Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mitochondrial ATP production is continually adjusted to energy demand through coordinated increases in oxidative phosphorylation and NADH production mediated by mitochondrial Ca2+([Ca2+]m). Elevated cytosolic Na+ impairs [Ca2+]m accumulation during rapid pacing of myocytes, resulting in a decrease in NADH/NAD+ redox potential. Here, we determined 1) if accentuating [Ca2+]m accumulation prevents the impaired NADH response at high [Na+]i; 2) if [Ca2+]m handling and NADH/NAD+ balance during stimulation is impaired with heart failure (induced by aortic constriction); and 3) if inhibiting [Ca2+]m efflux improves NADH/NAD+ balance in heart failure. [Ca2+]m and NADH were recorded in cells at rest and during voltage clamp stimulation (4Hz) with either 5 or 15 mmol/L [Na+]i. Fast [Ca2+]m transients and a rise in diastolic [Ca2+]m were observed during electric stimulation. [Ca2+]m accumulation was [Na+]i-dependent; less [Ca2+]m accumulated in cells with 15 Na+ versus 5 mmol/L Na+ and NADH oxidation was evident at 15 mmol/L Na+, but not at 5 mmol/L Na+. Treatment with either the mitochondrial Na+/Ca2+ exchange inhibitor CGP-37157 (1 micromol/L) or raising cytosolic Pi (2 mmol/L) enhanced [Ca2+]m accumulation and prevented the NADH oxidation at 15 mmol/L [Na+]i. In heart failure myocytes, resting [Na+]i increased from 5.2+/-1.4 to 16.8+/-3.1mmol/L and net NADH oxidation was observed during pacing, whereas NADH was well matched in controls. Treatment with CGP-37157 or lowering [Na+]i prevented the impaired NADH response in heart failure. We conclude that high [Na+]i (at levels observed in heart failure) has detrimental effects on mitochondrial bioenergetics, and this impairment can be prevented by inhibiting the mitochondrial Na+/Ca2+ exchanger.
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PMID:Enhancing mitochondrial Ca2+ uptake in myocytes from failing hearts restores energy supply and demand matching. 1859 68

Cardiovascular disease (CVD) remains the leading cause of morbidity and premature mortality in both women and men in most industrialized countries, and has for some time also established a prominent role in developing nations. In fact, obesity, diabetes mellitus and hypertension are now commonplace even in children and youths. Regular exercise is rapidly gaining widespread advocacy as a preventative measure in schools, medical circles and in the popular media. There is overwhelming evidence garnered from a number of sources, including epidemiological, prospective cohort and intervention studies, suggesting that CVD is largely a disease associated with physical inactivity. A rapidly advancing body of human and animal data confirms an important beneficial role for exercise in the prevention and treatment of CVD. In Part 1 of this review we discuss the impact of exercise on CVD, and we highlight the effects of exercise on (i) endothelial function by regulation of endothelial genes mediating oxidative metabolism, inflammation, apoptosis, cellular growth and proliferation, increased superoxide dismutase (SOD)-1, down-regulation of p67phox, changes in intracellular calcium level, increased vascular endothelial nitric oxide synthase (eNOS), expression and eNOS Ser-1177 phosphorylation; (ii) vascular smooth muscle function by either an increased affinity of the Ca2+ extrusion mechanism or an augmented Ca2+ buffering system by the superficial sarcoplasmic reticulum to increase Ca2+ sequestration, increase in K+ channel activity and/or expression, and increase in L-type Ca2+ current density; (iii) antioxidant systems by elevation of Mn-SOD, Cu/Zn-SOD and catalase, increases in glutathione peroxidase activity and activation of vascular nicotinamide adenine dinucleotide phosphate [(NAD(P)H] oxidase and p22phox expression; (iv) heat shock protein (HSP) expression by stimulating HSP70 expression in myocardium, skeletal muscle and even in human leucocytes, probably through heat shock transcription factor 1 activity; (v) inflammation by reducing serum inflammatory cytokines such as high-sensitivity C-reactive protein (hCRP), interleukin (IL)-6, IL-18 and tumour necrosis factor-alpha and by regulating Toll-like receptor 4 pathway. Exercise also alters vascular remodelling, which involves two forms of vessel growth including angiogenesis and arteriogenesis. Angiogenesis refers to the formation of new capillary networks. Arteriogenesis refers to the growth of pre-existent collateral arterioles leading to formation of large conductance arteries that are well capable to compensate for the loss of function of occluded arteries. Another aim of this review is to focus on exercise-related cardiovascular protection against CVD and associated risk factors such as aging, coronary heart disease, hypertension, heart failure, diabetes mellitus and peripheral arterial diseases mediated by vascular remodelling. Lastly, this review examines the benefits of exercise in mitigating pre-eclampsia during pregnancy by mechanisms that include improved blood flow, reduced blood pressure, enhanced placental growth and vascularity, increased activity of antioxidant enzymes, reduced oxidative stress and restored vascular endothelial dysfunction.
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PMID:Exercise, vascular wall and cardiovascular diseases: an update (Part 1). 1902 18

Sirt1 is a human homologue of the silent information regulator factor 2 (Sir2) and has an NAD+-dependent histone deacetylase activity. This protein is reported to have a pathogenetic role in muscle differentiation, diabetic nephropathy, and heart failure. In this study, we investigated the expression of sirt1 in spontaneously hypertensive rat (SHR) to obtain insight into the function of sirt1 in hypertensive cardiovascular hypertrophy. The gene and protein expression of sirt1 was increased in the heart in SHR compared with normotensive WKY rats. Sirt1 mRNA was not different in the aorta between SHR and WKY rats. Sirt1 mRNA expression in heart and aorta was not related to hemodynamic parameters in SHR. Hypertensive left ventricular hypertrophy was significantly and positively related to the expression of heart tissue sirt1 mRNA in SHR. Aortic hypertrophy, however, was not related to sirt1 mRNA in the aorta. The increased sirt1 protein expression was accompanied by severe cardiac hypertrophy in older SHR. These results suggest that the increase of sirt1 gene and protein expression in the heart was associated with cardiac hypertrophy.
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PMID:Sirt1 hyperexpression in SHR heart related to left ventricular hypertrophy. 1914 16

The sustained elevation of plasma and interstitial catecholamine levels, namely adrenaline (ADR), and the generation of reactive oxygen species (ROS) are well recognized hallmarks of several cardiopathologic conditions, like cardiac ischemia/reperfusion (I/R) and heart failure (HF). The present work aimed to investigate the proteomics and energetic metabolism of cardiomyocytes incubated with ADR and/or ROS. To mimic pathologic conditions, freshly isolated calcium-tolerant cardiomyocytes from adult rat were incubated with ADR alone or in the presence of a system capable of generating ROS [(xanthine with xanthine oxidase) (XXO)]. Two-dimensional electrophoresis with matrix-assisted laser desorption/ionization and time-of-flight mass spectrometer analysis were used to define protein spot alterations in the cardiomyocytes incubated with ADR and/or ROS. Moreover, the energetic metabolism and the activity of mitochondrial complexes were evaluated by nuclear magnetic resonance and spectrophotometric determinations, respectively. The protein extract was mainly constituted by cardiac mitochondrial proteins and the alterations found were included in five functional classes: (i) structural proteins, notably myosin light chain-2; (ii) redox regulation proteins, in particular superoxide dismutase (SOD); (iii) energetic metabolism proteins, encompassing ATP synthase alpha chain and dihydrolipoyllysine-residue acetyltransferase component of pyruvate dehydrogenase complex; (iv) stress response proteins, like the heat shock proteins; and (v) regulatory proteins, like cytochrome c and voltage-dependent anion channel 1. The XXO system elicited alterations in cardiac contractile proteins, as they showed high levels of cleavage, and also altered energetic metabolism, through increased lactate and alanine levels. The cardiomyocytes incubation with ADR resulted in an accentuated increase in mitochondrial complexes activity and the decrease in alanine/lactate ratio, thus reflecting a high cytosolic NADH/NAD(+) ratio. Furthermore, an increase in manganese SOD expression and total SOD activity occurred in the ADR group, as the increase in the mitochondrial complexes presumably led to higher 'electron leakage'. The modifications in proteins, enzymes activity, and energetic metabolism were indicative that different pathways are activated by catecholamines and ROS. These alterations altogether determine the I/R and HF specific features and contribute for the initiation or aggravation of those cardiopathologic conditions.
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PMID:Adrenaline and reactive oxygen species elicit proteome and energetic metabolism modifications in freshly isolated rat cardiomyocytes. 1946 73

Since the discovery of NAD-dependent deacetylases, sirtuins, it has been recognized that maintaining intracellular levels of NAD is crucial for the management of stress response of cells. Here we show that agonist-induced cardiac hypertrophy is associated with loss of intracellular levels of NAD, but not exercise-induced physiologic hypertrophy. Exogenous addition of NAD was capable of maintaining intracellular levels of NAD and blocking the agonist-induced cardiac hypertrophic response in vitro as well as in vivo. NAD treatment blocked the activation of pro-hypertrophic Akt1 signaling, and augmented the activity of anti-hypertrophic LKB1-AMPK signaling in the heart, which prevented subsequent induction of mTOR-mediated protein synthesis. By using gene knock-out and transgenic mouse models of SIRT3 and SIRT1, we showed that the anti-hypertrophic effects of exogenous NAD are mediated through activation of SIRT3, but not SIRT1. SIRT3 deacetylates and activates LKB1, thus augmenting the activity of the LKB1-AMPK pathway. These results reveal a novel role of NAD as an inhibitor of cardiac hypertrophic signaling, and suggest that prevention of NAD depletion may be critical in the treatment of cardiac hypertrophy and heart failure.
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PMID:Exogenous NAD blocks cardiac hypertrophic response via activation of the SIRT3-LKB1-AMP-activated kinase pathway. 1994 Jan 31

Oxidative stress plays a pivotal role in chronic heart failure. SIRT1, an NAD(+)-dependent histone/protein deacetylase, promotes cell survival under oxidative stress when it is expressed in the nucleus. However, adult cardiomyocytes predominantly express SIRT1 in the cytoplasm, and its function has not been elucidated. The purpose of this study was to investigate the functional role of SIRT1 in the heart and the potential use of SIRT1 in therapy for heart failure. We investigated the subcellular localization of SIRT1 in cardiomyocytes and its impact on cell survival. SIRT1 accumulated in the nucleus of cardiomyocytes in the failing hearts of TO-2 hamsters, postmyocardial infarction rats, and a dilated cardiomyopathy patient but not in control healthy hearts. Nuclear but not cytoplasmic SIRT1-induced manganese superoxide dismutase (Mn-SOD), which was further enhanced by resveratrol, and increased the resistance of C2C12 myoblasts to oxidative stress. Resveratrol's enhancement of Mn-SOD levels depended on the level of nuclear SIRT1, and it suppressed the cell death induced by antimycin A or angiotensin II. The cell-protective effects of nuclear SIRT1 or resveratrol were canceled by the Mn-SOD small interfering RNA or SIRT1 small interfering RNA. The oral administration of resveratrol to TO-2 hamsters increased Mn-SOD levels in cardiomyocytes, suppressed fibrosis, preserved cardiac function, and significantly improved survival. Thus, Mn-SOD induced by resveratrol via nuclear SIRT1 reduced oxidative stress and participated in cardiomyocyte protection. SIRT1 activators such as resveratrol could be novel therapeutic tools for the treatment of chronic heart failure.
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PMID:Induction of manganese superoxide dismutase by nuclear translocation and activation of SIRT1 promotes cell survival in chronic heart failure. 2008 51

The primary function of cardiac mitochondria is the production of ATP to support heart contraction. Examination of the mitochondrial redox state is therefore crucially important to sensitively detect early signs of mitochondrial function in pathophysiological conditions, such as ischemia, diabetes and heart failure. We study fingerprinting of mitochondrial metabolic oxidative state in living cardiomyocytes with spectrally-resolved fluorescence lifetime spectroscopy of NAD(P)H, the principal electron donor in mitochondrial respiration responsible for vital ATP supply. Here NAD(P)H is studied as a marker for non-invasive fluorescent probing of the mitochondrial function. NAD(P) H fluorescence is recorded in cardiac cells following excitation with 375nm UV-light and detection by spectrally-resolved time-correlated single photon counting (TCSPC), based on the simultaneous measurement of the fluorescence spectra and fluorescence lifetimes. Modulation of NADH production and/or mitochondrial respiration is tested to study dynamic characteristics of NAD(P) H fluorescence decay. Our results show that at least a 3-exponential decay model, with 0.4-0.7ns, 1.2-1.9ns and 8.0-13. Ons lifetime pools is necessary to describe cardiomyocyte autofluorescence (AF) within 420-560nm spectral range. Increased mitochondrial NADH production by ketone bodies enhanced the fluorescence intensity, without significant change in fluorescent lifetimes. Rotenone, the inhibitor of Complex I of the mitochondrial respiratory chain, increased AF intensity and shortened the average fluorescence lifetime. Dinitrophenol (DNP), an uncoupling agent of the mitochondrial oxidative phosphorylation, lowered AF intensity, broadened the spectral shoulder at 520 nm and increased the average fluorescence lifetime. These effects are comparable to the study of NADH fluorescence decay in vitro. In the present contribution we demonstrated that spectrally-resolved fluorescence lifetime technique provides promising new tool for analysis of mitochondrial NAD(P) H fluorescence with good reproducibility in living cardiomyocytes. This approach will enhance our knowledge about cardiomyocyte oxidative metabolism and/or its dysfunction at a cellular level. In the future, this approach can prove helpful in the clinical diagnosis and treatment of mitochondrial disorder.
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PMID:[Assessment of mitochondrial metabolic oxidative state in living cardiomyocytes with spectrally-resolved fluorescence lifetime spectroscopy of NAD(P)H]. 2009 67

Oxidative and hypertrophic stresses contribute to the pathogenesis of heart failure. Insulin-like growth factor-1 (IGF-1) is a peptide hormone with a complex post-transcriptional regulation, generating distinct isoforms. Locally acting IGF-1 isoform (mIGF-1) helps the heart to recover from toxic injury and from infarct. In the murine heart, moderate overexpression of the NAD(+)-dependent deacetylase SirT1 was reported to mitigate oxidative stress. SirT1 is known to promote lifespan extension and to protect from metabolic challenges. Circulating IGF-1 and SirT1 play antagonizing biological roles and share molecular targets in the heart, in turn affecting cardiomyocyte physiology. However, how different IGF-1 isoforms may impact SirT1 and affect cardiomyocyte function is unknown. Here we show that locally acting mIGF-1 increases SirT1 expression/activity, whereas circulating IGF-1 isoform does not affect it, in cultured HL-1 and neonatal cardiomyocytes. mIGF-1-induced SirT1 activity exerts protection against angiotensin II (Ang II)-triggered hypertrophy and against paraquat (PQ) and Ang II-induced oxidative stress. Conversely, circulating IGF-1 triggered itself oxidative stress and cardiomyocyte hypertrophy. Interestingly, potent cardio-protective genes (adiponectin, UCP-1 and MT-2) were increased specifically in mIGF-1-overexpressing cardiomyocytes, in a SirT1-dependent fashion. Thus, mIGF-1 protects cardiomyocytes from oxidative and hypertrophic stresses via SirT1 activity, and may represent a promising cardiac therapeutic.
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PMID:Local IGF-1 isoform protects cardiomyocytes from hypertrophic and oxidative stresses via SirT1 activity. 2037 67

There is compelling evidence to indicate an important role for increased local renin-angiotensin system activity in the pathogenesis of cardiac hypertrophy and heart failure. Resveratrol is a natural polyphenol that activates SIRT1, a novel cardioprotective and longevity factor having NAD(+)-dependent histone deacetylase activity. We tested the hypothesis whether resveratrol could prevent from angiotensin II (Ang II)-induced cardiovascular damage. Four-week-old double transgenic rats harboring human renin and human angiotensinogen genes (dTGR) were treated for 4 weeks either with SIRT1 activator resveratrol or SIRT1 inhibitor nicotinamide. Untreated dTGR and their normotensive Sprague-Dawley control rats (SD) received vehicle. Untreated dTGR developed severe hypertension as well as cardiac hypertrophy, and showed pronounced cardiovascular mortality compared with normotensive SD rats. Resveratrol slightly but significantly decreased blood pressure, ameliorated cardiac hypertrophy and prevented completely Ang II-induced mortality, whereas nicotinamide increased blood pressure without significantly influencing cardiac hypertrophy or survival. Resveratrol decreased cardiac ANP mRNA expression and induced cardiac mRNA expressions of mitochondrial biogenesis markers peroxisome proliferator-activated receptor-gamma coactivator (PGC-1alpha), mitochondrial transcription factor (Tfam), nuclear respiratory factor 1 (NRF-1) and cytochrome c oxidase subunit 4 (cox4). Resveratrol dose-dependently increased SIRT1 activity in vitro. Our findings suggest that the beneficial effects of SIRT1 activator resveratrol on Ang II-induced cardiac remodeling are mediated by blood pressure-dependent pathways and are linked to increased mitochondrial biogenesis.
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PMID:Resveratrol induces mitochondrial biogenesis and ameliorates Ang II-induced cardiac remodeling in transgenic rats harboring human renin and angiotensinogen genes. 2042 90

Increases in oxidative stress in the heart play an important role in mediating hypertrophy, apoptosis, fibrosis, mitochondrial dysfunction, and the consequent development of heart failure. Although it has been widely believed that electron leakage from the mitochondrial electron transport chain is the primary source of oxidative stress in the failing heart, increasing lines of evidence suggest that enzymes which produce reactive oxygen species may also contribute to it. NADPH oxidases are transmembrane enzymes dedicated to producing superoxide (O(2)(-)) by transferring an electron from NAD(P)H to molecular oxygen. Nox4 is a major NADPH oxidase isoform expressed in the heart. Nox4 is localized primarily at mitochondria in cardiac myocytes, and upregulation of Nox4 hypertrophic stimuli enhances O(2)(-) production, apoptosis, and mitochondrial dysfunction, thereby playing an important role in mediating cardiac dysfunction. Since Nox4 could be a key molecule mediating oxidative stress and pathological hypertrophy, it may serve as an important target of heart failure treatment. In this review, the importance of NADPH oxidases as sources of increased oxidative stress in the failing heart and the role of Nox4 in mediating growth and death of cardiac myocytes are discussed.
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PMID:NADPH oxidase and cardiac failure. 2055 80


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