Gout as a risk factor for acute myocardial infarction: evidence from competing risk model analysis.

Chronic inflammation, a hallmark of gout, is implicated in the pathogenesis of atherosclerosis. Thus, in theory, gout can be expected to increase the risk of acute myocardial infarction (AMI). Yet, results from several epidemiological studies have been inconclusive. A retrospective cohort study was conducted using the National Health Insurance Research Database of Taiwan dated from 2000 to 2013. The study cohort comprised 3581 patients with gout (the gout cohort) and 14,324 patients without gout (the non-gout cohort). The primary outcome was the incidence of AMI. To estimate the effect of gout on the risk of AMI, the Lunn-McNeil competing risk model was fitted to estimate cause-specific hazard ratios (HRs) and their 95% confidence intervals (CIs). The cumulative incidence of AMI was significantly higher in the gout cohort than in the non-gout cohort, resulting in an adjusted HR of 1.36 (95% CI 1.04 to 2.76). Further, HRs of gout with incident AMI were higher in patients without hypertension, diabetes mellitus, or hyperlipidemia (ranging from 1.63 to 2.09) than in those with each of these comorbidities (ranging from 0.95 to 1.13). The results of this study suggest that patients with gout have an increased risk of AMI. The AMI risk associated with gout was conditional on patients' cardiovascular risk profile. Future work is needed to confirm these findings.

Cardiovascular Outcomes Associated With Clinical Use of Citalopram and Omeprazole: A Nationwide Population-Based Cohort Study.

Background Recent studies have raised concerns about the reduced efficacy of citalopram when used concurrently with proton pump inhibitors. The aim of this study was to evaluate the associations between clinical use of citalopram and omeprazole and the risk of sudden cardiac arrest (SCA) in an Asian population. Methods and Results A retrospective cohort study was conducted using the National Health Insurance Research Database of Taiwan dated from 2000 to 2013. The study cohorts comprised 3882 patients with citalopram use alone, 31 090 patients with omeprazole use alone, and 405 patients with concomitant use of citalopram and omeprazole (as the exposed cohort), and 141 508 patients received treatment with antidepressants without the risk of SCA and/or proton pump inhibitors other than omeprazole (as the comparison cohort). The primary outcome was the occurrence of SCA. The hazard ratios and 95% CIs derived from the time-dependent Cox regression model were used to assess the association between the proposed drug treatments and risk of SCA. The adjusted hazard ratios of SCA was 1.32 (95% CI, 1.17-1.50) for citalopram use alone, 1.08 (95% CI, 0.98-1.20) for omeprazole use alone, and 2.23 (95% CI, 1.79-2.78) for concomitant use of citalopram and omeprazole. The cumulative incidence of SCA over the Kaplan-Meier curves was more pronounced in patients with concomitant use of citalopram and omeprazole than those treated with citalopram alone and omeprazole alone. Conclusions This cohort study demonstrated use of citalopram and omeprazole either in isolation use or in concomitant use to be at increased risk for SCA.

Phosphorylation of signal transducer and activator of transcription 3 induced by hyperglycemia is different with that induced by lipopolysaccharide or erythropoietin via receptor­coupled signaling in cardiac cells.

The signal transducer and activator of transcription 3 (STAT3) is known to be involved in hypertrophy and fibrosis in cardiac dysfunction. The activation of STAT3 via the phosphorylation of STAT3 is required for the production of functional activity. It has been established that lipopolysaccharide (LPS)­induced phosphorylation of STAT3 in cardiomyocytes primarily occurs through a direct receptor­mediated action. This effect is demonstrated to be produced rapidly. STAT3 in cardiac fibrosis of diabetes is induced by high glucose through promotion of the STAT3­associated signaling pathway. However, the time schedule for STAT3 activation between LPS and high glucose appears to be different. Therefore, the difference in STAT3 activation between LPS and hyperglycemia in cardiomyocytes requires elucidation. The present study investigated the phosphorylation of STAT3 induced by LPS and hyperglycemia in the rat cardiac cell line H9c2. Additionally, phosphorylation of STAT3 induced by erythropoietin (EPO) via receptor activation was compared. Then, the downstream signals for fibrosis, including the connective tissue growth factor (CTGF) and matrix metalloproteinase (MMP)­9, were determined using western blotting, while the mRNA levels were quantified. LPS induced a rapid elevation of STAT3 phosphorylation in H9c2 cells within 30 min, similar to that produced by EPO. However, LPS or EPO failed to modify the mRNA level of STAT3, and/or the downstream signals for fibrosis. High glucose increased STAT3 phosphorylation to be stable after a long period of incubation. Glucose incubation for 24 h may augment the STAT3 expression in a dose­dependent manner. Consequently, fibrosis­associated signals, including CTGF and MMP­9 protein, were raised in parallel. In the presence of tiron, an antioxidant, these changes by hyperglycemia were markedly reduced, demonstrating the mediation of oxidative stress. Therefore, LPS­ or EPO­induced STAT3 phosphorylation is different compared with that caused by high glucose in H9c2 cells. Sustained activation of STAT3 by hyperglycemia may promote the expression of fibrosis­associated signals, including CTGF and MMP­9, in H9c2 cells. Therefore, regarding the cardiac dysfunctions associated with diabetes and/or hyperglycemia, the identification of nuclear STAT3 may be more reliable compared with the assay of phosphorylated STAT3 in cardiac cells.

Loperamide-induced Cardiac Depression Is Enhanced by Hyperglycemia: Evidence Relevant to Loperamide Abuse.

BACKGROUND AND AIMS: Cardiac dysryhthmias and death are reported after loperamide abuse. The mechanism of death is not clear and cardiac depression may play a role in this mechanism. Loperamide is widely used as an agonist of the µ-opioid receptor (MOR) in clinical practice. In skeletal muscle, an increase in MOR in response to hyperglycemia is largely attributable to higher expression of the transducer and activator of transcription 3 (STAT3), which binds to the promoter of the MOR genes. Therefore, we investigated the changes in cardiac MOR caused by hyperglycemia both in vivo and in vitro. METHODS: Streptozotocin-induced type 1-like diabetic rats (STZ rats) were used to estimate cardiac performance and changes in cardiac MOR under the influence of loperamide. STAT3 was measured in cultured cardiomyocytes under high glucose (HG) to mimic the in vivo changes. RESULTS: Loperamide-induced reduction of cardiac performance was more marked in STZ rats than in normal rats. The increased MOR in the hearts of STZ rats was reversed by the reduction of hyperglycemia. Higher MOR expression paralleled the increase in STAT3 in cardiomyocytes under HG and was reversed by siRNA of STAT3. Stattic at a dose sufficient to inhibit STAT3 reduced MOR both in vivo and in vitro. CONCLUSION: Cardiac depression induced by loperamide is enhanced by hyperglycemia due to higher MOR expression, which is associated with higher expression of STAT3 in the heart. These results suggest that loperamide abuse is particularly dangerous for individuals with hyperglycemia.

IVUS-Guided Implantation of Bioresorbable Vascular Scaffolds for Very Late Paclitaxel Stent Thrombosis.

Bioresorbable vascular scaffold (BVS) implantation has been shown to be safe in patients with stable coronary disease, and effective against the thrombotic lesion and the in-stent restenosis (ISR) of the drug-eluting stent (DES). BVSs have the advantages of a snow racket concept, positive vessel remodeling, and better conformability compared with DES in acute coronary syndrome (ACS). We report on a young patient with ST-elevation myocardial infarction (STEMI) who presented to our emergency department arising from very late stent thrombosis (VLST) of a 2.5 × 28 mm paclitaxel-eluting stent (Coroflex® Please) three years after its implantation. After the patient was treated with balloon dilation, intravascular ultrasound (IVUS) revealed a short segment of a guide wire outside the DES mesh. Two BVSs were implanted to prevent a DES recoil. Post-scaffold-implantation IVUS showed adequately expanded strut of BVSs. Six months later, optical coherence tomography (OCT) revealed that some segments of the scaffold had been absorbed and that there was no in-scaffold restenosis. The patient had not complained about angina during the out-patient clinic follow-up. This is the first report of successful BVS implantation for a STEMI patient attributable to DES VLST.

Amarogentin ameliorates diabetic disorders in animal models.

Amarogentin is a bitter-tasting secoiridoid glycoside isolated from an herb. Inhibition of aldose reductase by amarogentin has been documented as an antidiabetic action. However, the mechanisms of action of amarogentin in diabetic disorders remain unknown. The present study employed streptozotocin-induced type 1 diabetic (T1DM) rats to investigate the antihyperglycemic action of amarogentin. Changes in the protein expression of glucose transporter 4 (GLUT4) and phosphoenolpyruvate carboxykinase (PEPCK) in skeletal muscle and liver, respectively, were also detected by Western blotting. Additionally, a type 2 diabetes (T2DM) animal model induced using a fructose-rich diet was also applied to assess the effect of amarogentin on insulin resistance according to the homeostasis model assessment-insulin resistance (HOMA-IR). Amarogentin dose-dependently attenuated hyperglycemia in the T1DM rats lacking insulin. The action of amarogentin was further supported in rats administered the oral glucose tolerance test. Western blotting showed that amarogentin reversed the decreased GLUT4 level in skeletal muscle and reduced the elevated PEPCK expression in livers isolated from the T1DM rats. Moreover, amarogentin decreased the HOMA-IR and increased insulin sensitivity in the T2DM rats. These data show that amarogentin may ameliorate glucose homeostasis in diabetic rats, indicating its potential for future development as an antidiabetic drug.

Pigment Epithelium-Derived Factor Mediates Autophagy and Apoptosis in Myocardial Hypoxia/Reoxygenation Injury.

Pigment epithelium-derived factor (PEDF) is a multifunctional protein that exhibits anti-angiogenic, antitumor, anti-inflammatory, antioxidative, anti-atherogenic, and cardioprotective properties. While it was recently shown that PEDF expression is inhibited under low oxygen conditions, the functional role of PEDF in response to hypoxia/reoxygenation (H/R) remains unclear. The goal of this study was to therefore investigate the influence of PEDF on myocardial H/R injury. For these analyses, PEDF-specific small interfering RNA-expressing and PEDF-expressing lentivirus (PEDF-LV) vectors were utilized to knockdown or stably overexpress PEDF, respectively, within human cardiomyocytes (HCM) in vitro. We noted that reactive oxygen species (ROS) play important roles in the induction of cell death pathways, including apoptosis and autophagy in ischemic hearts. Our findings demonstrate that overexpression of PEDF resulted in a significant reduction in ROS production and attenuation of mitochondrial membrane potential depletion under H/R conditions. Furthermore, PEDF inhibited the activation of a two-step apoptotic pathway in which caspase-dependent (caspase-9 and caspase-3) and caspase-independent (apoptosis inducing factor and endonuclease G), which in turn cleaves several crucial substrates including the DNA repair enzyme poly (ADP-ribose) polymerase. Meanwhile, overexpression of PEDF also promoted autophagy, a process that is typically activated in response to H/R. Therefore, these findings suggest that PEDF plays a critical role in preventing H/R injury by modulating anti-oxidant and anti-apoptotic factors and promoting autophagy.

Eucommia bark (Du-Zhong) improves diabetic nephropathy without altering blood glucose in type 1-like diabetic rats.

BACKGROUND: Eucommia bark, Eucommia ulmoides Oliver barks (Du-Zhong in Mandarin), is an herb used for renal dysfunction in Chinese traditional medicine. In an attempt to develop this herb as a treatment for diabetic nephropathy (DN), we investigated the effects of Du-Zhong on renal dysfunction in type 1-like diabetic rats. METHODS: Streptozotocin (STZ) was used to induce type 1-like diabetes in rats (STZ-diabetic rats). In addition to hyperglycemia, STZ-diabetic rats showed significant nephropathy, including higher plasma levels of blood urea nitrogen, creatinine, and renal fibrosis. Western blot analysis of renal cortical tissue was applied to characterize the changes in potential signals related to nephropathy. RESULTS: Oral administration of Du-Zhong (1 g/kg/day) to STZ-diabetic rats for 20 days not only decreased the plasma levels of blood urea nitrogen and creatinine but also improved renal fibrosis, whereas the plasma glucose level was not changed. The higher expressions of protein levels of transforming growth factor-beta (TGF-ß) and connective tissue growth factor in diabetic rats were markedly attenuated by Du-Zhong. The increased phosphorylation of Smad2/3 in STZ-diabetic rats was also reduced by Du-Zhong. However, Du-Zhong cannot reverse the hyperglycemia-induced overproduction of signal transducers and activators of transcription 3 in the diabetic kidney. CONCLUSION: Oral administration of Du-Zhong improves STZ-induced DN in rats by inhibiting TGF-ß/Smad signaling and suppressing TGF-ß/connective tissue growth factor expression. Therefore, active principle from Du-Zhong is suitable to develop as new agent for DN in the future.

Development of PPAR-agonist GW0742 as antidiabetic drug: study in animals.

BACKGROUND: The development of new drugs for the treatment of diabetes mellitus (DM) is critically important. Insulin resistance (IR) is one of the main problems associated with type-2 DM (T2DM) seen in clinics. GW0742, a selective peroxisome proliferator-activated receptor (PPAR)-δ agonist, has been shown to ameliorate metabolic abnormalities including IR in skeletal muscle in mice fed high-fructose corn syrup. However, the influence of GW0742 on systemic insulin sensitivity has still not been elucidated. Therefore, it is important to investigate the effect of GW0742 on systemic IR in diabetic rats for the development of new drugs. METHODS: The present study used a T2DM animal model to compare the effect of GW0742 on IR using homeostasis model assessment-IR (HOMA-IR) and hyperinsulinemic euglycemic clamping. Additionally, the insulinotropic action of GW0742 was investigated in type-1 DM (T1DM) rats. Changes in the protein expression of glucose transporter 4 (GLUT4) and phosphoenolpyruvate carboxykinase (PEPCK) in skeletal muscle and in liver, respectively, were also identified by Western blots. RESULTS: GW0742 attenuated the increased HOMA-IR in diabetic rats fed a fructose-rich diet. This action was blocked by GSK0660 at the dose sufficient to inhibit PPAR-δ. Improvement of IR by GW0742 was also characterized in diabetic rats using hyperinsulinemic euglycemic clamping. Additionally, an increase of insulin sensitivity due to GW0742 was observed in these diabetic rats. Moreover, GW0742 reduced the hyperglycemia in T1DM rats lacking insulin. Western blotting analysis indicated that GW0742 reversed the decrease in GLUT4 and markedly reduced the increased PEPCK in liver. CONCLUSION: The data showed that GW0742 has the ability to improve glucose homeostasis in diabetic rats through activation of PPAR-δ. Therefore, PPAR-δ is a good target for the development of antidiabetic drugs in the future.

Canavanine induces insulin release via activation of imidazoline I3 receptors.

The aim of the present study was to identify the effect of canavanine on the imidazoline receptor because canavanine is a guanidinium derivative that has a similar structure to imidazoline receptor ligands. Transfected Chinese hamster ovary-K1 cells expressing imidazoline receptors (nischarin (NISCH)-CHO-K1 cells) were used to elucidate the direct effects of canavanine on imidazoline receptors. In addition, the imidazoline I3 receptor has been implicated in stimulation of insulin secretion from pancreatic ß-cells. Wistar rats were used to investigate the effects of canavanine (0.1, 1 and 2.5 mg/kg, i.v.) on insulin secretion. In addition the a specific I3 receptor antagonist KU14R (4 or 8 mg/kg, i.v.) was used to block I3 receptors. Canavanine decreased blood glucose by increasing plasma insulin in rats. In addition, canavanine increased calcium influx into NISCH-CHO-K1 cells in a manner similar to agmatine, the endogenous ligand of imidazoline receptors. Moreover, KU12R dose-dependently attenuated canavanine-induced insulin secretion in HIT-T15 pancreatic ß-cells and in the plasma of rats. The data suggest that canavanine is an agonist of I3 receptors both in vivo and in vitro. Thus, canavanine would be a useful tool in imidazoline receptor research.

Rosiglitazone increases cerebral klotho expression to reverse baroreflex in type 1-like diabetic rats.

Reduced baroreflex sensitivity (BRS) is widely observed in diabetic human and animals. Rosiglitazone is one of the clinically used thiazolidinediones (TZD) known as PPAR γ agonist. Additionally, the klotho protein produced from choroid plexus in the central nervous system is regulated by PPAR γ . In an attempt to develop the new therapeutic strategy, we treated streptozotocin-induced diabetic rats (STZ) with rosiglitazone (STZ + TZD) orally at 10 mg/kg for 7 days. Also, STZ rats were subjected to intracerebroventricular (ICV) infusion of recombinant klotho at a dose of 3 µ g/2.5 µ L via syringe pump (8 µ g/hr) daily for 7 days. The BRS and heart rate variability were then estimated under challenge with a depressor dose of sodium nitroprusside (50 µ g/kg) or a pressor dose of phenylephrine (8 µ g/kg) through an intravenous injection. Lower expression of klotho in medulla oblongata of diabetic rats was identified. Cerebral infusion of recombinant klotho or oral administration of rosiglitazone reversed BRS in diabetic rats. In conclusion, recovery of the decreased klotho in brain induced by rosiglitazone may restore the impaired BRS in diabetic rats. Thus, rosiglitazone is useful to reverse the reduced BRS through increasing cerebral klotho in diabetic disorders.

Inoue-Balloon Percutaneous Transvenous Mitral Valvuloplasty through the Left Femoral Vein in Anomalous Inferior Vena Cava.

UNLABELLED: Inoue-balloon percutaneous transvenous mitral valvuloplasty is conventionally performed via the right femoral vein. However, atrial transseptal access can be technically challenging. Herein, we describe a 54-year-old male who had balloon mitral valvuloplasty performed via the left femoral vein because of an anomalous inferior vena cava course, including the technical issues encountered using this approach. KEY WORDS: Anomalous inferior vena cava; Left femoral vein approach; Mitral valvuloplasty.

IVUS-guided rotational atherectomy for unexpandable paclitaxel-eluting stent: A case report and review of literature.

We describe a patient suffering from late stent thrombosis in a paclitaxel-eluting stent which had an underexpanded ring due to the three-hundred-sixty-degree circumferential calcified plaque. Intravascular ultrasound (IVUS) revealed rotational atherectomy could successfully ablate both the metallic ring and the calcified ring. The ablated segment was scaffolded with a new paclitaxel-eluting stent, well expanded and documented by IVUS. To our knowledge, this is the first case report of stent ablation for an unexpanded paclitaxel-eluting stent. From the Medline index, there were only six case reports of stent ablation. We review and summarize the operation details of stent ablation from these reports.

Mechanism and management of burr entrapment: A nightmare of interventional cardiologists.

Entrapment of the burr within calcified lesion is an uncommon, but serious complication during rotational atherectomy and usually needs surgical retrieval. We report a case series of this complication and also review the possible mechanisms, such as kokesi phenomenon or insufficient pecking motion with decreased rotational speed. We also review the potential techniques ever proposed to rescue this complication percutaneously, including simple manual traction, balloon dilation to release the trap, snaring the burr as distal as possible for forceful local traction and wedging the burr with a child catheter to facilitate retrieval. Gentle pecking motion of the burr for sufficient ablation and shortening the run less than 15 s may avoid such complications. Interventional cardiologists using the rotablator should be familiar with the tips and tricks to avoid and rescue this complication.

Increase in cardiac M2-muscarinic receptor expression is regulated by GATA binding protein 4 (GATA-4) in streptozotocin-induced diabetic rats.

BACKGROUND: An increase in cardiac M2-muscarinic receptor (M2-mAChR) expression in diabetic rats has been observed, but the molecular mechanism of this increase remains unclear. The transcriptional activity of GATA binding protein 4 (GATA-4) has been documented to regulate the expression of M2-mAChR genes. In this study, we were interested in identifying the role of GATA-4 in the increase in M2-mAChR in diabetic rats and a primary culture of cardiomyocytes. METHODS: Streptozotocin-induced diabetic rats (STZ-rats) and high-glucose (D-glucose 30 mM, 24h)-treated primary cultures of cardiomyocytes from neonatal rats were used to investigate the role of GATA-4 in the change in M2-mAChR. The protein expression was determined by Western blot analysis. Phlorizin (Na(+)-glucose co-transport inhibitor), insulin, tiron (radical scavenger), PD98059 (ERK inhibitor) and SB203580 (p38 inhibitor) were used. We also silenced GATA-4 by RNAi to investigate the changes in M2-mAChR expression. RESULTS: The cardiac output was reduced in STZ-rats with a higher expression of M2-mAChR or phosphorylated GATA-4 in the heart. These changes were reversed after correction of the blood sugar level. In cardiomyocytes, high glucose treatment also increased M2-mAChR expression and GATA-4 phosphorylation. These changes were reversed by tiron (ROS scavenger) or PD98059 (MEK/ERK inhibitor). However, an increase in M2-mAChR expression was not observed when GATA-4 was silenced by small interfering RNA (siRNA) in cardiomyocytes. CONCLUSIONS: We suggest that hyperglycemia can cause a higher expression of M2-mAChR in cardiomyocytes mainly through ROS to enhance MEK/ERK for phosphorylation of GATA-4.

Improvement in door-to-balloon (D2B) time in acute ST-elevation myocardial infarction through the D2B alliance--experience of 15 primary percutaneous coronary intervention centers in Taiwan.

BACKGROUND: Currently, the door-to-balloon (D2B) times observed in clinical practice in Taiwan are different from those recommended by evidence-based guidelines. D2B Alliance, a countrywide initiative for quality supported by the Taiwan Joint Commission on Hospital Accreditation, sought to achieve the goal of administering treatment to 75% of patients with ST-elevation myocardial infarction (STEMI) within 90min of hospital presentation. METHODS AND RESULTS: The current study was designed to be prospective, national, and multicenter. We conducted a longitudinal study of the D2B times recorded in 15 primary percutaneous coronary intervention centers and examined the changes caused by implementing the D2B Alliance strategies. A total of 1,726 patients were enrolled in the D2B Alliance and implementation of the D2B Alliance strategies resulted in a significant decrease in the average D2B times (128.8 ± 42.9 min vs. 83.2 ± 16.2 min; P<0.001) from those at baseline. By the end of the year-long study, the percentage of patients treated under 90 min had increased from 46.2% to 80.1% in the hospitals enrolled in the D2B Alliance. CONCLUSIONS: Over the 1 year, hospitals enrolled in the D2B Alliance achieved the goal of reducing the D2B times of 75% of STEMI patients to less than 90 min.

Oleic acid activates peroxisome proliferator-activated receptor δ to compensate insulin resistance in steatotic cells.

Nonalcoholic fatty liver disease is frequently associated with type 2 diabetes; however, this idea is challenged by recent studies because hepatic steatosis is not always associated with insulin resistance (IR). Oleic acid (OA) is known to induce hepatic steatosis with normal insulin sensitivity; however, the mechanism is still unknown. Previous studies depict that activation of peroxisome proliferator-activated receptor δ (PPARδ) improves hepatic steatosis and IR, whereas the role of PPARδ in the improvement of insulin sensitivity by OA is unknown. Here we induced steatosis in HepG2 cells by incubation with OA and OA significantly increased the expression of PPARδ through a calcium-dependent pathway. OA also induced the expression of G protein-coupled receptor 40 (GPR40), and deletion of GPR40 by small interfering ribonucleic acid transfection partially reversed the effect of OA on PPARδ. Inhibition of phospholipase C (PLC) by U73122 also reversed OA-induced PPARδ expression. Otherwise, deletion of PPARδ augmented the OA-induced steatosis in HepG2 cells. Furthermore, IR was developed in OA-treated HepG2 cells with PPARδ deletion, while insulin-related signals and insulin-stimulated glycogen synthesis were reduced through increase of phosphatase and tensin homolog (PTEN) expression. In conclusion, OA activates GPR40-PLC-calcium pathway to increase the expression of PPARδ and PPARδ further decreased the expression of PTEN to regulate insulin sensitivity in hepatic steatosis.

Molecular role of GATA binding protein 4 (GATA-4) in hyperglycemia-induced reduction of cardiac contractility.

BACKGROUND: Diabetic cardiomyopathy, a diabetes-specific complication, refers to a disorder that eventually leads to left ventricular hypertrophy in addition to diastolic and systolic dysfunction. In recent studies, hyperglycemia-induced reactive oxygen species (ROS) in cardiomyocytes have been linked to diabetic cardiomyopathy. GATA binding protein 4 (GATA-4) regulates the expression of many cardio-structural genes including cardiac troponin-I (cTnI). METHODS: Streptozotocin-induced diabetic rats and H9c2 embryonic rat cardiomyocytes treated with a high concentration of glucose (a D-glucose concentration of 30 mM was used and cells were cultured for 24 hr) were used to examine the effect of hyperglycemia on GATA-4 accumulation in the nucleus. cTnI expression was found to be linked to cardiac tonic dysfunction, and we evaluated the expression levels of cTnI and GATA-4 by Western blot analysis. RESULTS: Cardiac output was lowered in STZ-induced diabetic rats. In addition, higher expressions of cardiac troponin I (cTnI) and phosphorylated GATA-4 were identified in these rats by Western blotting. The changes were reversed by treatment with insulin or phlorizin after correction of the blood sugar level. In H9c2 cells, ROS production owing to the high glucose concentration increased the expression of cTnI and GATA-4 phosphorylation. However, hyperglycemia failed to increase the expression of cTnI when GATA-4 was silenced by small interfering RNA (siRNA) in H9c2 cells. Otherwise, activation of ERK is known to be a signal for phosphorylation of serine105 in GATA-4 to increase the DNA binding ability of this transcription factor. Moreover, GSK3ß could directly interact with GATA-4 to cause GATA-4 to be exported from the nucleus. GATA-4 nuclear translocation and GSK3ß ser9 phosphorylation were both elevated by a high glucose concentration in H9c2 cells. These changes were reversed by tiron (ROS scavenger), PD98059 (MEK/ERK inhibitor), or siRNA of GATA-4. Cell contractility measurement also indicated that the high glucose concentration decreased the contractility of H9c2 cells, and this was reduced by siRNA of GATA-4. CONCLUSIONS: Hyperglycemia can cause systolic dysfunction and a higher expression of cTnI in cardiomyocytes through ROS, enhancing MEK/ERK-induced GATA-4 phosphorylation and accumulation in the cell nucleus.