Paulette S. Wehner

Gender bias in the evaluation of chest pain in the emergency department.

Abstract In conclusion, although coronary artery disease is the number one cause of mortality in women, those with new-onset chest pain who present with similar symptoms as men are approached, diagnosed, and treated less aggressively than men.

Cerium oxide nanoparticles attenuate monocrotaline induced right ventricular hypertrophy following pulmonary arterial hypertension

Cerium oxide (CeO2) nanoparticles have been posited to exhibit potent anti-oxidant activity which may allow for the use of these materials in biomedical applications. Herein, we investigate whether CeO2 nanoparticle administration can diminish right ventricular (RV) hypertrophy following four weeks of monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH). Male Sprague Dawley rats were randomly divided into three groups: control, MCT only (60 mg/kg), or MCT + CeO2 nanoparticle treatment (60 mg/kg; 0.1 mg/kg). Compared to the control group, the RV weight to body weight ratio was 45% and 22% higher in the MCT and MCT + CeO2 groups, respectively (p < 0.05). Doppler echocardiography demonstrated that CeO2 nanoparticle treatment attenuated monocrotaline-induced changes in pulmonary flow and RV wall thickness. Paralleling these changes in cardiac function, CeO2 nanoparticle treatment also diminished MCT-induced increases in right ventricular (RV) cardiomyocyte cross sectional area, β-myosin heavy chain, fibronectin expression, protein nitrosylation, protein carbonylation and cardiac superoxide levels. These changes with treatment were accompanied by a decrease in the ratio of Bax/Bcl2, diminished caspase-3 activation and reduction in serum inflammatory markers. Taken together, these data suggest that CeO2 nanoparticle administration may attenuate the hypertrophic response of the heart following PAH.

Aging influences multiple indices of oxidative stress in the heart of the Fischer 344/NNia x Brown Norway/BiNia rat

Abstract We report the influence of aging on multiple markers of oxidative-nitrosative stress in the heart of adult (6-month), aged (30-month) and very aged (36-month) Fischer 344/NNiaHSd × Brown Norway/BiNia (F344/NXBN) rats. Compared to adult (6-month) hearts, indices of oxidative (superoxide anion [O2•−], 4-hydroxy-2-nonenal [4-HNE]) and nitrosative (protein nitrotyrosylation) stress were 34.1 ± 28.1%, 186 ± 28.1% and 94 ± 5.8% higher, respectively, in 36-month hearts and these findings were highly correlated with increases in left ventricular wall thickness (r > 0.669; r > 0.710 and P < 0.01, respectively). Regression analysis showed that increases in cardiac oxidative-nitrosative stress with aging were significantly correlated with changes in the expression and/or regulation of proteins involved in transcriptional (NF-κB) activities, signaling (mitogen-activated protein kinases along with Src), apoptotic (Bcl-2, Traf-2), and cellular stress (HSPs). These results suggest that the aging F344/NXBN heart may be highly suited for unraveling the molecular events that lead to age-associated alterations in cardiac oxidative stress.

Altered cardiac muscle mTOR regulation during the progression of cancer cachexia in the ApcMin/+ mouse

Cancer cachexia is a muscle wasting condition that occurs in response to a malignant growth in the body. The mechanisms regulating cardiac muscle mass with cachexia are not well understood. Using the ApcMin/+ mouse model of colorectal cancer, we investigated how cachexia affects the regulation of 5′-adenosine monophosphate-activated protein kinase (AMPK), protein kinase B (Akt) and mammalian target of rapamycin (mTOR) signaling in the heart. Compared to age-matched C57BL/6 (BL6) mice, ApcMin/+ body mass and heart mass were lower at 12 (11±5 and 8±3%, respectively) and 20 weeks (26±3 and 6±4%, respectively) of age (P<0.05). Diminished heart mass in the 20-week-old ApcMin/+ mice coincided with a decreased rate of myofibrillar protein synthesis and increased AMPKα phosphorylation. Cachexia decreased mTOR phosphorylation and the phosphorylation of the mTOR substrates, S6 ribosomal protein and 4EBP1 independent of Akt activation. These changes in mTOR-related protein signaling were accompanied by modest increases in the amount of Beclin1 but not protein ubiquitination or cardiomyocyte apoptosis. Taken together, these data suggest that loss of cardiac mass during cachexia progression in the ApcMin/+ mouse is associated with an Akt-independent suppression of anabolic signaling and evidence of increased autophagy.

Possible Molecular Mechanisms Underlying Age-Related Cardiomyocyte Apoptosis in the F344XBN Rat Heart

Despite advances in treatment, age-related cardiac dysfunction still remains a leading cause of cardiovascular death. Recent data have suggested that increases in cardiomyocyte apoptosis may be involved in the pathological remodeling of heart. Here, we examine the effects of aging on cardiomyocyte apoptosis in 6-, 30-, and 36-month-old Fischer344 x Brown Norway F1 hybrid rats (F344XBN). Compared with 6-month hearts, aged hearts exhibited increased TdT-mediated dUTP nick end labeling-positive nuclei, caspase-3 activation, caspase-dependent cleavage of alpha-fodrin and diminished phosphorylation of protein kinase B/Akt (Thr 308). These age-dependent increases in cardiomyocyte apoptosis were associated with alterations in the composition of the cardiac dystrophin glycoprotein complex and elevated cytoplasmic IgG and albumin immunoreactivity. Immunohistochemical analysis confirmed these data and demonstrated qualitative differences in localization of dystrophin-glycoprotein complex (DGC) molecules with aging. Taken together, these data suggest that aging-related increases in cardiac apoptotic activity model may be due, at least in part, to age-associated changes in DGC structure.

Uniaxial stretch-induced regulation of mitogen-activated protein kinase, Akt and p70S6 kinase in the ageing Fischer 344 × Brown Norway rat aorta

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 × Brown Norway/BiNia (FBN) rats. Western blotting of the MAPK family proteins extracellular signal‐regulated kinase (Erk) 1/2, p38‐ and c‐Jun NH2‐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.

A Moderately High Fat Diet Promotes Salt-Sensitive Hypertension in Obese Zucker Rats by Impairing Nitric Oxide Production

The objective of this research was to examine the contribution of a moderately high fat (MHF) diet to the development of salt-sensitive hypertension in obese Zucker rats. Lean and obese Zucker rats were fed either a MHF diet or a diet of standard rat chow (control diet) for 10 weeks. From week 4 through week 10, the drinking water was supplemented with 1% NaCl. Blood pressure was measured weekly, and urinary excretion of nitric oxide metabolites (NOx) was determined at weeks 4 and 10. At week 10, renal nitric oxide synthase (NOS) activity was assessed in kidney homogenates. Blood pressures of obese, but not lean, rats on the MHF fat diet were significantly increased by salt-supplementation, whereas blood pressures of rats on the control diet were not appreciably affected. NOx excretion was increased in response to salt-supplementation in rats on the control diet, with the effect being particularly dramatic in obese rats. After salt-supplementation, NOx excretion by rats on the MHF diet was lower than rats on the control diet. In obese rats on the MHF diet, this decrease in NO production was accompanied by a reduction in renal NOS activity. These results indicate that obese rats are more inclined than lean rats to develop diet-induced hypertension in response to a moderately high fat, salt-supplemented diet. Furthermore, they suggest that MHF diet-induced defects in NO production may promote the salt-sensitivity of blood pressure in obese Zucker rats, which appear to require more NO to maintain blood pressure during a salt challenge.

Effect of fasting on vascular contractility in lean and obese Zucker rats

We compared the effects of fasting (36 h) on blood pressure and aortic contractile responsiveness in lean and obese Zucker rats. Fasting of lean animals resulted in a significant loss in body weight (-9.1 +/- 0.1%) and reduction in systolic blood pressure (-11.4 +/- 1.9 mmHg). Fasting plasma triacylglycerols (-76%) and beta-hydroxybutryic acid (beta-HBA) (+ 218%) were significantly decreased and increased, respectively. The fasting plasma concentrations of insulin (-72%) were significantly decreased, whereas glucose and epinephrine (Epi) were not changed in lean rats. The fasting of obese rats also resulted in weight loss (-5.6 +/- 1.3%) but did not cause a significant reduction of blood pressure. The plasma total cholesterol (+18%) was increased, triacylglycerols (-42%) were decreased and beta-HBA levels were unchanged in fasted obese rats. Similar to lean animals, the insulin levels of fasted obese rats were significantly decreased (-85%), whereas glucose and Epi concentrations were not significantly changed. Fasting of lean animals had no effect on the maximal contractile response of aortae to high K(+) and phorbol 12, 13 dibutyrate (PDBu) but significantly reduced the response to norepinephrine (NE) (% reference: fed, 61.1 +/- 11.0; fasted, 45.6 +/- 4.5). In addition, the concentration for half-maximal response (ED(50)) to NE was increased in fasted lean rats (fed, 1.8+/-0.2 x 10(-8)M; fasted, 3.0+/-0.3 x 10(-8)M). By comparison, fasting of obese rats had no significant effect on the contractile response to K(+), NE, or PDBu. The results show that short-term food withdrawal induces significant changes in vascular contractile properties of lean but not obese rats. Because fasting-induced changes were variable depending on the agonist, the results further suggest that the mechanism did not involve a general loss or enhancement in functional status.

The Effects of Aging on Indices of Oxidative Stress and Apoptosis in the Female Fischer 344/Nnia X Brown Norway/BiNia Rat Heart

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.

Curcumin nanoparticles attenuate cardiac remodeling due to pulmonary arterial hypertension

Abstract Herein, we investigate whether curcumin nanoparticles (Cur NPs) are effective for the treatment of monocrotaline (MCT)-induced pulmonary arterial hypertension in Sprague Dawley rat. Echocardiography was performed at the start of the study and 28 days after MCT injection. Compared to MCT only animals, Cur NP administration was associated with reduced right ventricular (RV) wall thickness and a decreased right ventricle weight/body weight ratio. Cur NPs also attenuated MCT induced increase in RV mRNA expression of TNF-α and IL-1β. These changes were also associated with decreased RV expression of nitrotyrosine, fibronectin and myosin heavy chain-β.