Curcumin nanoparticles attenuate cardiac remodeling due to pulmonary arterial hypertension.

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-1ß. These changes were also associated with decreased RV expression of nitrotyrosine, fibronectin and myosin heavy chain-ß.

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, ß-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.

The short-term consumption of a moderately high-fat diet alters nitric oxide bioavailability in lean female Zucker rats.

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.

The dangers of gathering data: surgeon-specific outcomes revisited.

The accuracy of risk adjustment is important in developing surgeon profiles. As surgeon profiles are obtained from observational, nonrandomized data, we hypothesized that selection bias exists in how patients are matched with surgeons and that this bias might influence surgeon profiles. We used the Society of Thoracic Surgeons risk model to calculate observed to expected (O/E) mortality ratios for each of six cardiac surgeons at a single institution. Propensity scores evaluated selection bias that might influence development of risk-adjusted mortality profiles. Six surgeons (four high and two low O/E ratios) performed 2298 coronary artery bypass grafting (CABG) operations over 4 years. Multivariate predictors of operative mortality included preoperative shock, advanced age, and renal dysfunction, but not the surgeon performing CABG. When patients were stratified into quartiles based on the propensity score for operative death, 83% of operative deaths (50 of 60) were in the highest risk quartile. There were significant differences in the number of high-risk patients operated upon by each surgeon. One surgeon had significantly more patients in the highest risk quartile and two surgeons had significantly less patients in the highest risk quartile (p < 0.05 by chi-square). Our results show that high-risk patients are preferentially shunted to certain surgeons, and away from others, for unexplained (and unmeasured) reasons. Subtle unmeasured factors undoubtedly influence how cardiac surgery patients are matched with surgeons. Problems may arise when applying national database benchmarks to local situations because of this unmeasured selection bias.

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.

Acetaminophen combinations protect against iron-induced cardiac damage in gerbils.

This study tested if acetaminophen, N-methyl-D-glucamine dithiocarbamate (NMGDTC), deferoxamine, and combinations of these agents reduce excess iron content, prevent iron-induced pathology, reduce cardiac arrhythmias, and reduce mortality in iron-overloaded gerbils. Eight groups of 16 gerbils received iron dextran injections (ferric hydroxide dextran complex, 120 mg/kg, ip) or saline solution (controls) twice/wk for 8 wk. The 8 groups were treated every Monday, Wednesday, and Friday with one of the following: saline control, acetaminophen, 150 mg/kg, ip), acetaminophen (150 mg/kg, po), deferoxamine, 83 mg/kg, ip), NMGDTC (200 mg/kg, ip), or combinations of acetaminophen (75 mg/kg) with deferoxamine (42 mg/kg, each ip, separately) or acetaminophen (75 mg/kg) with NMGDTC (100 mg/kg, each ip, separately). The treatments were given 4 hr after each iron injection on days when both iron administration and treatment occurred during iron overloading (8 wk) and were continued 4 wk thereafter. Echocardiography (ECHO) was used to evaluate iron-induced cardiac changes and detect arrhythmias. Acetaminophen and NMGDTC, or combinations thereof, reduced cardiac and hepatic excess iron content as measured by inductively coupled plasma atomic emission spectrometry (ICP-AES). Acetaminophen was effective whether administered po or ip. Acetaminophen treatment had a positive inotropic effect on cardiac function. Acetaminophen-deferoxamine combination conferred equal cardioprotection as acetaminophen or deferoxamine alone, was equally able to remove hepatic iron, and was superior to either acetaminophen or deferoxamine in removing cardiac iron from iron-overloaded gerbils. Acetaminophen-NMGDTC combination was also effective in removing cardiac and hepatic iron and protecting against iron-induced cardiac damage. ECHO evaluation of iron-overloaded, untreated gerbils demonstrated a high incidence of cardiac arrhythmias, usually PVCs (10/16 = 63%), and mortality prior to completion of the experiment (4/16 = 25%). All treatments except deferoxamine, alone, reduced the incidence of cardiac arrhythmias and deaths. All treatments reduced iron-induced increases in hepatic and cardiac weights. This study demonstrates injection alternates that are equally or more effective than deferoxamine injections and shows oral acetaminophen to be effective in treatment of iron-overload and associated cardiac complications.

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 (NO(x)) 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. NO(x) 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, NO(x) 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.

Uniaxial stretch-induced regulation of mitogen-activated protein kinase, Akt and p70 S6 kinase in the ageing Fischer 344 x 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 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.

Progression of renal damage in the obese Zucker rat in response to deoxycorticosterone acetate-salt-induced hypertension.

This study assessed the progression of renal damage in obese Zucker rats in response to deoxycorticosterone acetate (DOCA)-salt-induced hypertension. Renal damage was evaluated by light microscopy and urine analysis at weekly intervals during the developmental phase of DOCA-salt hypertension and once during the plateau phase 42 days after the onset of treatment. Decreased tubular function was evident by day 8, as indicated by a significant increase in urine N-acetyl-beta-D-glucosaminidase activity and glucose excretion. The tubular index, a measure of tubular damage, was significantly elevated by day 15 and continued to increase throughout the experiment. Glomerular damage, which was evident by day 8, was followed by increased urine albumin excretion by day 15. Only a few sclerotic renal glomeruli were apparent before the plateau phase; however, by day 42, approximately 50% of the glomeruli were sclerotic. Hyperplastic vascular changes were mild at day 8 and slowly increased in severity during the developmental phase. By day 42 the vascular changes were severe with some vessels so hyperplastic that their lumens were almost occluded. These findings show progressive changes in renal structure and function that begin as early as day 8 and increase progressively until severe changes are present at day 42, resulting in an end-stage

Obesity and the risk for cardiovascular disease.

Coronary heart disease (CHD) is the leading cause of mortality in the United States. Hypertension, diabetes mellitus, hypercholesterolemia, and smoking have all been directly related to CHD. Obesity is on the rise in the United States and has also been associated with CHD. This review clearly establishes obesity as an independent risk factor for CHD as demonstrated by the Framingham Heart Study, Nurses Health Study, Buffalo Health Study, and the Cancer Prevention Study II. Morbid obesity was found to correlate with a significant risk of mortality from CHD, especially in young men. Prevention of obesity, and therefore reduction in risk from cardiovascular disease, is paramount in the management of obesity. New approaches to behavioral, medical, and surgical management of obesity are reviewed, including thalidomide, an antiangiogenic agent. A primary and secondary prevention model details a multidisciplinary approach to reducing risk in obesity.

Increased sensitivity of the obese Zucker rat to deoxycorticosterone-salt-induced hypertension.

OBJECTIVE: The objective of this study was to test the hypothesis that obesity increases the sensitivity of rats to experimentally induced hypertension. DESIGN AND METHODS: To induce hypertension, unilaterally nephrectomized lean and obese Zucker rats were injected with 25 mg/kg of deoxycorticosterone acetate (DOCA) twice weekly for 5 weeks and given water containing 1% NaCl to drink. Unilaterally nephrectomized control rats were injected with vehicle and drank tap water. Systolic blood pressure (SBP) was measured by the tail cuff method. Renal histology and urinary albumin excretion were used to assess the effects of the experimental treatment on the kidney. RESULTS: Obese rats exhibited a significant rise in SBP at 4 days after the start of DOCA-salt treatment. In contrast, SBP of DOCA-treated lean rats was not significantly elevated from pretreatment measurements until day 22. Moreover, SBP was significantly higher during the plateau phase of blood pressure development in obese DOCA-salt treated rats (196 mmHg) than in correspondingly treated lean rats (150 mmHg). Both obesity and DOCA-salt treatment promoted glomerulosclerosis and mild tubulointerstitial damage in the kidney with DOCA-salt treatment exacerbating the effect of obesity. Urinary albumin excretion was significantly greater in obese control rats compared with lean controls and in DOCA-treated obese rats relative to vehicle-treated obese rats. CONCLUSION: Results of this study indicate that obese Zucker rats are more sensitive to mineralocorticoid-induced hypertension than lean rats. This study provides experimental evidence supporting the epidemiological findings that obesity is a risk factor for the development of hypertension.