS Women had less reproducible musculoskeletal pain and more use of over-the-counter medicines, hormones, and pulmonary medications before presenting to the ED. Treatment with nitroglycerin and gastrointestinal medications occurred more commonly in women. Regarding evaluations of symptoms, women received more electrocardiograms, cardiac monitoring, and laboratory testing in comparison to 25 years prior. Cardiology consultations and emergency catheterization as well as the use of aspirin, heparin, antibiotics, anxiolytics, and thrombolytic agents were more commonly used in the treatment of women in comparison to 25 years prior. CONCLUSIONS In comparison to 25 years prior, there were documented improvements in the management of women presenting to the ED and experiencing new-onset, non-traumatic chest pain.
To determine whether short-term consumption of a moderately high-fat diet (MHFD) affects nitric oxide (NO) production, the concentration of stable NO metabolites (NOx) in urine and plasma of rats fed a MHFD (15.6 %g fat) or control diet (4.5 %g fat) was measured weekly for 4 weeks. Plasma and urine NOx levels were significantly depressed in the MHFD group by week 1 and remained so for the duration of the study. Decreased NO bioavailability may result from a decrease in NO production or the scavenging of NO by reactive oxygen species (ROS). Because endothelial NOS (eNOS) is the major contributor to NO production and circulating levels of NOx, eNOS expression was measured in several tissues. At week 1, there was a MHFD-associated decrease in eNOS expression in the liver. Subsequently, eNOS expression declined in the heart and kidney medulla of MHFD-fed rats at weeks 3 and 4, respectively. The expression of eNOS in the kidney cortex and adipose tissue did not change. These results suggest that a MHFD alters eNOS expression in a time-dependent and tissue-specific manner. In the liver, NOS activity and tissue levels of NOx and nitrotyrosine were measured. Nitrotyrosine levels were used as an indirect measure of the NO scavenged by ROS. There was a decrease in NOS activity, suggesting that the low levels of hepatic NOx were due, in part, to a decrease in NO production. In addition, there was a dramatic increase in nitrotyrosine formation, suggesting that the decline in hepatic NOx was also due to an increased interaction of NO with ROS. Tyrosine nitration commonly has detrimental effects on proteins. The decrease in NO and increase in protein nitration could potentially have adverse effects on tissue function.
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