Abstract-Enhanced tissue angiotensin (Ang) II levels have been reported in diabetes and might lead to cardiac dysfunction through oxidative stress. This study examined the effect of blocking the Ang II type 1 (AT 1 ) receptor on high glucose-induced cardiac contractile dysfunction. Rat ventricular myocytes were maintained in normal-(NG, 5.5 mmol/L) or high-(HG, 25.5 mmol/L) glucose medium for 24 hours. Mechanical and intracellular Ca 2ϩ properties were assessed as peak shortening (PS), time to PS (TPS), time to 90% relengthening (TR 90 ), maximal velocity of shortening/relengthening (ϮdL/dt), and intracellular Ca 2ϩ decay (). HG myocytes exhibited normal PS; decreased ϮdL/dt; and prolonged TPS, TR 90 , and . Interestingly, the HG-induced abnormalities were prevented with the AT 1 blocker L-158,809 (10 to 1000 nmol/L) but not the Janus kinase-2 (JAK2) inhibitor AG-490 (10 to 100 mol/L). The only effect of AT 1 blockade on NG myocytes was enhanced PS at 1000 nmol/L. AT 1 antagonist-elicited cardiac protection against HG was nullified by the NADPH oxidase activator sodium dodecyl sulfate (80 mol/L) and mimicked by the NADPH oxidase inhibitors diphenyleneiodonium (10 mol/L) or apocynin (100 mol/L). Western blot analysis confirmed that the protein abundance of NADPH oxidase subunit p47 phox and the AT 1 but not the AT 2 receptor was enhanced in HG myocytes. In addition, the HG-induced increase of p47 phox was prevented by L-158,809. Enhanced reactive oxygen species production observed in HG myocytes was prevented by AT 1 blockade or NADPH oxidase inhibition. Collectively, our data suggest that local Ang II, acting via AT 1 receptor-mediated NADPH oxidase activation, is involved in hyperglycemia-induced cardiomyocyte dysfunction, which might play a role in diabetic cardiomyopathy.

Abstract-Obesity is commonly associated with impaired myocardial contractile function. However, a direct link between these 2 states has not yet been established. There has been an indication that leptin, the product of the human obesity gene, may play a role in obesity-related metabolic and cardiovascular dysfunctions. The purpose of this study was to determine whether leptin exerts any direct cardiac contractile action that may contribute to altered myocardial function. Ventricular myocytes were isolated from adult male Sprague-Dawley rats. Contractile responses were evaluated by use of video-based edge detection. Contractile properties analyzed in cells electrically stimulated at 0.5 Hz included peak shortening, time to 90% peak shortening, time to 90% relengthening, and fluorescence intensity change. Leptin exhibited a dose-dependent inhibition in myocyte shortening and intracellular Ca 2ϩ change, with maximal inhibitions of 22.4% and 26.2%, respectively. Pretreatment with the NO synthase inhibitor N -nitro-L-arginine methyl ester (L-NAME, 100 mol/L) blocked leptin-induced inhibition of both peak shortening and fluorescence intensity change. Leptin also stimulated NO synthase activity in a time-and concentration-dependent manner, as reflected in the dose-related increase in NO accumulation in these cells. Addition of an NO donor (S-nitroso-N-acetyl-penicillamine [SNAP]) to the medium mimicked the effects of leptin administration. In summary, this study demonstrated a direct action of leptin on cardiomyocyte contraction, possibly through an increased NO production. These data suggest that leptin may play a role in obesity-related cardiac contractile dysfunction. (Hypertension. 2000;36:501-505.)

1 Endothelin-1 (ET-1), an endothelium-derived vasoactive peptide, participates in the regulation of endothelial function through mechanisms that are not fully elucidated. This study examined the impact of ET-1 on oxidative stress, apoptosis and cell proliferation in human umbilical vein endothelial cells (HUVEC). HUVECs were challenged for 24 h with ET-1 (10 pM-10 nM) in the absence or presence of the ET B receptor antagonist BQ788 (1 mM) or the NADPH oxidase inhibitor apocynin (1 mM). Reactive oxygen species (ROS) were detected using chloromethyl-2 0 ,7 0 -dichlorodihydrofluorescein diacetate. Apoptosis was evaluated with 4 0 ,6 0 -diamidino-2 0 -phenylindoladihydrochloride staining and by the caspase-3 assay. Cell proliferation was measured by a colorimetric assay. Expression of NADPH oxidase, Akt, pAkt, Bcl-2, Bax, IkB, caveolin-1 and eNOS was evaluated by Western blot analysis. 2 ET-1 significantly enhanced ROS generation and cell proliferation following 24-h incubation, both of which were prevented by BQ788 or apocynin, consistent with the ability of ET-1 to directly upregulate NADPH oxidase. ET-1 itself did not affect apoptosis but attenuated homocysteineinduced apoptosis through an ET B receptor-mediated mechanism. Western blot analysis indicated that ET-1 alleviated homocysteine (Hcy)-induced apoptosis, likely acting by antagonizing the Hcy-induced decreases in Akt, pAkt, pAkt-to-Akt, Bcl-2-to-Bax ratios and increases in Bax and caveolin-1 expression. Furthermore, ET-1 downregulated expression of caveolin-1 and eNOS, which was attenuated by BQ788 or apocynin. 3 In summary, our results suggest that ET-1 affects oxidative stress, proliferation and apoptosis possibly through ET B , NADPH oxidase, Akt, Bax and caveolin-1-mediated mechanisms.

Cardiovascular disease is the most common cause of death in the diabetic population and is currently one of the leading causes of death in the United States and other industrialized countries. The health care expenses associated with cardiovascular disease are staggering, reaching more than US$350 billion in 2003. The risk factors for cardiovascular disease include high fat/cholesterol levels, alcoholism, smoking, genetics, environmental factors and hypertension, which are commonly used to gauge an individual's risk of cardiovascular disease and to track their progress during therapy. Most recently, these factors have become important in the early prevention of cardiovascular diseases. Oxidative stress, the imbalance between reactive oxygen species production and breakdown by endogenous antioxidants, has been implicated in the onset and progression of cardiovascular diseases such as congestive heart failure and diabetes‐associated heart dysfunction (diabetic cardiomyopathy). Antioxidant therapy has shown promise in preventing the development of diabetic heart complications. This review focuses on recent advances in oxidative stress theory and antioxidant therapy in diabetic cardiomyopathy, with an emphasis on the stress signaling pathways hypothesized to be involved. Many of these stress signaling pathways lead to activation of reactive oxygen species, major players in the development and progression of diabetic cardiomyopathy.

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Cancer patients frequently suffer from fatigue, a complex syndrome associated with loss of muscle mass, weakness, and depressed mood. Cancer-related fatigue (CRF) can be present at the time of diagnosis, during treatment, and persists for years after treatment. CRF negatively influences quality of life, limits functional independence, and is associated with decreased survival in patients with incurable disease. Currently there are no effective treatments to reduce CRF. The aim of this study was to use a mouse model of tumor growth and discriminate between two main components of fatigue: loss of muscle mass/function and altered mood/motivation. Here we show that tumor growth increased fatigue- and depressive-like behaviors, and reduced body and muscle mass. Decreased voluntary wheel running activity (VWRA) and increased depressive-like behavior in the forced swim and sucrose preference tests were evident in tumor-bearing mice within the first two weeks of tumor growth and preceded the loss of body and muscle mass. At three weeks, tumor-bearing mice had reduced grip strength but this was not associated with altered expression of myosin isoforms or impaired contractile properties of muscles. These increases in fatigue and depressive-like behaviors were paralleled by increased expression of IL-1β mRNA in the cortex and hippocampus. Minocycline administration reduced tumor-induced expression of IL-1β in the brain, reduced depressive-like behavior, and improved grip strength without altering muscle mass. Taken together, these results indicate that neuroinflammation and depressed mood, rather than muscle wasting, contribute to decreased voluntary activity and precede major changes in muscle contractile properties with tumor growth.

Compromised heart function is regularly seen in patients with chronic alcohol ingestion and is often manifested as cardiomegaly, reduced myocardial contractility (with concomitant reductions in ejection fraction and stroke volume), myocardial fibrosis, enhanced risk of stroke and hypertension, and disruptions in the myofibrillary structure. A number of mechanisms including oxidative damage, deposition of triglycerides, altered fatty acid extraction, decreased myofilament Ca(2+) sensitivity, and impaired protein synthesis have been proposed for the development of alcoholic cardiomyopathy. Nonetheless, the underlying mechanism(s) has not been delineated. Several alcohol metabolites have been identified as specific toxins of myocardial tissue, including ethanol, its first and major metabolic product--acetaldehyde--and fatty acid ethyl esters. Acetaldehyde directly impairs cardiac contractile function, disrupts cardiac excitation-contraction coupling and promotes oxidative damage and lipid peroxidation. Unfortunately, the most direct approach to studying this (direct administration of acetaldehyde) is impossible, since direct intake of acetaldehyde is highly toxic and unsuitable for chronic studies. In order to overcome this obstacle, transgenic mice have recently been produced to artificially alter ethanol/acetaldehyde metabolism, resulting in elevated acetaldehyde levels after ethanol ingestion. This review will summarize some of the postulated mechanisms for alcoholic cardiomyopathy, with special emphasis on animal models.

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