We conclude that increased cardiac fatty acid oxidation in response to high-fat feeding is controlled, in part, via the down-regulation of SIRT3 and concomitant increased acetylation of mitochondrial β-oxidation enzymes.

The high energy demands of the heart are primarily met by the mitochondrial oxidation of fatty acids and carbohydrates (glucose and lactate). 1 The amount of ATP produced depends on overall mitochondrial oxidative capacity, oxygen supply to the myocardium, and the supply of substrates for oxidative metabolism.1 In hypertrophy and HF, a decrease in high-energy phosphates in the heart has been observed. 5,6 However, it is not clear whether this is attributable entirely to a decrease in mitochondrial oxidative capacity, a switch in energy substrate preference, or a less efficient use of energy. The question also arises as to whether these metabolic changes are a consequence of HF, per se, or whether they are an early event that may contribute to the development and progression of HF.Glucose use in the heart is highly dependent on insulin, and any decrease in responsiveness of the heart to insulin can create a state of cardiac insulin-resistance.7 Insulin facilitates glucose entry by inducing the translocation of glucose transporter 4 (GLUT4) from intracellular storage vesicles to the sarcolemmal membrane.8 Decreasing GLUT4 availability exacerbates Background-Cardiac hypertrophy is accompanied by significant alterations in energy metabolism. Whether these changes in energy metabolism precede and contribute to the development of heart failure in the hypertrophied heart is not clear. Methods and Results-Mice were subjected to cardiac hypertrophy secondary to pressure-overload as a result of an abdominal aortic constriction (AAC). The rates of energy substrate metabolism were assessed in isolated working hearts obtained 1, 2, and 3 weeks after AAC. Mice subjected to AAC demonstrated a progressive development of cardiac hypertrophy. In vivo assessment of cardiac function (via echocardiography) demonstrated diastolic dysfunction by 2 weeks (20% increase in E/E′), and systolic dysfunction by 3 weeks (16% decrease in % ejection fraction). Marked cardiac insulin-resistance by 2 weeks post-AAC was evidenced by a significant decrease in insulin-stimulated rates of glycolysis and glucose oxidation, and plasma membrane translocation of glucose transporter 4. Overall ATP production rates were decreased at 2 and 3 weeks post-AAC (by 37% and 47%, respectively) because of a reduction in mitochondrial oxidation of glucose, lactate, and fatty acids that was not accompanied by an increase in myocardial glycolysis rates. Reduced mitochondrial complex V activity was evident at 3 weeks post-AAC, concomitant with a reduction in the ratio of phosphocreatine to ATP. Conclusions-The development of cardiac insulin-resistance and decreased mitochondrial oxidative metabolism are early metabolic changes in the development of cardiac hypertrophy, which create an energy deficit that may contribute to the progression from hypertrophy to heart failure.

Preeclampsia is a pregnancy-specific disorder characterised by hypertension and proteinuria occurring after the 20th week of gestation. Delivery of the placenta results in resolution of the condition, implicating the placenta as a central culprit in the pathogenesis of preeclampsia. In preeclampsia, an inadequate placental trophoblast invasion of the maternal uterine spiral arteries results in poor placental perfusion, leading to placental ischaemia. This could result in release of factors into the maternal circulation that cause widespread activation or dysfunction of the maternal endothelium. Factors in the maternal circulation might induce oxidative stress and/or elicit an inflammatory response in the maternal endothelium, resulting in the altered expression of several genes involved in the regulation of vascular tone. This review addresses the potential circulating factors and the molecular mechanisms involved in the alteration of vascular function that occurs in preeclampsia.

Abstract-Preeclampsia is a hypertensive disorder unique to pregnancy, in which the placenta may release factors into the maternal circulation resulting in systemic effects. Small dense low-density lipoprotein (LDL; which is susceptible for oxidation) is increased in preeclampsia. Lectin-like oxidized LDL receptor-1 (LOX-1) is a receptor for oxidized LDL. However, the expression levels and the regulation of LOX-1 in the maternal vasculature of women with preeclampsia are unknown. We hypothesized that there is an increased LOX-1 expression in arteries from women with preeclampsia. We further hypothesized that circulating factors in the plasma of women with preeclampsia would upregulate the LOX-1 expression in vascular endothelial cells and contribute to vascular endothelial oxidative stress. We observed abundant LOX-1 expression and the presence of oxidized LDL in arteries from women with preeclampsia, which was negligible in arteries from normotensive pregnant women. Human umbilical vein endothelial cells treated for 24 hours with 2% plasma from preeclamptic women increased LOX-1 expression and oxidized LDL uptake, as well as induced oxidative stress, as evidenced by increased NADPH oxidase activity and superoxide and peroxynitrite levels. These effects were significantly reduced by pretreatment with blocking antibody or small interfering RNA to LOX-1, as well as 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato iron (III), chloride (FeTPPS), a peroxynitrite scavenger. Exogenous peroxynitrite and 3-morpholino sydnonimine (SIN-1) increased LOX-1 protein and mRNA expression. In conclusion, increased LOX-1 expression in the systemic vasculature of preeclampsia women provides a fundamental insight into the pathology of preeclampsia and likely contributes to the induction and maintenance of vascular oxidative stress. Key Words: preeclampsia Ⅲ LOX-1 Ⅲ NADPH oxidase Ⅲ endothelium Ⅲ peroxynitrite P reeclampsia is a pregnancy-specific disorder in humans, characterized by hypertension and proteinuria occurring after the 20th week of gestation. These symptoms resolve after delivery, suggesting that the placenta plays a central role in the pathogenesis of this disorder. It is generally agreed that poor invasion of the uterine spiral arteries by the trophoblast leads to an ischemic placenta that subsequently releases a number of circulating factors into the maternal circulation. 1 The factors released into the maternal circulation include a number of vasoactive molecules and proinflammatory cytokines, which can potentially cause dysfunction of the maternal endothelium. Such factors can induce the endothelial cells to generate excess of oxygen-derived free radicals, resulting in the development of oxidative stress. 2 One of the early changes that may occur as a result of endothelial injury in the uterine spiral arteries is the accumulation of neutral lipids, a phenomenon called "acute atherosis" of pregnancy. 3 Whether lipid accumulation occurs in the maternal systemic vasculature and, if so, the possible mechanisms involve...

Increased arginase expression in preeclampsia can induce uncoupling of NOS as a source of superoxide in the maternal vasculature in preeclampsia. However, l-arginine supplementation in the face of oxidative stress could lead to a further increase in peroxynitrite.

Recent studies suggest improved outcomes and survival in obese heart failure patients (i.e., the obesity paradox), although obesity and heart failure unfavorably alter cardiac function and metabolism. We investigated the effects of weight loss on cardiac function and metabolism in obese heart failure mice. Obesity and heart failure were induced by feeding mice a high-fat (HF) diet (60% kcal from fat) for 4 weeks, following which an abdominal aortic constriction (AAC) was produced. Four weeks post-AAC, mice were switched to a low-fat (LF) diet (12% kcal from fat; HF AAC LF) or maintained on an HF (HF AAC HF) for a further 10 weeks. After 18 weeks, HF AAC LF mice weighed less than HF AAC HF mice. Diastolic function was improved in HF AAC LF mice, while cardiac hypertrophy was decreased and accompanied by decreased SIRT1 expression, increased FOXO1 acetylation, and increased atrogin-1 expression compared with HF AAC HF mice. Insulin-stimulated glucose oxidation was increased in hearts from HF AAC LF mice, compared with HF AAC HF mice. Thus lowering body weight by switching to LF diet in obese mice with heart failure is associated with decreased cardiac hypertrophy and improvements in both cardiac insulin sensitivity and diastolic function, suggesting that weight loss does not negatively impact heart function in the setting of obesity.Obesity is a recognized risk factor for heart failure (1,2). Obesity is associated with left ventricular (LV) hypertrophy and dilatation, features that are known to precede the development of overt heart failure (3,4). For every increase in BMI by 1, the risk of heart failure increases by 5% in men and 7% in women (5). In a prospective study of 21,094 men, every 1 kg/m 2 increase in BMI was associated with an 11% increase in heart failure risk (6). Compared with lean subjects, overweight and obese individuals have a 49 and 180% increased risk of developing heart failure, respectively.Despite the fact that obesity increases the incidence of heart failure, several studies suggest that there is a protective effect of being obese in patients with heart failure, known as the obesity paradox (7-13). A low BMI in heart failure patients is associated with decreased survival. This paradoxical association is found in patients with preserved and reduced ejection fraction, with a nadir of mortality in one individual patient meta-analysis (n = 23,967) of 34.0-34.9 kg/m 2 (8). A number of experimental studies have also shown favorable effects of high-fat (HF) diet on cardiac function and survival in different disease states such as myocardial infarction, heart failure, and hypertension (see ref. 14 for review).The obesity paradox would suggest that intentional weight loss in obese heart failure patients could have a detrimental effect on cardiac function. However, weight loss can decrease cardiac hypertrophy and improve LV systolic and diastolic filling in obese heart failure patients (15,16).

Pressure overload of the heart, such as seen with pulmonary hypertension and/or systemic hypertension, can result in cardiac hypertrophy and the eventual development of heart failure. The development of hypertrophy and heart failure is accompanied by numerous molecular changes in the heart, including alterations in cardiac energy metabolism. Under normal conditions, the high energy (adenosine triphosphate [ATP]) demands of the heart are primarily provided by the mitochondrial oxidation of fatty acids, carbohydrates (glucose and lactate), and ketones. In contrast, the hypertrophied failing heart is energy deficient because of its inability to produce adequate amounts of ATP. This can be attributed to a reduction in mitochondrial oxidative metabolism, with the heart becoming more reliant on glycolysis as a source of ATP production. If glycolysis is uncoupled from glucose oxidation, a decrease in cardiac efficiency can occur, which can contribute to the severity of heart failure due to pressure-overload hypertrophy. These metabolic changes are accompanied by alterations in the enzymes that are involved in the regulation of fatty acid and carbohydrate metabolism. It is now becoming clear that optimizing both energy production and the source of energy production are potential targets for pharmacological intervention aimed at improving cardiac function in the hypertrophied failing heart. In this review, we will focus on what alterations in energy metabolism occur in pressure overload induced left and right heart failure. We will also discuss potential targets and pharmacological approaches that can be used to treat heart failure occurring secondary to pulmonary hypertension and/or systemic hypertension.

Endothelial dysfunction has been observed systemically in women with gestational diabetes (GDM). Important cardiovascular adaptations occur during pregnancy, including enhanced endothelium-dependent vasodilation in systemic and uterine arteries, which are necessary to ensure the health of both mother and fetus. The effects of GDM, however, on uterine artery function and the possible mechanisms that mediate endothelial dysfunction remain unknown. The aim of this study was to utilize a mouse model of GDM to investigate (a) effects on uteroplacental flow, (b) endothelial function of uterine and mesenteric arteries, and (c) possible mechanisms of any dysfunction observed. Pregnant mice heterozygous for a leptin receptor mutation (Lepr(db) (/+); He) spontaneously develop GDM and were compared to wild-type (WT) mice at day 18.5 of gestation. Uterine artery flow was assessed using ultrasound biomicroscopy. Uterine and mesenteric artery function was assessed using wire myography. Arterial superoxide production was measured using oxidative fluorescence microphotography. In vivo uteroplacental perfusion was impaired in mice with GDM, indicated by a significant increase in uterine artery resistance index. Maximal endothelium-dependent relaxation to methacholine was significantly impaired in mesenteric arteries from mice with GDM, while sensitivity was significantly reduced in uterine arteries. Both uterine and mesenteric arteries from mice with GDM exhibited a greater dependence on nitric oxide and increased superoxide production compared with those from mice with a healthy pregnancy. A significant source of superoxide in GDM mice was uncoupled nitric oxide synthase. These changes may contribute to the development of some of the fetal and maternal complication associated with GDM.