Abstract Myocardial ischemia/reperfusion (I/R) injury is a major determinant of infarct size and clinical outcome, yet effective therapies remain limited. Although metabolic remodeling is central to I/R pathology, the contribution of nucleotide biosynthesis remains unclear. Here, we identify CAD, the multifunctional rate-limiting enzyme of de novo pyrimidine biosynthesis, as a previously unrecognized regulator of myocardial reperfusion injury. CAD activation exacerbated cardiomyocyte death during simulated I/R, whereas CAD knockdown or pharmacological inhibition was protective in vitro. Mechanistically, CAD enhanced dihydroorotate dehydrogenase (DHODH)-dependent electron transfer, increased the CoQH 2 /CoQ ratio, and promoted complex I reverse electron transport (RET), thereby amplifying mitochondrial ROS. In parallel, CAD suppressed de novo purine synthesis, causing purine insufficiency, DIS3L-dependent RNA decay, and cytosolic ROS. Importantly, cardiomyocyte-specific CAD deletion protected against cardiac I/R injury in vivo. Together, these findings establish CAD as a metabolic hub linking nucleotide flux to dual-compartment ROS signaling and identify nucleotide metabolism as a therapeutic vulnerability in myocardial I/R injury. Graphical Abstract

Doxorubicin (DOX) remains a cornerstone in the treatment of various cancers. However, its clinical utilization is significantly hampered by dose-dependent cardiotoxicity. The generation of reactive oxygen species (ROS) constitutes the central component of the pathogenesis of DOX-induced cardiotoxicity. Activating transcription factor 4 (ATF4) has been demonstrated to exert a cardioprotective effect and augment cardiac antioxidative capacity in settings of heart failure. However, the role of ATF4 in DOX-induced cardiomyopathy (DIC) remains unknown. To explore the role of ATF4 in DOX-induced cardiomyopathy, cardiac-specific ATF4 conditional heterozygous mice and AAV9 mediated ATF4 overexpression mouse models were utilized. Cardiac function was assessed by echocardiography. The upstream regulator and downstream mediator of ATF4 were evaluated using RNA-seq analysis and further verified using ChIP assay and luciferase reporter assay. We found a substantial decrease in ATF4 expression levels in the heart of DIC mice. ATF4 +/- mice exhibited a higher degree of susceptibility to DOX-induced cardiotoxicity in comparison with ATF4 flox/flox mice, as evidenced by the manifestation of more severe cardiac dysfunction and a significantly earlier mortality rate. In contrast, cardiacc-specific overexpression ATF4 by AAV9 confers robust cardioprotection against DOX-induced cardiomyopathy. Mechanistically, we identified the upstream regulator of ATF4 as KLF16, which was significantly suppressed during DOX treatment. Further, the decrease of ATF4 led to a reduction in cystathionine γ-lyase (CSE) transcription and hydrogen sulfide (H 2 S) production in the context of DOX-induced cardiotoxicity. ChIP and luciferase reporter assays revealed that ATF4 functioned as the transcription factor of the CSE gene, which is a key enzyme in the synthesis of H 2 S to counteract oxidative stress. Consistently, ROS scavengers or H 2 S donors was shown to mitigate the consequences of ATF4 deficiency. In contrast, the ectopic expression of ATF4 mitigated oxidative stress and apoptosis in DOX-induced cardiotoxicity, both in vivo and in vitro . Our study revealed a novel function of ATF4 in counteracting oxidative stress in DOX cardiotoxicity by promoting the transcription of CSE. ATF4 may represent a promising therapeutic target for the treatment of DOX-induced cardiomyopathy.

Background Doxorubicin (DOX) remains a cornerstone in the treatment of various cancers. However, its clinical utilization is significantly hampered by dose-dependent cardiotoxicity. The generation of reactive oxygen species (ROS) constitutes the central component of the pathogenesis of DOX-induced cardiotoxicity. Activating transcription factor 4 (ATF4) has been demonstrated to exert a cardioprotective effect and augment cardiac antioxidative capacity in settings of heart failure. However, the role of ATF4 in DOX-induced cardiomyopathy (DIC) remains unknown. Methods To explore the role of ATF4 in DOX-induced cardiomyopathy, cardiac-specific ATF4 conditional heterozygous mice and AAV9 mediated ATF4 overexpression mouse models were utilized. Cardiac function was assessed by echocardiography. The upstream regulator and downstream mediator of ATF4 were evaluated using RNA-seq analysis and further verified using ChIP assay and luciferase reporter assay. Results We found a substantial decrease in ATF4 expression levels in the heart of DIC mice. ATF4+/- mice exhibited a higher degree of susceptibility to DOX-induced cardiotoxicity in comparison with ATF4flox/flox mice, as evidenced by the manifestation of more severe cardiac dysfunction and a significantly earlier mortality rate. In contrast, cardiacc-specific overexpression ATF4 by AAV9 confers robust cardioprotection against DOX-induced cardiomyopathy. Mechanistically, we identified the upstream regulator of ATF4 as KLF16, which was significantly suppressed during DOX treatment. Further, the decrease of ATF4 led to a reduction in cystathionine γ-lyase (CSE) transcription and hydrogen sulfide (H2S) production in the context of DOX-induced cardiotoxicity. ChIP and luciferase reporter assays revealed that ATF4 functioned as the transcription factor of the CSE gene, which is a key enzyme in the synthesis of H2S to counteract oxidative stress. Consistently, ROS scavengers or H2S donors was shown to mitigate the consequences of ATF4 deficiency. In contrast, the ectopic expression of ATF4 mitigated oxidative stress and apoptosis in DOX-induced cardiotoxicity, both in vivo and in vitro . Conclusions Our study revealed a novel function of ATF4 in counteracting oxidative stress in DOX cardiotoxicity by promoting the transcription of CSE. ATF4 may represent a promising therapeutic target for the treatment of DOX-induced cardiomyopathy. ### Competing Interest Statement The authors have declared no competing interest. * DOX : Doxorubicin ROS : reactive oxygen species ATF4 : Activating transcription factor 4 DIC : DOX-induced cardiomyopathy CSE : cystathionine γ-lyase H2S : hydrogen sulfide ISR : integrated stress response elF2a : α-subunit of eukaryotic initiation factor 2 ER : endoplasmic reticulum TFs : transcription factors KLFs : Krüppel-like factors DCM : dilated cardiomyopathy iPSC-CMs : induced pluripotent stem cell-derived cardiomyocytes ACM : arrhythmogenic cardiomyopathy CBS : cystathionine β-synthase 3-MST : 3-mercaptopyruvate sulfurtransferase

OBJECTIVE:To investigate the mechanisms underlying the therapeutic effects of Kuanxiong aerosol (KXA) in heart failure after myocardial infarction (HFAMI). METHODS:A HFAMI rat model was established. Echocardiography, H&E and TUNEL staining of heart tissue, and ELISA for HFAMI-related biomarkers were performed after KXA treatment. qPCR, Western blot, and flow cytometry were used to identify potential KXA targets in vivo and in vitro. Cell viability and apoptosis were evaluated using the Cell Counting Kit-8. RESULTS:KXA significantly decreased left ventricular end diastolic diameter (LVIDD, 6.49±0.40 mm, P<0.001) and left ventricular end-systolic dimension (LVISD, 3.72±0.27 mm, P<0.001), while increasing left ventricular ejection fraction (LVEF, 64.66±2.69%, P<0.001) and left ventricular fraction shortening (LVFS, 43.20±5.93%, P<0.001). KXA also suppressed cardiomyocyte apoptosis and reduced levels of NT-proBNP, ST2, IL-6, TNF-α, MMP2, and MMP9 (all P<0.05). Additionally, KXA reduced immune cell infiltration (Neutrophils, Macrophages, Th1, NK cells) and upregulated DLL4, NOTCH1, NICD, and Hes1 expression in the infarction zone. In doxorubicin-treated cells, KXA enhanced cell viability and upregulated Bcl-2, Bcl-xL, and NOTCH pathway proteins, while reducing cleaved caspase-3 (all P<0.05). CONCLUSION:KXA improves HFAMI by modulating immune responses and activating the NOTCH1 signaling pathway.

The ISR is a cellular signaling pathway that responds to various physiological changes and types of stimulation. The mitochondrial integrated stress response (ISRmt) is a stress response specific to mitochondria which is initiated by eIF2α phosphorylation and is responsive to mitochondrial stressors. The ISRmt triggers diverse metabolic responses reliant on activating transcription factor 4 (ATF4). The preliminary phases of ISRmt can provoke an adaptive stress response that antagonizes age-related diseases and promotes longevity. In this review, we provide an overview of the molecular mechanisms of the ISRmt, with a particular focus on its potential as a therapeutic target for age-related disease and the promotion of longevity.

BACKGROUND:Cardiomyocyte growth is coupled with active protein synthesis, which is one of the basic biological processes in living cells. However, it is unclear whether the unfolded protein response transducers and effectors directly take part in the control of protein synthesis. The connection between critical functions of the unfolded protein response in cellular physiology and requirements of multiple processes for cell growth prompted us to investigate the role of the unfolded protein response in cell growth and underlying molecular mechanisms. METHODS:Cardiomyocyte-specific inositol-requiring enzyme 1α (IRE1α) knockout and overexpression mouse models were generated to explore its function in vivo. Neonatal rat ventricular myocytes were isolated and cultured to evaluate the role of IRE1α in cardiomyocyte growth in vitro. Mass spectrometry was conducted to identify novel interacting proteins of IRE1α. Ribosome sequencing and polysome profiling were performed to determine the molecular basis for the function of IRE1α in translational control. RESULTS:We show that IRE1α is required for cell growth in neonatal rat ventricular myocytes under prohypertrophy treatment and in HEK293 cells in response to serum stimulation. At the molecular level, IRE1α directly interacts with eIF4G and eIF3, 2 critical components of the translation initiation complex. We demonstrate that IRE1α facilitates the formation of the translation initiation complex around the endoplasmic reticulum and preferentially initiates the translation of transcripts with 5' terminal oligopyrimidine motifs. We then reveal that IRE1α plays an important role in determining the selectivity and translation of these transcripts. We next show that IRE1α stimulates the translation of epidermal growth factor receptor through an unannotated terminal oligopyrimidine motif in its 5' untranslated region. We further demonstrate a physiological role of IRE1α-governed protein translation by showing that IRE1α is essential for cardiomyocyte growth and cardiac functional maintenance under hemodynamic stress in vivo. CONCLUSIONS:These studies suggest a noncanonical, essential role of IRE1α in orchestrating protein synthesis, which may have important implications in cardiac hypertrophy in response to pressure overload and general cell growth under other physiological and pathological conditions.

Background: Cellular redox control is maintained by generation of reactive oxygen/nitrogen species balanced by activation of antioxidative pathways. Disruption of redox balance leads to oxidative stress, a central causative event in numerous diseases including heart failure. Redox control in the heart exposed to hemodynamic stress, however, remains to be fully elucidated. Methods: Pressure overload was triggered by transverse aortic constriction in mice. Transcriptomic and metabolomic regulations were evaluated by RNA-sequencing and metabolomics, respectively. Stable isotope tracer labeling experiments were conducted to determine metabolic flux in vitro. Neonatal rat ventricular myocytes and H9c2 cells were used to examine molecular mechanisms. Results: We show that production of cardiomyocyte NADPH, a key factor in redox regulation, is decreased in pressure overload-induced heart failure. As a consequence, the level of reduced glutathione is downregulated, a change associated with fibrosis and cardiomyopathy. We report that the pentose phosphate pathway and mitochondrial serine/glycine/folate metabolic signaling, 2 NADPH-generating pathways in the cytosol and mitochondria, respectively, are induced by transverse aortic constriction. We identify ATF4 (activating transcription factor 4) as an upstream transcription factor controlling the expression of multiple enzymes in these 2 pathways. Consistently, joint pathway analysis of transcriptomic and metabolomic data reveal that ATF4 preferably controls oxidative stress and redox-related pathways. Overexpression of ATF4 in neonatal rat ventricular myocytes increases NADPH-producing enzymes‚ whereas silencing of ATF4 decreases their expression. Further, stable isotope tracer experiments reveal that ATF4 overexpression augments metabolic flux within these 2 pathways. In vivo, cardiomyocyte-specific deletion of ATF4 exacerbates cardiomyopathy in the setting of transverse aortic constriction and accelerates heart failure development, attributable, at least in part, to an inability to increase the expression of NADPH-generating enzymes. Conclusions: Our findings reveal that ATF4 plays a critical role in the heart under conditions of hemodynamic stress by governing both cytosolic and mitochondrial production of NADPH.

Ischemic disease is among the deadliest and most disabling illnesses. Prominent examples include myocardial infarction and stroke. Most, if not all, underlying pathological changes, including oxidative stress, inflammation, and nutrient deprivation, are potent inducers of the integrated stress response (ISR). Four upstream kinases are involved in ISR signaling that sense a myriad of input stress signals and converge on the phosphorylation of serine 51 of eukaryotic translation initiation factor 2α (eIF2α). As a result, translation initiation is halted, creating a window of opportunity for the cell to repair itself and restore homeostasis. A growing number of studies show strong induction of the ISR in ischemic disease. Genetic and pharmacological evidence suggests that the ISR plays critical roles in disease initiation and progression. Here, we review the basic regulation of the ISR, particularly in response to ischemia, and summarize recent findings relevant to the actions of the ISR in ischemic disease. We then discuss therapeutic opportunities by modulating the ISR to treat ischemic heart disease, brain ischemia, ischemic liver disease, and ischemic kidney disease. Finally, we propose that the ISR represents a promising therapeutic target for alleviating symptoms of ischemic disease and improving clinical outcomes.

Background:The integrated stress response (ISR) is an evolutionarily conserved process to cope with intracellular and extracellular disturbances. Myocardial infarction is a leading cause of death worldwide. Coronary artery reperfusion, the most effective means to mitigate cardiac damage of myocardial infarction, causes additional reperfusion injury. This study aimed to investigate the role of the ISR in myocardial ischemia/reperfusion (I/R). Methods:Cardiac-specific gain- and loss-of-function approaches for the ISR were used in vivo. Myocardial I/R was achieved by ligation of the cardiac left anterior descending artery for 45 minutes followed by reperfusion for different times. Cardiac function was assessed by echocardiography. Cultured H9c2 cells, primary rat cardiomyocytes, and mouse embryonic fibroblasts were used to dissect underlying molecular mechanisms. Tandem mass tag labeling and mass spectrometry was conducted to identify protein targets of the ISR. Pharmacologic means were tested to manipulate the ISR for therapeutic exploration. Results:We show that the PERK (PKR-like endoplasmic reticulum resident kinase)/eIF2 & alpha; (& alpha; subunit of eukaryotic initiation factor 2) axis of the ISR is strongly induced by I/R in cardiomyocytes in vitro and in vivo. We further reveal a physiologic role of PERK/eIF2 & alpha; signaling by showing that acute activation of PERK in the heart confers robust cardioprotection against reperfusion injury. In contrast, cardiac-specific deletion of PERK aggravates cardiac responses to reperfusion. Mechanistically, the ISR directly targets mitochondrial complexes through translational suppression. We identify NDUFAF2 (NADH:ubiquinone oxidoreductase complex assembly factor 2), an assembly factor of mitochondrial complex I, as a selective target of PERK. Overexpression of PERK suppresses the protein expression of NDUFAF2 and PERK inhibition causes an increase of NDUFAF2. Silencing of NDUFAF2 significantly rescues cardiac cell survival from PERK knockdown under I/R. We show that activation of PERK/eIF2 & alpha; signaling reduces mitochondrial complex-derived reactive oxygen species and improves cardiac cell survival in response to I/R. Moreover, pharmacologic stimulation of the ISR protects the heart against reperfusion damage, even after the restoration of occluded coronary artery, highlighting clinical relevance for myocardial infarction treatment. Conclusions:These results suggest that the ISR improves cell survival and mitigates reperfusion damage by selectively suppressing mitochondrial protein synthesis and reducing oxidative stress in the heart.

The hexosamine biosynthetic pathway (HBP) plays critical roles in nutrient sensing, stress response, and cell growth. However, its contribution to cardiac hypertrophic growth and heart failure remains incompletely understood. Here, we show that the HBP is induced in cardiomyocytes during hypertrophic growth. Overexpression of Gfat1 (glutamine:fructose-6-phosphate amidotransferase 1), the rate-limiting enzyme of HBP, promotes cardiomyocyte growth. On the other hand, Gfat1 inhibition significantly blunts phenylephrine-induced hypertrophic growth in cultured cardiomyocytes. Moreover, cardiac-specific overexpression of Gfat1 exacerbates pressure overload-induced cardiac hypertrophy, fibrosis, and cardiac dysfunction. Conversely, deletion of Gfat1 in cardiomyocytes attenuates pathological cardiac remodeling in response to pressure overload. Mechanistically, persistent upregulation of the HBP triggers decompensated hypertrophy through activation of mTOR while Gfat1 deficiency shows cardioprotection and a concomitant decrease in mTOR activity. Taken together, our results reveal that chronic upregulation of the HBP under hemodynamic stress induces pathological cardiac hypertrophy and heart failure through persistent activation of mTOR.

BACKGROUND:The unfolded protein response plays versatile roles in physiology and pathophysiology. Its connection to cell growth, however, remains elusive. Here, we sought to define the role of unfolded protein response in the regulation of cardiomyocyte growth in the heart. METHODS:We used both gain- and loss-of-function approaches to genetically manipulate XBP1s (spliced X-box binding protein 1), the most conserved signaling branch of the unfolded protein response, in the heart. In addition, primary cardiomyocyte culture was used to address the role of XBP1s in cell growth in a cell-autonomous manner. RESULTS:We found that XBP1s expression is reduced in both human and rodent cardiac tissues under heart failure. Furthermore, deficiency of XBP1s leads to decompensation and exacerbation of heart failure progression under pressure overload. On the other hand, cardiac-restricted overexpression of XBP1s prevents the development of cardiac dysfunction. Mechanistically, we found that XBP1s stimulates adaptive cardiac growth through activation of the mechanistic target of rapamycin signaling, which is mediated via FKBP11 (FK506-binding protein 11), a novel transcriptional target of XBP1s. Moreover, silencing of FKBP11 significantly diminishes XBP1s-induced mechanistic target of rapamycin activation and adaptive cell growth. CONCLUSIONS:Our results reveal a critical role of the XBP1s-FKBP11-mechanistic target of rapamycin axis in coupling of the unfolded protein response and cardiac cell growth regulation.

Cardiovascular disease is the leading cause of death worldwide. Despite overwhelming socioeconomic impact and mounting clinical needs, our understanding of the underlying pathophysiology remains incomplete. Multiple forms of cardiovascular disease involve an acute or chronic disturbance in cardiac myocytes, which may lead to potent activation of the Unfolded Protein Response (UPR), a cellular adaptive reaction to accommodate protein-folding stress. Accumulation of unfolded or mis-folded proteins in the Endoplasmic Reticulum (ER) elicits three signaling branches of the UPR, which otherwise remain quiescent. This ER stress response then transiently suppresses global protein translation, augments production of protein-folding chaperones, and enhances ER-associated protein degradation, with an aim to restore cellular homeostasis. Ample evidence has established that the UPR is strongly induced in heart disease. Recently, the mechanisms of action and multiple pharmacological means to favorably modulate the UPR are emerging to curb the initiation and progression of cardiovascular disease. Here, we review the current understanding of the UPR in cardiovascular disease and discuss existing therapeutic explorations and future directions.

The heart manifests hypertrophic growth in response to elevation of afterload pressure. Cardiac myocyte growth involves new protein synthesis and membrane expansion, of which a number of cellular quality control machineries are stimulated to maintain function and homeostasis. The unfolded protein response is potently induced during cardiac hypertrophy to enhance protein-folding capacity and eliminate terminally misfolded proteins. However, whether the unfolded protein response directly regulates cardiac myocyte growth remains to be fully determined. Here, we show that GRP78 (glucose-regulated protein of 78 kDa)—an endoplasmic reticulum-resident chaperone and a critical unfolded protein response regulator—is induced by cardiac hypertrophy. Importantly, overexpression of GRP78 in cardiomyocytes is sufficient to potentiate hypertrophic stimulus-triggered growth. At the in vivo level, TG (transgenic) hearts overexpressing GRP78 mount elevated hypertrophic growth in response to pressure overload. We went further to show that GRP78 increases GATA4 (GATA-binding protein 4) level, which may stimulate Anf (atrial natriuretic factor) expression and promote cardiac hypertrophic growth. Silencing of GATA4 in cultured neonatal rat ventricular myocytes significantly diminishes GRP78-mediated growth response. Our results, therefore, reveal that protein-folding chaperone GRP78 may directly enhance cardiomyocyte growth by stimulating cardiac-specific transcriptional factor GATA4.

Rationale: Restoration of coronary artery blood flow is the most effective means of ameliorating myocardial damage triggered by ischemic heart disease. However, coronary reperfusion elicits an increment of additional injury to the myocardium. Accumulating evidence indicates that the unfolded protein response (UPR) in cardiomyocytes is activated by ischemia/reperfusion (I/R) injury. Xbp1s (spliced X-box binding protein 1), the most highly conserved branch of the unfolded protein response, is protective in response to cardiac I/R injury. GRP78 (78 kDa glucose-regulated protein), a master regulator of the UPR and an Xbp1s target, is upregulated after I/R. However, its role in the protective response of Xbp1s during I/R remains largely undefined. Objective: To elucidate the role of GRP78 in the cardiomyocyte response to I/R using both in vitro and in vivo approaches. Methods and Results: Simulated I/R injury to cultured neonatal rat ventricular myocytes induced apoptotic cell death and strong activation of the UPR and GRP78. Overexpression of GRP78 in neonatal rat ventricular myocytes significantly protected myocytes from I/R-induced cell death. Furthermore, cardiomyocyte-specific overexpression of GRP78 ameliorated I/R damage to the heart in vivo. Exploration of underlying mechanisms revealed that GRP78 mitigates cellular damage by suppressing the accumulation of reactive oxygen species. We go on to show that the GRP78-mediated cytoprotective response involves plasma membrane translocation of GRP78 and interaction with PI3 kinase, culminating in stimulation of Akt. This response is required as inhibition of the Akt pathway significantly blunted the antioxidant activity and cardioprotective effects of GRP78. Conclusions: I/R induction of GRP78 in cardiomyocytes stimulates Akt signaling and protects against oxidative stress, which together protect cells from I/R damage.

Objective: The spliced transcription factor Xbp1 (Xbp1s), a transducer of the unfolded protein response (UPR), regulates lipolysis. Lipolysis is stimulated by fasting when uridine synthesis is also activated in adipocytes. Methods: Here we have examined the regulatory role Xbp1s in stimulation of uridine biosynthesis in adipocytes and triglyceride mobilization using inducible mouse models. R esults: Xbp1s is a key molecule involved in adipocyte uridine biosynthesis and release by activation of carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, dihydroorotase (CAD), the rate-limiting enzyme for UMP biosynthesis. Adipocyte Xbp1s overexpression drives energy mobilization and protects mice from obesity through activation of the pyrimidine biosynthesis pathway. Conclusion: These observations reveal that Xbp1s is a potent stimulator of uridine production in adipocytes, enhancing lipolysis and invoking a potential anti-obesity strategy through the induction of a futile biosynthetic cycle. (C) 2018 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license.

Objective To investigate the clinical characteristics of coronary heart disease risk fac tors,and explore the relationship of severity of coronary artery lesions in patients with coronary heart disease and coronary heart disease risk factors.Methods In our hospital for treatment of coronary artery disease patients during April 2013 to August 2014,230 cases of hospitalized patients were divided into two groups after coronary angiography diagnosis,including 170 cases of patients with coronary heart disease as the observation group,and 60 patients with coronary atherosclerosis as the control group with the degree of stenosis less than 50％.The clinical data of two groups were used to study the risk factors for coronary heart disease.The relationship was analyzed between severity of coronary artery pathological changes and coronary heart disease risk factors.Results For the observation group,type 2 diabetes,smoking,and men were associated with coronary heart disease (CHD),with the corresponding OR (95％ CI) of 17.489 (11.013-30.017),48.632 (20.379-117.178),and 18.976 (13.105-28.331),respectively.Smoking and type 2 diabetes were associated with coronary artery stenosis degree (P ＜ 0.05),with OR 95％ (CI) of 10.15 (2.012-2.584),and of 7.23 (1.613-2.176).The results found there was no relationship among hypertension,dyslipidemia,coronary heart disease (CHD),and age.There was a link between the body mass index (BMI) and the severity of the disease.For observation group,left ventricular ejection function,high-sensitivity C-reactive protein (hs-CRP),and Ccr were related to the severity of coronary lesions,and the patients existed lower Ccr,left ventricular ejection function abate,and increased hs-CRP levels increase,P＜0.05,and the OR (95％ CI) were 1.986 (5.204-17.627),1.103 (1.012-1.027),and 2.131 (1.901-2.369).Conclusions Type 2 diabetes,smoking,male patients with coronary heart disease risk factors had a close relationship,and the severity of coronary artery lesions included the reduced re nal function in patients and the increased hs-CRP level.

Objective To analyze the different continuous renal replacement therapy (CRRT) in coronary heart disease patients complicated with chronic renal failure undergoing pereutaneous coronary intervention (PCI).Methods We performed a prospective study on 56 patients in our hospital from January 2016 to August 2017.All patients were divided into 2 groups:Normal group(CRRT did in first 12 hours after PCI treatment);Reinforcement group:CRRT did in 24 hours before and 12 hours after PCI treatment.Chronic health conditions,acute physiology,incidence of contrast-induced nephropathy(CIN) and serum creatinine were compared between the two groups.Results There was no significant difference in general information between general group and reinforcement group.CIN incidence in reinforcement group was significantly lower than the that in normal group(7.14％ vs.39.28％,P＜0.01).In the common group,the serum creatinine level at 24 hours after PCI was higher than that before PCI [(308.14±45.08)μmol/L vs.(254.59±80.44)μmol/L,P=0.02],while the serum creatinine level at 48 h and 72 h after PCI had no significant difference with that before PCI[(232.49±20.12)μmol/L vs.(247.52±54.81)μmol/L vs (254.59±80.44)μmol/L,P＞0.05].In reinforcement group,the serum creatinine level at 24 hours after PCI had no significant difference with that before PCI[(274.04±71.06)μmol/L vs.(286.65±53.04)μmol/L,P＞0.05],but the serum creatinine level at 48 h and 72 h after PCI was significantly lower than that before PCI [(220.12±23.87)μmol/L vs.(286.65±53.04)μmol/L,P=0.01],[(250.17±44.20)μmol/L vs.(286.65±53.00)μmol/L,P=0.02].Conclusion The effect of CRRT achieved both before and after PCI is better than CRRT only did after PCI,which has a positive effect on reducing the contrast-induced nephropathy.

Ischemic heart disease is a severe stress condition that causes extensive pathological alterations and triggers cardiac cell death. Accumulating evidence suggests that the unfolded protein response (UPR) is strongly induced by myocardial ischemia. The UPR is an evolutionarily conserved cellular response to cope with protein-folding stress, from yeast to mammals. Endoplasmic reticulum (ER) transmembrane sensors detect the accumulation of unfolded proteins and stimulate a signaling network to accommodate unfolded and misfolded proteins. Distinct mechanisms participate in the activation of three major signal pathways, viz. protein kinase RNA-like ER kinase, inositol-requiring protein 1, and activating transcription factor 6, to transiently suppress protein translation, enhance protein folding capacity of the ER, and augment ER-associated degradation to refold denatured proteins and restore cellular homeostasis. However, if the stress is severe and persistent, the UPR elicits inflammatory and apoptotic pathways to eliminate terminally affected cells. The ER is therefore recognized as a vitally important organelle that determines cell survival or death. Recent studies indicate the UPR plays critical roles in the pathophysiology of ischemic heart disease. The three signaling branches may elicit distinct but overlapping effects in cardiac response to ischemia. Here, we outline the findings and discuss the mechanisms of action and therapeutic potentials of the UPR in the treatment of ischemic heart disease.

Secretory and transmembrane proteins rely on proper function of the secretory pathway for folding, posttranslational modification, assembly, and secretion. Accumulation of misfolded proteins in the endoplasmic reticulum (ER) stimulates the unfolded protein response (UPR), which communicates between the ER and other organelles to enhance ER-folding capacity and restore cellular homeostasis. Glucose-regulated protein of 78 kDa (GRP78), an ER-resident protein chaperone, is a master regulator of all UPR signaling branches. Accumulating studies have established a fundamental role of GRP78 in protein folding, ER stress response, and cell survival. However, role of GRP78 in the heart remains incompletely characterized. Here we showed that embryos lacking GRP78 specifically in cardiac myocytes manifest cardiovascular malformations and die in utero at late gestation. We went further to show that inducible knockout of GRP78 in adult cardiac myocytes causes early mortality due to cardiac cell death and severe decline in heart performance. At the cellular level, we found that loss of GRP78 increases apoptotic cell death, which is accompanied by reduction in AKT signaling and augmentation of production for reactive oxygen species. Importantly, enhancing AKT phosphorylation and activity leads to decreases in oxidative stress and increases in cardiac myocyte survival. Collectively, our results demonstrate an essential role of GRP78 in ensuring normal cardiogenesis and maintaining cardiac contractility and function.

Background: Spliced X-box binding protein 1 (Xbp1s) is a key signal transducer and the most conserved branch of the unfolded protein response (UPR). Its role in cardiac hypertrophy and heart failure however remains poorly understood. Aims: To explore the role of Xbp1s in the development of pathological cardiac hypertrophy and remodeling. Methods and Results: Here, we showed that the expression of Xbp1s was highly and acutely induced by pressure overload in mouse hearts. Transgenic overexpression of Xbp1s in vivo led to cardiac hypertrophy, and exacerbated the hypertrophic response in response to transverse aortic constriction. At the mechanistic levels, we found that FK506 binding protein 11 (Fkbp11) is a bona fide transcriptional target of Xbp1s. Overexpression of Xbp1s stimulated Fkbp11 at both in vitro and in vivo levels. In so doing, Xbp1s directly augmented the mTORC1 signaling, the master regulator of cell growth. Indeed, siRNA-mediated knockdown of Fkbp11 significantly diminished Xbp1s-induced mTORC1 activation and hypertrophic growth in cardiac myocytes. Conclusions: Our results uncovered a novel link between protein-folding and cell growth with Xbp1s, Fkbp11 and mTORC1 as the key mediators, which may provide insights about our understanding of pathological cardiac remodeling in pressure overload.