Autophagy in the heart: too much of a good thing?

Autophagy constitutes a catabolic process involving lysosomal degradation of damaged and redundant cytosolic components into biomolecules, via an elaborate lysosomal pathway. Autophagy is a highly regulated and evolutionary conserved process crucial for normal tissue homeostasis and cell life. Certain members of the Bcl-2 gene family, including the BH3 only protein Bnip3 regulate autophagy during cardiac stress during ischemic or hypoxic injury as means of discarding damaged mitochondria and organelles to avert cell death.

Akt regulates IL-10 mediated suppression of TNFα-induced cardiomyocyte apoptosis by upregulating Stat3 phosphorylation.

Background: We have already reported that TNF-α increases cardiomyocyte apoptosis and IL-10 treatment prevented these effects of TNF-α. Present study investigates the role of Akt and Jak/Stat pathway in the IL-10 modulation of TNF-α induced cardiomyocyte apoptosis.

Methodology/principal Findings: Cardiomyocytes isolated from adult Sprague Dawley rats were exposed to TNF-α (10 ng/ml), IL-10 (10 ng/ml) and TNF-α+IL-10 (ratio 1) for 4 h.

Mechanism of sarpogrelate action in improving cardiac function in diabetes.

Although sarpogrelate, a 5-HT(2A) receptor antagonist, has been reported to exert beneficial effects in diabetes, the mechanisms of its action are not understood. In this study, diabetes was induced in rats by an injection of streptozotocin (65 mg/kg) and the animals were assessed 7 weeks later. Decreased serum insulin as well as increased serum glucose, cholesterol, and triglyceride levels in diabetic animals were associated with increased blood pressure and heart/body weight ratio.

The utility of dobutamine stress echocardiography for the diagnosis of coronary artery disease in the HIV population.

Background: The introduction of highly active antiretroviral therapy (HAART) has increased human immunodeficiency virus (HIV) patient longevity by 10-15 years. This increased longevity has habituated new cardiovascular complications, in particular, accelerated coronary artery disease (CAD). Although dobutamine stress echocardiography (DSE) is a highly sensitive and specific test for the noninvasive detection of underlying CAD in the general population, its utility in the HIV population remains unknown.

β-adrenergic blockade attenuates cardiac dysfunction and myofibrillar remodelling in congestive heart failure.

Although β-adrenoceptor (β-AR) blockade is an important mode of therapy for congestive heart failure (CHF), subcellular mechanisms associated with its beneficial effects are not clear. Three weeks after inducing myocardial infarction (MI), rats were treated daily with or without 20 and 75 mg/kg atenolol, a selective β(1) -AR antagonist, or propranolol, a non-selective β-AR antagonist, for 5 weeks. Sham operated rats served as controls.

TNF-alpha-mediated signal transduction pathway is a major determinant of apoptosis in dilated cardiomyopathy.

Although J2N-k strain of cardiomyopathic hamsters is an excellent model of dilated cardiomyopathy, the presence and mechanisms of apoptosis in the hearts of these genetically modified animals have not been investigated. This study examined the hypothesis that cardiac dysfunction and apoptosis in the cardiomyopathic hamsters were associated with tumour necrosis factor-alpha (TNF-alpha)-mediated signalling pathway involving the activation of some pro-apoptotic proteins and/or deactivation of some antiapoptotic proteins. Echocardiographic assessment of 31-week-old hamsters indicated an increase in the internal dimension of the left ventricle as well as decreases in the ejection fraction, fractional shortening and cardiac output without any evidence of cardiac hypertrophy.

IL-10 attenuates TNF-alpha-induced NF kappaB pathway activation and cardiomyocyte apoptosis.

Aims: We have recently reported that tumour necrosis factor-alpha (TNF-alpha) increases oxidative stress and apoptosis in cardiomyocytes by upregulating p38 mitogen-activated protein (MAP) kinase (MAPK) phosphorylation. Interleukin-10 (IL-10) blocked these effects of TNF-alpha by upregulating extracellular signal-regulated kinase 1/2 (ERK 1/2) MAPK phosphorylation. However, the precise site of this IL-10 action is still unknown, and this is investigated in the present study.

Antiplatelet agents sarpogrelate and cilostazol affect experimentally-induced ventricular arrhythmias and mortality.

Antiplatelet agents, sarpogrelate (SAR), a 5-hydroxy tryptamine 2A receptor antagonist and cilostazol (CIL), a phosphodiesterase-III inhibitor, were observed to be beneficial in attenuating cardiac remodeling and improving cardiac function in congestive heart failure due to myocardial infarction in rats; however, CIL increased ventricular tachycardia and mortality. In order to study the effects of these antiplatelet agents on arrhythmias, Sprague-Dawley rats were pretreated with either SAR or CIL (5 mg/kg/day) for 2 weeks and were then either injected cumulative doses of epinephrine (Epi) or subjected to coronary occlusion. Saline-treated animals served as controls.

Antiplatelet therapy attenuates subcellular remodelling in congestive heart failure.

Antiplatelet agents, sarpogrelate (SAR), a 5-HT(2A) receptor antagonist, and cilostazol (CIL), a phosphodiesterase III (PDE-III) inhibitor, are used for the treatment of peripheral vascular disease. We tested whether these agents affect cardiac function and subcellular remodelling in congestive heart failure (CHF) induced by myocardial infarction (MI). Three weeks after MI, rats were treated daily with 5 mg/kg SAR or CIL as well as vehicle for 5 weeks.

Targeting platelets for prevention and treatment of cardiovascular disease.

Platelets play an important role in the development of thrombosis, atherosclerosis, hypertension, heart attack and stroke. As a result, pharmacologic interventions that influence platelet functions, such as adhesion, aggregation and the release of different factors, are considered useful for the prevention and treatment of cardiovascular disease. Although classical anti-platelet agents have proven beneficial effects for the treatment of some specific cardiovascular diseases, there are limitations for their use as these drugs target platelet function directly.

p38 and ERK1/2 MAPKs mediate the interplay of TNF-alpha and IL-10 in regulating oxidative stress and cardiac myocyte apoptosis.

It is known that TNF-alpha increases the production of ROS and decreases antioxidant enzymes, resulting in an increase in oxidative stress. IL-10 appears to modulate these effects. The present study investigated the role of p38 and ERK1/2 MAPKs in mediating the interplay of TNF-alpha and IL-10 in regulating oxidative stress and cardiac myocyte apoptosis in Sprague-Dawley male rats.

Role of subcellular remodeling in cardiac dysfunction due to congestive heart failure.

Although alterations in the size and shape of the heart (cardiac remodeling) are considered in explaining cardiac dysfunction during the development of congestive heart failure (CHF), there are several conditions including initial stages of cardiac hypertrophy, where cardiac remodeling has also been found to be associated with either an increased or no change in heart function. Extensive studies have indicated that cardiac dysfunction is related to defects in one or more subcellular organelles such as myofibrils, sarcoplasmic reticulum and sarcolemma, depending upon the stage of CHF. Such subcellular abnormalities in the failing hearts have been shown to occur at both genetic and protein levels.

Interplay of TNF-alpha and IL-10 in regulating oxidative stress in isolated adult cardiac myocytes.

Oxidative stress and inflammation are considered to be important factors in the pathogenesis of congestive heart failure subsequent to myocardial infarction. Endogenous TNF-alpha plays a central role in initiating and sustaining the inflammatory response. IL-10, an anti-inflammatory cytokine, has been shown to antagonize some of the deleterious effects of TNF-alpha.

Myofibrillar remodeling in cardiac hypertrophy, heart failure and cardiomyopathies.

Background: A wide variety of pathological conditions have been shown to result in cardiac remodelling and myocardial dysfunction. However, the mechanisms of transition from adaptive to maladaptive alterations, as well as those for changes in cardiac performance leading to heart failure, are poorly understood.

Observations: Extensive studies have revealed a broad spectrum of progressive changes in subcellular structures and function, as well as in signal transduction and metabolism in the heart, among different cardiovascular disorders.

Adriamycin-induced oxidative stress, activation of MAP kinases and apoptosis in isolated cardiomyocytes.

Background: Adriamycin (ADR) induced heart failure is associated with an increase in oxidative stress and apoptosis. Changes due to ADR in mitogen-activated protein kinases (ERK1/2 and p38 MAPKs), pro- and anti-apoptotic proteins (Bax and Bcl-xl) and apoptosis were examined in isolated adult rat cardiomyocytes.

Methods: Isolated adult rat cardiomyocytes were exposed to different concentrations of ADR (0.

Significance of changes in TNF-alpha and IL-10 levels in the progression of heart failure subsequent to myocardial infarction.

We tested whether a decrease in the ratio of interleukin-10 (IL-10) to tumor necrosis factor-alpha (TNF-alpha) correlates with the decrease in cardiac function in heart failure. It has been suggested that TNF-alpha plays a role in the progression of heart failure, and the effect of TNF-alpha in many tissues is modulated by IL-10. Any relation of these two cytokines to heart failure has never been examined.

Adenovirally delivered shRNA strongly inhibits Na+-Ca2+ exchanger expression but does not prevent contraction of neonatal cardiomyocytes.

The cardiac Na(+)-Ca(2+) exchanger (NCX1) is the main mechanism for Ca(2+) efflux in the heart and is thought to serve an essential role in cardiac excitation-contraction (E-C) coupling. The demonstration that an NCX1 gene knock-out is embryonic lethal provides further support for this essential role. However, a recent report employing the Cre/loxP technique for cardiac specific knock-out of NCX1 has revealed that cardiac function is remarkably preserved in these mice, which survived to adulthood.

TNF-alpha as a potential mediator of cardiac dysfunction due to intracellular Ca2+-overload.

TNF-alpha has been shown to be involved in cardiac dysfunction during ischemia/reperfusion injury; however, no information regarding the status of TNF-alpha production in myocardial injury due to intracellular Ca2+-overload is available in the literature. The intracellular Ca2+-overload was induced in the isolated rat hearts subjected to 5 min Ca2+-depletion and 30 min Ca2+-repletion (Ca2+-paradox). The Ca2+-paradox hearts exhibited a dramatic depression in left ventricular developed pressure, a marked elevation in left ventricular end diastolic pressure, and more than a 4-fold increase in TNF-alpha content.

Apoptosis of ventricular myocytes: a means to an end.

One of the most compelling issues to impact on contemporary cardiology is arguably the phenomenon of programmed cell death or apoptosis. Studies in the nematode Caenorhabditis elegans provided the first indication that determinants of cell fate crucial for normal worm development were under genetic influences of the ced-3 and ced-9 genes, which promote or prevent cell death, respectively. Extrapolation of these seminal findings led to the discovery of the mammalian ced-3 and ced-9 homologs, which broadly encompass a family of cellular cysteine proteases known collectively as caspases and the Bcl-2 proteins.

Propafenone and its metabolites preferentially inhibit IKr in rabbit ventricular myocytes.

Propafenone is an antiarrhythmic agent with recognized cardiac myocyte repolarizing K+ current inhibitory effects. It has two known electropharmacologically active metabolites, 5-hydroxy- and N-depropylpropafenone, whose K+ current inhibitory effects are less thoroughly elucidated than those of the parent compound. This study characterizes and directly compares the pharmacologic interaction of all three compounds with two key repolarizing K+ currents, the rapidly activating delayed rectifier IKr and the transient outward current Ito, using the whole-cell patch-clamp technique in isolated rabbit ventricular myocytes.

Mechanisms of lysophosphatidic acid-induced DNA synthesis in vascular smooth muscle cells.

In order to investigate the signal transduction mechanisms of lysophosphatidic acid (LPA)-induced vascular smooth muscle (VSM) DNA synthesis, rat aortic A10 cells were used as an experimental model and [ H]-thymidine incorporation was used as an index of DNA synthesis. LPA caused dose- and time-dependent increase in DNA synthesis in A10 VSM cells. LPA (10 microM) also stimulated the activity of casein kinase II (CKII) in a time-dependent manner.

Anti-apoptotic wild-type Alzheimer amyloid precursor protein signaling involves the p38 mitogen-activated protein kinase/MEF2 pathway.

Alzheimer amyloid precursor protein (APP) effectively protects against apoptosis in neuronal cells under stress, but the mechanisms of this anti-apoptotic effect remain largely unknown. Transcription factors act as critical molecular switches in promoting neuronal survival. The myocyte enhancer factor-2 (MEF2) is a transcription factor, and is known to be necessary for neurogenesis and activity-dependent neuronal survival.

Cellular signaling pathways affect the function of ribonucleotide reductase mRNA binding proteins: mRNA stabilization, drug resistance, and malignancy (Review).

Ribonucleotide reductase is an enzyme that is essential for DNA synthesis and repair. It is composed of 2 dimeric proteins called R1 and R2 that are both necessary for enzymatic activity that reduces ribonucleotides to deoxyribonucleotides. This is the rate-limiting reaction that provides a supply of precursors for DNA synthesis therefore it is essential for cell proliferation.

Maintenance of myocardial levels of vitamin A in heart failure due to adriamycin.

The therapeutic use of adriamycin (doxorubicin), a potent antitumor antibiotic, is limited by the development of dose-dependent cardiomyopathy. Increased oxidative stress due to adriamycin is considered to play a role in the pathogenesis of this toxic effect. In this study, we examined the levels and redistribution of vitamin A (a potent non-enzymatic antioxidant) in adriamycin-induced cardiomyopathy in rats.