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)

The endoplasmic reticulum (ER) is an organelle involved in protein folding, calcium homeostasis, and lipid biosynthesis. Various factors that interfere with ER function lead to accumulation of unfolded proteins, including oxidative stress, ischemia, disturbance of calcium homeostasis, and overexpression of normal and/or incorrectly folded proteins. The resulting ER stress triggers the unfolded protein response (UPR) that induces signal transduction events to reduce the accumulation of unfolded proteins by increasing ER resident chaperones, inhibiting protein translation, and accelerating the degradation of unfolded proteins. However, if stress is severe and/or prolonged, the ER also initiates apoptotic signaling that includes induction of the pro-apoptotic transcriptional factor C/EBP homologous protein, activation of c-Jun amino-terminal kinase, and cleavage of caspase-12. These ER-initiated events lead to cell death via mitochondria-dependent and -independent apoptotic pathways. Furthermore, the B cell lymphoma 2 family of proteins expressed on the ER and mitochondria are also involved in regulating cell death due to ER stress. Thus, the ER is now recognized as a vitally important organelle that can decide cell survival or death. Recent animal and human studies have revealed that the UPR and ER-initiated apoptosis are implicated in the pathophysiology of various cardiovascular diseases, including heart failure, ischemic heart disease, the development of atherosclerosis, and plaque rupture. Improved understanding of the molecular mechanisms underlying UPR activation and ER-initiated apoptosis in cardiovascular disease will provide us with new targets for drug discovery and therapeutic intervention.
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PMID:ER stress in cardiovascular disease. 1991 45

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

Among the players involved in Ca(2+) homeostasis in heart tissue are SERCA (sarco/endoplasmic reticulum Ca(2+) ATPase)-type Ca(2+) pumps. Until recently, human heart was known to coexpress major SERCA2a and minor SERCA2b isoforms. Here, we will summarize data showing that nonfailing human heart is equipped with an increasing variety of SERCA isoforms comprised new SERCA2 (ATP2A2) and SERCA3 (ATP2A3) gene products. The novel 3'-ends of the human SERCA2 and -3 genes, the corresponding mRNAs and the carboxyl termini of the SERCA2a-2c and SERCA3a-3f isoforms will be presented. The intrinsic characteristics and effects on cellular Ca(2+) homeostasis of the SERCA2 and SERCA3 recombinant isoforms will be summarized. Evidence for the expression of SERCA2c and SERCA3a, -3d, and -3f mRNAs and/or endogenous proteins in the human heart will be summarized, the latter having being visualized thanks to newly generated isoform-specific antibodies. We will show how the strategic localization of the SERCA2c, SERCA3a, -3d, and -3f isoforms in cytoplasmic compartments, and the nucleus enables them to contribute to subsarcolemmal, cytoplasmic, and nuclear Ca(2+) signalling in the human heart and isolated cardiomyocytes. Comparative expressions of the additional SERCA isoforms in some failing hearts will also be summarized. Lastly, we will present what is known regarding the role the SERCA2c, SERCA3a, -3d, or -3f isoforms in cardiac muscle pathophysiology. To focus on up-to-date topics, this multi-SERCA system of human heart may sustain a distinct internal endoplasmic reticulum (ER) compartment in cardiomyocytes, as well as potential compensatory mechanisms and both SR/ER abnormalities in heart failure.
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PMID:Multiple and diverse coexpression, location, and regulation of additional SERCA2 and SERCA3 isoforms in nonfailing and failing human heart. 1996 89

The cardiac isoform of the sarco/endoplasmic reticulum Ca(2+)ATPase (SERCA2a) plays a major role in controlling excitation/contraction coupling. In both experimental and clinical heart failure, SERCA2a expression is significantly reduced which leads to abnormal Ca(2+) handling and deficient contractility. A large number of studies in isolated cardiac myocytes and in small and large animal models of heart failure showed that restoring SERCA2a expression by gene transfer corrects the contractile abnormalities and improves energetics and electrical remodeling. Following a long line of investigation, a clinical trial is underway to restore SERCA2a expression in patients with heart failure using adeno-associated virus type 1. This review addresses the following issues regarding heart failure gene therapy: i) new insights on calcium regulation by SERCA2a; ii) SERCA2a as a gene therapy target in animal models of heart failure; iii) advances in the development of viral vectors and gene delivery; and iv) clinical trials on heart failure using SERCA2a. This review focuses on the new advances in SERCA2a- targeted gene therapy made in the last three years. In conclusion, SERCA2a is an important therapeutic target in various cardiovascular disorders. Ongoing clinical gene therapy trials will provide answers on its safety and applicability.
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PMID:Sarcoplasmic reticulum Ca(2+) ATPase as a therapeutic target for heart failure. 2007 30

Ryanodine receptors (RyRs) are high conductance intracellular cation channels that release calcium ions from stores such as the endoplasmic reticulum and sarcoplasmic reticulum. Although RyRs are expressed in many cell types, their roles have only been extensively characterised in tissues in which they are abundant: RyR1 is essential for excitation-contraction coupling in skeletal muscle; whereas RyR2 is required for the analogous signal transduction pathway in heart. Defects in RyR1 cause malignant hyperthermia and a spectrum of myopathies in skeletal muscle; whereas RyR2 dysregulation can result in fatal cardiac arrhythmias and is involved in heart failure. Altered RyR gating has been implicated in a range of other diseases, including epilepsy, neurodegeneration, pain and cancer. RyRs interact with a range of toxic substances, providing insights into their functional and structural properties. Consequently, these channel complexes represent potential therapeutic targets for treatment of numerous diseases. Furthermore, strategies for combating multicellular parasites and agricultural pests could exploit pharmacological differences between their RyRs and those of vertebrates. However, available pharmacological tools for manipulation of RyR gating are generally unsuitable for clinical, veterinary or agricultural use, owing to their lack of selectivity, inappropriate solubility in the aqueous or lipid environment, or generation of side-effects. The expression, subcellular distribution and gating of RyRs is modified by a wide variety of cellular proteins, some of which are expressed in a developmentally or tissue-restricted manner. This commentary examines the possibility of manipulating the expression and function of such proteins in order develop new drugs acting on RyR channel complexes.
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PMID:Ryanodine receptor calcium channels and their partners as drug targets. 2009 79

Cytotoxic concentrations of imatinib mesylate (10-50 microM) were required to trigger markers of apoptosis and endoplasmic reticulum stress response in neonatal rat ventricular myocytes and fibroblasts, with no significant differences observed between c-Abl silenced and nonsilenced cells. In mice, oral or intraperitoneal imatinib treatment did not induce cardiovascular pathology or heart failure. In rats, high doses of oral imatinib did result in some cardiac hypertrophy. Multi-organ toxicities may have increased the cardiac workload and contributed to the cardiac hypertrophy observed in rats only. These data suggest that imatinib is not cardiotoxic at clinically relevant concentrations (5 microM).
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PMID:Imatinib does not induce cardiotoxicity at clinically relevant concentrations in preclinical studies. 2012 31

The unfolded protein response (UPR) is triggered to assist protein folding when endoplasmic reticulum (ER) function is impaired. Recent studies demonstrated that ER stress can also induce cell-specific genes. In this study, we examined whether X-box binding protein 1 (XBP1), a major UPR-linked transcriptional factor, regulates the expression of brain natriuretic peptide (BNP) in cardiomyocytes. In samples from failing human hearts, extensive splicing of XBP1 was observed along with increased expression of glucose-regulated protein of 78 kDa (GRP78), a target of spliced XBP1 (sXBP1), suggesting that the UPR was induced in heart failure in humans. Interestingly, quantitative real-time PCR revealed a positive correlation between cardiac expression of GRP78 and BNP, leading us to test the hypothesis that sXBP1 regulates BNP as well as GRP78 in cardiomyocytes. A pharmacological ER stressor caused a dose-dependent increase in the expression of sXBP1 and BNP by cultured cardiomyocytes. Short interfering RNA targeting XBP1 suppressed the induction of BNP expression by a pharmacological ER stressor or norepinephrine, which was rescued by the adenovirus-mediated overexpression of sXBP1. The promoter assay with overexpression of sXBP1 or norepinephrine showed that the proximal AP1/CRE-like element in the promoter region of BNP was critical for transcriptional regulation of BNP by sXBP1. Direct binding of sXBP1 to this element was confirmed by the chromatin immunoprecipitation assay. These findings suggest that ER stress observed in failing hearts regulates cardiac BNP expression through a novel promoter region of the AP1/CRE-like element.
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PMID:X-box binding protein 1 regulates brain natriuretic peptide through a novel AP1/CRE-like element in cardiomyocytes. 2017 Jun 59

To identify novel transmembrane and secretory molecules expressed in cardiac myocytes, signal sequence trap screening was performed in rat neonatal cardiac myocytes. One of the molecules identified was a transmembrane protein, prostatic androgen repressed message-1 (PARM-1). While PARM-1 has been identified as a gene induced in prostate in response to castration, its function is largely unknown. Our expression analysis revealed that PARM-1 was specifically expressed in hearts and skeletal muscles, and in the heart, cardiac myocytes, but not non-myocytes expressed PARM-1. Immunofluorescent staining showed that PARM-1 was predominantly localized in endoplasmic reticulum (ER). In Dahl salt-sensitive rats, high-salt diet resulted in hypertension, cardiac hypertrophy and subsequent heart failure, and significantly stimulated PARM-1 expression in the hearts, with a concomitant increase in ER stress markers such as GRP78 and CHOP. In cultured cardiac myocytes, PARM-1 expression was stimulated by proinflammatory cytokines, but not by hypertrophic stimuli. A marked increase in PARM-1 expression was observed in response to ER stress inducers such as thapsigargin and tunicamycin, which also induced apoptotic cell death. Silencing PARM-1 expression by siRNAs enhanced apoptotic response in cardiac myocytes to ER stresses. PARM-1 silencing also repressed expression of PERK and ATF6, and augmented expression of CHOP without affecting IRE-1 expression and JNK and Caspase-12 activation. Thus, PARM-1 expression is induced by ER stress, which plays a protective role in cardiac myocytes through regulating PERK, ATF6 and CHOP expression. These results suggested that PARM-1 is a novel ER transmembrane molecule involved in cardiac remodeling in hypertensive heart disease.
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PMID:PARM-1 is an endoplasmic reticulum molecule involved in endoplasmic reticulum stress-induced apoptosis in rat cardiac myocytes. 2030 82

Accumulation of unfolded proteins in the endoplasmic reticulum (ER) evokes the ER stress response, including activating transcription factor 6 (ATF6), a key transcriptional activator to maintain cellular homeostasis. The ER stress has recently been reported to cause various diseases, but the role of ATF6 in the heart remains unknown. We clarified the role of ATF6 in the heart. The ATF6 activity was increased in the murine heart after myocardial infarction (MI). Treatment of mice with 4-(2-aminoethyl) benzenesulfonyl fluoride, an inhibitor of ATF6, further reduced cardiac function and increased the mortality rate at 14days after MI. Pharmacological inhibition of ATF6 induced dilatation of left ventricle and depression of cardiac function even in sham-operated murine hearts. The transgenic mice that expressed dominant negative mutant of ATF6 showed larger left ventricular dimension and reduced fractional shortening compared with wild-type littermates, resulting in death of heart failure at approximately 8weeks of age. In contrast, cardiac function after MI was better in transgenic mice that expressed constitutively active mutant of ATF6, compared with wild-type littermates. These results suggest that activation of the ER stress response factor ATF6 plays a critical role in not only protecting hearts under the pathological state but also maintaining cardiac function under the physiological state.
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PMID:ATF6 is important under both pathological and physiological states in the heart. 2038 Aug 36

Dysregulation of programmed cell death due to abnormal expression of Bcl-2 proteins is implicated in cancer, neurodegenerative diseases, and heart failure. Among Bcl-2 family members, BNip proteins uniquely stimulate cell death with features of both apoptosis and necrosis. Localization of these factors to mitochondria and endoplasmic reticulum (ER) provides additional complexity. Previously, we observed regulation of intracellular calcium stores by reticular Nix. Here, we report effects of Nix targeting to mitochondria or ER on cell death pathways and heart failure progression. Nix-deficient fibroblasts expressing mitochondrial-directed or ER-directed Nix mutants exhibited similar cytochrome c release, caspase activation, annexin V and TUNEL labeling, and cell death. ER-Nix cells, but not mitochondrial-Nix cells, showed dissipation of mitochondrial inner membrane potential, Deltapsi(m), and were protected from cell death by cyclosporine A or ppif ablation, implicating the mitochondrial permeability transition pore (MPTP). ER-Nix cells were not protected from death by caspase inhibition or combined ablation of Bax and Bak. Combined inhibition of caspases and the MPTP fully protected against Nix-mediated cell death. To determine the role of the dual pathways in heart failure, mice conditionally overexpressing Nix or Nix mutants in hearts were created. Cardiomyocte death caused by mitochondrial- and ER-directed Nix was equivalent, but ppif ablation fully protected only ER-Nix. Thus, Nix stimulates dual autonomous death pathways, determined by its subcellular localization. Mitochondrial Nix activates Bax/Bak- and caspase-dependent apoptosis, whereas ER-Nix activates Bax/Bak-independent, MPTP-dependent necrosis. Complete protection against programmed cell death mediated by Nix and related factors can be achieved by simultaneous inhibition of both pathways.
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PMID:Dual autonomous mitochondrial cell death pathways are activated by Nix/BNip3L and induce cardiomyopathy. 2041 3


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