Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018799 (heart disease)
 34,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In an earlier study, we showed that dietary conjugated linoleic acid (CLA) isomers can exert differential effects on heart function in male and female rats, but the underlying mechanisms for these actions are not known. Cardiomyocyte Ca2+ cycling is a key event in normal cardiac contractile function and defects in Ca2+ cycling are associated with cardiac dysfunction and heart disease. We therefore hypothesized that abnormalities in the sarcolemmal (SL) and sarcoplasmic reticulum (SR)-mediated regulation of intracellular Ca2+ contribute to altered cardiac contractile function of male and female rats owing to dietary CLA isomers. Healthy male and female Sprague-Dawley rats were fed different CLA isomers, (cis-9, trans-11 (c9,t11) and trans-10, cis-12 (t10,c12)) individually and in combination (50:50 mix as triglyceride or fatty acids) from 4 to 20 weeks of age. We determined the mRNA levels of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) 2a, ryanodine receptor, phospholamban, calsequestrin, Na+-Ca2+-exchanger (NCX), and L-type Ca2+ channel in the left ventricle (LV) by RT-PCR. The SR function was assessed by measurement of Ca2+-uptake and -release. Significant gender differences were seen in the LV NCX, L-type Ca2+ channel, and ryanodine receptor mRNA expression levels in control male and female rats. Dietary CLA isomers in the various forms induced changes in the mRNA levels of SERCA 2a, NCX, and L-type Ca2+ channel in the LV of both male and female hearts. Whereas protein contents of the Ca2+ cycling proteins were altered, changes in SR Ca2+-uptake and -release were also detected in both male and female rats in response to dietary CLA. The results of this study demonstrate that long-term dietary supplementation can modulate cardiac gene expression and SR function in a gender-related manner and may, in part, contribute to altered cardiac contractility.
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PMID:Gender differences in the modulation of cardiac gene expression by dietary conjugated linoleic acid isomers. 1761 56

Exercise provides protection against myocardial ischemia-reperfusion (IR) injury. Understanding the mechanisms of this protection may lead to new interventions for the prevention and/or treatment of heart disease. Although presently these mechanisms are not well understood, reports suggest that manganese superoxide dismutase (MnSOD) and calpain may be critical mediators of this protection. We hypothesized that an exercise-induced increase in MnSOD would provide cardioprotection by attenuating IR-induced oxidative modification to critical Ca(2+)-handling proteins, thereby decreasing calpain-mediated cleavage of these and other proteins attenuating cardiomyocyte death. After IR, myocardial apoptosis and infarct size were significantly reduced in hearts of exercised animals compared with sedentary controls. In addition, exercise prevented IR-induced calpain activation as well as the oxidative modification and calpain-mediated degradation of myocardial Ca(2+)-handling proteins (L-type Ca(2+) channels, phospholamban, and sarcoplasmic/endoplasmic reticulum calcium ATPase). Further, IR-induced activation of proapoptotic proteins was attenuated in exercised animals. Importantly, prevention of the exercise-induced increase in MnSOD activity via antisense oligonucleotides greatly attenuated the cardioprotection conferred by exercise. These results suggest that MnSOD provides cardioprotection by attenuating IR-induced oxidation and calpain-mediated degradation of myocardial Ca(2+)-handling proteins, thereby preventing myocardial apoptosis and necrosis.
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PMID:Exercise-induced protection against myocardial apoptosis and necrosis: MnSOD, calcium-handling proteins, and calpain. 1841 47

The long-QT syndrome (LQTS) is an inherited cardiac disorder associated with syncope and a high risk of sudden death. The molecular basis of type-1 LQTS (LQT1) is a missense or nonsense mutation in KCNQ channels that reduces slowly activating delayed rectifier potassium channel (I(Ks)) resulting in a prolonged action potential. Noticeably, the S2-S3 linker is a highly congregating region of LQT1 mutations. To further explore the mechanism, a KCNQ mutant (L191P) identified in one Chinese pedigree with LQT1 was chosen for this purpose. As Leu-191 is located in the middle of a well-known endoplasmic reticulum (ER) localization signal (RXR) in the intracellular S2-S3 linker, we examined the kinetics and the surface expression of both the KCNQ1 and L191 mutants. Our results showed that the mutation did not affect the channel kinetics, whereas the surface expression increased with increasing hydrophobicity of the middle residue 'X' of the RXR motif. Based on an analysis of fractional fluorescence data using a binomial model, we also found that the percentage of KCNQ1/L191P heteromeric channels expressed at the cell surface were 22.0%, 40.5%, 27.9%, 8.6% and 1.0% of heteromeric channels with 0, 1, 2, 3 and 4 subunits of L191P, respectively, in a transfected ratio of KCNQ1: L191P=1:1. These experiments demonstrated that coexpression of L191P resulted in a trafficking factor alpha<1, causing a trafficking deficiency of heteromeric channels that underlay the dominant-negative effect. This study suggests several trafficking signals coexisting in this region, and expands our understanding of possible dominant-negative mechanisms underlying LQTS.
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PMID:A hydrophobicity-dependent motif responsible for surface expression of cardiac potassium channel. 1904 15

Diseases of the heart (e.g. myocardial ischaemia reperfusion injury) remain the major cause of death in the industrialized world. Therefore, developing a pragmatic countermeasure to reduce myocardial ischaemia reperfusion injury is vital. In this regard, a plethora of evidence indicates that regular exercise can protect the heart during an ischaemia reperfusion insult (i.e. cardioprotection). This review summarizes studies indicating that both short-term (i.e. 1-5 days) and long-term (i.e. weeks to months) endurance exercise provides cardioprotection. Data are presented showing that exercise duration and exercise intensity are both important factors in achieving a cardioprotective phenotype. Importantly, it appears that the exercise duration of a single exercise session should last for 60 minutes and should be performed at about 75% maximum oxygen consumption in order to achieve exercise-induced cardioprotection. Furthermore, data are presented showing that exercise-induced cardioprotection against myocardial stunning can persist for at least 9 days after the cessation of exercise training, but is lost 18 days after exercise. This review also summarizes the exercise-induced adaptations that occur to the myocardium. In particular, extrinsic changes observed in human and animal models include neural, hormonal, humoral, vascular and reduced body fat. Other anatomical and biochemical/molecular changes that have been studied as putative mechanisms in exercise-induced cardioprotection include alterations in anatomic coronary arteries, induction of myocardial heat shock proteins, increased myocardial cyclooxygenase-2 activity, elevated endoplasmic reticulum stress proteins, nitric oxide production, improved function of sarcolemmal and/or mitochondrial adenosine triphosphate (ATP)-sensitive potassium channels and increased myocardial antioxidant capacity. However, the most compelling evidence for exercise-induced cardioprotection is the fact that exercise training upregulates key antioxidant enzymes that have been shown to promote cardioprotection. Moreover, data are presented showing that exercise training induces cardiac mitochondrial changes that result in reduced oxidant production. In addition, recently our laboratory has shown that exercise training evokes changes in mitochondrial phenotype that are protective against apoptotic stimuli. Specifically, data are presented showing that several mitochondrial proteins are altered following repeated bouts of endurance exercise and several of these differentially expressed proteins are potential important cardioprotective mediators. Finally, in hopes of stimulating debate and future research, this review concludes with a discussion of unanswered questions related to exercise-induced cardioprotection.
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PMID:Exercise preconditioning of the myocardium. 1982 60

MCP-1 (monocyte chemotactic protein-1) plays a critical role in the development of heart failure that is known to involve apoptosis. How MCP-1 contributes to cell death involved in the development of heart disease is not understood. In the present study we show that MCP-1 causes death in cardiac myoblasts, H9c2 cells, by inducing oxidative stress which causes ER stress leading to autophagy via a novel zinc-finger protein, MCPIP (MCP-1-induced protein). MCPIP expression caused cell death, and knockdown of MCPIP attenuated MCP-1-induced cell death. It caused induction of iNOS (inducible NO synthase), translocation of the NADPH oxidase subunit phox47 from the cytoplasm to the membrane, production of ROS (reactive oxygen species), and induction of ER (endoplasmic reticulum) stress markers HSP40 (heat-shock protein 40), PDI (protein disulfide-isomerase), GRP78 (guanine-nucleotide-releasing protein 78) and IRE1alpha (inositol-requiring enzyme 1alpha). It also caused autophagy, as indicated by beclin-1 induction, cleavage of LC3 (microtubule-associated protein 1 light chain 3) and autophagolysosome formation, and apoptosis, as indicated by caspase 3 activation and TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP nick-end labelling) assay. Inhibitors of oxidative stress, including CeO2 nanoparticles, inhibited ROS formation, ER stress, autophagy and cell death. Specific inhibitors of ER stress inhibited autophagy and cell death as did knockdown of the ER stress signalling protein IRE1. Knockdown of beclin-1 and autophagy inhibitors prevented cell death. This cell death involved caspase 2 and caspase 12, as specific inhibitors of these caspases prevented MCPIP-induced cell death. Microarray analysis showed that MCPIP expression caused induction of a variety of genes known to be involved in cell death. MCPIP caused activation of JNK (c-Jun N-terminal kinase) and p38 and induction of p53 and PUMA (p53 up-regulated modulator of apoptosis). Taken together, these results suggest that MCPIP induces ROS/RNS (reactive nitrogen species) production that causes ER stress which leads to autophagy and apoptosis through caspase 2/12 and IRE1alpha-JNK/p38-p53-PUMA pathway. These results provide the first molecular insights into the mechanism by which elevated MCP-1 levels associated with chronic inflammation may contribute to the development of heart failure.
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PMID:MCP-1 causes cardiomyoblast death via autophagy resulting from ER stress caused by oxidative stress generated by inducing a novel zinc-finger protein, MCPIP. 1992 54

B-cell leukemia/lymphoma 2 (BCL-2)/adenovirus E1B interacting protein 3 (BNIP3) and Nip-like protein X (NIX) are atypical BCL-2 homology domain 3-only proteins involved in cell death, autophagy, and programmed mitochondrial clearance. BNIP3 and NIX cause cell death by targeting mitochondria, directly through BCL-2-associated X protein- or BCL-2-antagonist/killer-dependent mechanisms, or indirectly through an effect on calcium stores in the endoplasmic reticulum. BNIP3 and NIX also induce autophagy through an effect on mitochondrial reactive oxygen species production, or by releasing Beclin 1 from inhibitory interactions with antiapoptotic BCL-2 family proteins. BNIP3 downregulates mitochondrial mass in hypoxic cells, whereas NIX is required for mitochondrial elimination during erythroid development. BNIP3 and NIX have an emerging role in human health. Cell death mediated by BNIP3 and NIX is implicated in heart disease and ischemic injury. Cancer progression is linked to loss of the prodeath function of BNIP3, but also to induction of its prosurvival activity. Finally, BNIP3 and NIX are implicated in mitochondrial quality control, which is important in aging and degenerative disease. Elucidation of the mechanisms by which BNIP3 and NIX regulate cell death, autophagy, and mitochondrial clearance may lead to treatments for these conditions.
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PMID:Mechanisms and biology of B-cell leukemia/lymphoma 2/adenovirus E1B interacting protein 3 and Nip-like protein X. 2112 15

Epicardial adipose tissue (EAT) has been implicated in the development of heart disease. Nonetheless, the crosstalk between factors secreted from EAT and cardiomyocytes has not been studied. Here, we examined the effect of factors secreted from EAT on contractile function and insulin signalling in primary rat cardiomocytes. EAT and subcutaneous adipose tissue (SAT) were isolated from guinea pigs fed a high-fat (HFD) or standard diet. HFD feeding for 6 months induced glucose intolerance, and decreased fractional shortening and ejection fraction (all P < 0.05). Conditioned media (CM) generated from EAT and SAT explants were subjected to cytokine profiling using antibody arrays, or incubated with cardiomyocytes to assess the effects on insulin action and contractile function. Eleven factors were differentially secreted by EAT when compared to SAT. Furthermore, secretion of 30 factors by EAT was affected by HFD feeding. Most prominently, activin A-immunoreactivity was 6.4-fold higher in CM from HFD versus standard diet-fed animals and, 2-fold higher in EAT versus SAT. In cardiomyocytes, CM from EAT of HFD-fed animals increased SMAD2-phosphorylation, a marker for activin A-signalling, decreased sarcoplasmic-endoplasmic reticulum calcium ATPase 2a expression, and reduced insulin-mediated phosphorylation of Akt-Ser473 versus CM from SAT and standard diet-fed animals. Finally, CM from EAT of HFD-fed animals as compared to CM from the other groups markedly reduced sarcomere shortening and cytosolic Ca(2+) fluxes in cardiomyocytes. These data provide evidence for an interaction between factors secreted from EAT and cardiomyocyte function.
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PMID:Secretory products of guinea pig epicardial fat induce insulin resistance and impair primary adult rat cardiomyocyte function. 2114 87

Tail-anchored (TA) proteins are post-translationally targeted to and inserted into the endoplasmic reticulum (ER) membrane through their single C-terminal transmembrane domain. Membrane insertion of TA proteins in mammalian cells is mediated by the ATPase TRC40/Asna1 (Get3 in yeast) and a receptor in the ER membrane. We have identified tryptophan-rich basic protein (WRB), also known as congenital heart disease protein 5 (CHD5), as the ER membrane receptor for TRC40/Asna1. WRB shows sequence similarity to Get1, a subunit of the membrane receptor complex for yeast Get3. Using biochemical and cell imaging approaches, we demonstrate that WRB is an ER-resident membrane protein that interacts with TRC40/Asna1 and recruits it to the ER membrane. We identify the coiled-coil domain of WRB as the binding site for TRC40/Asna1 and show that a soluble form of the coiled-coil domain interferes with TRC40/Asna1-mediated membrane insertion of TA proteins. The identification of WRB as a component of the TRC (Get) pathway for membrane insertion of TA proteins raises new questions concerning the proposed roles of WRB (CHD5) in congenital heart disease, and heart and eye development.
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PMID:WRB is the receptor for TRC40/Asna1-mediated insertion of tail-anchored proteins into the ER membrane. 2144 55

Phosphatidylcholine (PC) is the major phospholipid component of all plasma lipoprotein classes. PC is the only phospholipid which is currently known to be required for lipoprotein assembly and secretion. Impaired hepatic PC biosynthesis significantly reduces the levels of circulating very low density lipoproteins (VLDLs) and high density lipoproteins (HDLs). The reduction in plasma VLDLs is due in part to impaired hepatic secretion of VLDLs. Less PC within the hepatic secretory pathway results in nascent VLDL particles with reduced levels of PC. These particles are recognized as being defective and are degraded within the secretory system by an incompletely defined process that occurs in a post-endoplasmic reticulum compartment, consistent with degradation directed by the low-density lipoprotein receptor and/or autophagy. Moreover, VLDL particles are taken up more readily from the circulation when the PC content of the VLDLs is reduced, likely due to a preference of cell surface receptors and/or enzymes for lipoproteins that contain less PC. Impaired PC biosynthesis also reduces plasma HDLs by inhibiting hepatic HDL formation and by increasing HDL uptake from the circulation. These effects are mediated by elevated expression of ATP-binding cassette transporter A1 and hepatic scavenger receptor class B type 1, respectively. Hepatic PC availability has recently been linked to the progression of liver and heart disease. These findings demonstrate that hepatic PC biosynthesis can regulate the amount of circulating lipoproteins and suggest that hepatic PC biosynthesis may represent an important pharmaceutical target. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease.
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PMID:Phosphatidylcholine biosynthesis and lipoprotein metabolism. 2197 51

Stress to the endoplasmic reticulum (ER) is a recognized factor in Alzheimer's and Parkinson's diseases, diabetes, heart disease, liver disorders and cancer. Thus, drugs that interfere with ER stress have wide therapeutic potential. Here we review the effects of drugs on three arms of ER stress: the protein kinase RNA-activated (PKR)-like ER kinase (PERK) arm, the activated transcription factor 6 (ATF6) arm and the inositol-requiring enzyme 1 (IRE1) arm. Drugs fall into five groups: (i) compounds directly binding to ER stress molecules; (ii) chemical chaperones; (iii) inhibitors of protein degradation; (iv) antioxidants; (v) drugs affecting calcium signaling. Treatments are generally inhibitory and lead to increased viability, except when applied to cancer cells. A focus on interfering with the ATF6 arm is required, and more in vivo testing of these compounds concurrently across all three arms is needed if the full importance of ER stress to human disease is to be realized.
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PMID:InterfERing with endoplasmic reticulum stress. 2211 65


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