[show abstract][hide abstract] ABSTRACT: Midkine is a multifunctional growth factor, and its serum levels are increased with the functional severity of heart failure. This study aimed to examine the role of midkine in heart failure pathogenesis. Midkine expression levels were increased in the kidney and lung after transverse aortic constriction (TAC) surgery, but not sufficiently increased in the heart. After TAC, phosphorylation of extracellular signal-regulated kinase1/2 and AKT, and the expression levels of foetal genes in the heart were considerably increased in transgenic mice with cardiac-specific overexpression of midkine (MK-Tg) compared with wild-type (WT) mice. MK-Tg mice showed more severe cardiac hypertrophy and dysfunction, and showed lower survival rate after TAC than WT mice. We conclude that midkine plays a critical role in cardiac hypertrophy and remodelling.
Biochemical and Biophysical Research Communications 11/2013; · 2.41 Impact Factor
[show abstract][hide abstract] ABSTRACT: Low-grade inflammation associated with heart failure (HF) is known to deteriorate cardioembolic stroke in patients with atrial fibrillation (AF). Little is known about the relationship between atrial endothelial impairment induced by innate immunity and thrombus formation. We examined whether atrial endothelial impairment through Toll-like receptor (TLR) 4 signaling causes atrial thrombogenesis. TLR4, heat shock protein 60, and vascular cell adhesion molecule (VCAM)-1 expression were higher in the atrium of AF patients who underwent valve replacement surgery with HF compared with those without it (p < 0.05). We created thoracic transverse aortic constriction (TAC) in TLR4 knock-out (KO) and wild-type (WT) mice. Atrial thrombosis was observed less frequently in TLR4 KO mice (4/15) than in WT mice (16/20) 4 weeks after TAC despite similar severity of heart failure. The decrease in endothelial nitric oxide synthase (eNOS) phosphorylation and increase in VCAM-1 and plasminogen activator inhibitor (PAI)-1 expression, observed in the atrium of WT mice following TAC, were significantly attenuated in TLR4 KO mice (p < 0.05). Nuclear factor-κB (NF-κB) activation after TAC was attenuated in TLR4 KO mice compared with WT mice. Activation of mitogen-activated protein kinase p38 (p38) after TAC was also attenuated in TLR4 KO mice (p < 0.05). Thus, increased VCAM-1 and PAI-1, and decreased eNOS phosphorylation through the TLR4/NFκB/p38 pathway, may be associated with atrial thrombogenesis in the heart failure mice model. Atrial endothelial impairment through the TLR4 signaling may play a role in atrial thrombogenesis in AF patients with HF.
[show abstract][hide abstract] ABSTRACT: Early coronary reperfusion of the ischemic myocardium is a desired therapeutic goal for the preservation of myocardial function. However, reperfusion itself causes additional myocardium injuries. Activation of the diacylglycerol-protein kinase C (DAG-PKC) cascade has been implicated in the cardioprotective effects occurring after ischemia/reperfusion (I/R). DAG kinase (DGK) controls cellular DAG levels by converting DAG to phosphatidic acid, and may act as an endogenous regulator of DAG-PKC signaling. In the present study, we examined the functional role of DGKα in cardiac injury after I/R in in vivo mouse hearts. We generated transgenic mice with cardiac-specific overexpression of DGKα (DGKα-TG). The left anterior descending coronary artery was transiently occluded for 20 min and reperfused for 24 h in DGKα-TG mice and wild-type littermate (WT) mice. The levels of phosphorylation activity of PKCε, extracellular-signal regulated kinase (ERK) 1/2, and p70 ribosomal S6 kinase (p70S6K) were increased after I/R in WT mouse hearts. However, in DGKα-TG mice, activation of PKCε, ERK1/2, and p70S6K was attenuated compared to WT mice. After 24 h, Evans blue/triphenyltetrazolium chloride double staining and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining showed that DGKα-TG mice had significantly larger myocardial infarctions and larger numbers of TUNEL-positive cardiomyocytes than WT mice. Echocardiography and cardiac catheterization revealed that left ventricular systolic function was more severely depressed in DGKα-TG mice than in WT mice after I/R. These findings suggest that DGKα exacerbates I/R injury by inhibiting the cardioprotective effects of PKCε, ERK1/2, and p70S6K activation.
[show abstract][hide abstract] ABSTRACT: BACKGROUND: Left ventricular hypertrophy is enhanced by an inflammatory state and stimulation of various cytokines. Pentraxin 3 (PTX3) is rapidly produced in response to inflammatory signals, and high plasma PTX3 levels are seen in patients with heart failure. This study aimed to examine the influence of PTX3 on cardiac hypertrophy and left ventricular dysfunction with respect to pressure overload. METHODS AND RESULTS: PTX3 systemic knockout (PTX3-KO) mice, transgenic mice with cardiac-specific overexpression of PTX3 (PTX3-TG), and the respective wild-type (WT) littermate mice were subjected to transverse aortic constriction (TAC) or a sham operation. Cardiac PTX3 expression increased after TAC in WT mice. In vitro, hydrogen peroxide induced the expression of PTX3 in both cardiac myocytes and cardiac fibroblasts. Recombinant PTX3 phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2) in cardiac fibroblasts. Phosphorylation of cardiac ERK1/2 and nuclear factor kappa-B after TAC was attenuated in the PTX3-KO mice but was enhanced in the PTX3-TG mice compared with WT mice. Interleukin-6 and connective tissue growth factor production was lower in the PTX3-KO mice than in the WT mice, but this was augmented in the PTX3-TG mice than in the WT mice. Echocardiography revealed that adverse remodeling with left ventricular dysfunction, as well as with increased interstitial fibrosis, was enhanced in PTX3-TG mice, while these responses were suppressed in PTX3-KO mice. CONCLUSION: The local inflammatory mediator PTX3 directly modulates the hypertrophic response and ventricular dysfunction following an increased afterload.
PLoS ONE 01/2013; 8(1):e53133. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: Evidence from several studies indicates the importance of Gαq protein-coupled receptor (GPCR) signaling pathway, which includes diacylglycerol (DAG), and protein kinase C, in the development of heart failure. DAG kinase (DGK) acts as an endogenous regulator of GPCR signaling pathway by catalyzing and regulating DAG. Expressions of DGK isoforms α, ε, and ζ in rodent hearts have been detected; however, the expression and alteration of DGK isoforms in a failing human heart has not yet been examined. In this study, we detected mRNA expressions of DGK isoforms γ, η, ε, and ζ in failing human heart samples obtained from patients undergoing cardiovascular surgery with cardiopulmonary bypass. Furthermore, we investigated modulation of DGK isoform expression in these hearts. We found that expressions of DGKη and DGKζ were increased and decreased, respectively, whereas those of DGKγ and DGKε remained unchanged. This is the first report that describes the differential regulation of DGK isoforms in normal and failing human hearts.
Journal of Cardiothoracic Surgery 01/2011; 6:65. · 0.90 Impact Factor
[show abstract][hide abstract] ABSTRACT: Serum neopterin concentration was measured in 198 patients with chronic heart failure (CHF) and 62 control subjects by ELISA. Patients were prospectively followed during a median follow-up period of 745 days with end points of cardiac death or re-hospitalization due to progressive heart failure. Serum concentration of neopterin increased with advancing New York Heart Association (NYHA) functional class (P<0.001). High neopterin group had a significantly higher incidence of cardiac events than low neopterin group (P<0.0001). In the multivariate Cox analysis, serum neopterin concentration was an independent risk factor for cardiac events (hazard ratio 1.70, 95%CI 1.16-2.50, P=0.0068). Serum neopterin concentration is a novel prognostic marker for CHF.
International journal of cardiology 11/2010; 145(2):318. · 7.08 Impact Factor
[show abstract][hide abstract] ABSTRACT: Human cartilage glycoprotein-39 (YKL-40), a novel inflammatory marker, is secreted into circulation by macrophages, neutrophils, chondrocytes, vascular smooth muscle cells and cancer cells. Circulating levels of YKL-40 are related to the degree of inflammation, tissue remodeling, fibrosis, and cancer progression.
We examined serum YKL-40 levels in 121 patients with chronic heart failure (CHF) and 39 control subjects. The patients were followed up to register cardiac events for a mean of 720 days. Serum YKL-40 levels were measured by sandwich enzyme-linked immunoassay. Serum YKL-40 was significantly higher in New York Heart Association (NYHA) Class III/IV patients than control subjects and NYHA Class I/II patients (P < .0001). Serum YKL-40 was also higher in patients with cardiac events than in event-free patients (P = .0023). Cutoff value of YKL-40 was determined by receiver operating characteristic curve analysis. Kaplan-Meier analysis demonstrated that high level of YKL-40 was associated with higher rates of cardiac events than low levels of YKL-40 (P = .003). The multivariate Cox hazard analysis demonstrated that serum YKL-40 level was an independent prognostic factor of cardiac events (hazard ratio 2.085, 95% confidence interval 1.233-3.499, P < .0048).
Serum YKL-40, a new marker of inflammation, was increased in CHF, and YKL-40 detected high risk patients for adverse outcomes in CHF.
Journal of cardiac failure 11/2010; 16(11):873-9. · 3.25 Impact Factor
[show abstract][hide abstract] ABSTRACT: Midkine, a heparin-binding growth factor, has various functions such as migration of inflammatory cell and anti-apoptotic effect. Invasion of inflammatory cell and cardiomyocyte apoptosis are involved in development and progression of heart failure (HF). However, the relationship between midkine and HF has not been previously examined. Therefore, we examined clinical significance of serum midkine levels to determine the prognosis of HF patients.
Serum levels of midkine were measured at admission in 216 consecutive patients hospitalized for HF and 60 control subjects. Patients were prospectively followed during a mean follow-up period of 653 +/- 375 days with the end points of cardiac death and progressive HF requiring rehospitalization. Serum concentrations of midkine were significantly higher in patients with HF than in controls. Patients with cardiac events had significantly higher concentrations of midkine than those without cardiac events. Kaplan-Meier analysis revealed that cardiac event rates increased markedly as midkine levels rose. Furthermore in the multivariate analysis, after adjustment for age, gender ,and complications, midkine was the independent predictor of cardiac events.
Serum midkine levels are increased in HF patients, and midkine is a novel marker for risk stratifying HF patients.
Journal of cardiac failure 04/2010; 16(4):308-13. · 3.25 Impact Factor
[show abstract][hide abstract] ABSTRACT: Although there is substantial interest in the use of newer biomarkers to identify patients with chronic heart failure (CHF), recently few investigations have evaluated the incremental usefulness of multiple conventional biomarkers. Combination of several biomarkers simultaneously could enhance risk stratification in CHF.
We analyzed 7 biomarkers (brain natriuretic peptide, uric acid, sodium, hemoglobin, creatinine, creatinine clearance, high-sensitivity C-reactive protein), which were known as established prognostic markers for CHF, in 154 consecutive CHF patients, and patients were prospectively followed with endpoints of cardiac death or re-hospitalization. When there was an abnormal value, we scored it for one point to calculate multimarker score. Patients were categorized into 3 strata according to multimarker score. There were 83 cardiac events during the follow-up period. A Cox proportional hazard model showed that patients in the high stratum were associated with the highest risk of cardiac events among the 3 strata. Kaplan-Meier analysis revealed that patients in the high stratum had a significantly higher cardiac event rate compared with lower strata.
The combination of conventional biomarkers could potentially improve the risk stratification of CHF patients for the prediction of cardiac events with low cost and wide availability.
Journal of Cardiology 05/2009; 53(2):179-87. · 2.30 Impact Factor
[show abstract][hide abstract] ABSTRACT: B-type natriuretic peptide (BNP), heart-type fatty acid-binding protein (H-FABP), and pentraxin 3 (PTX3) each predict adverse cardiac events in chronic heart failure (CHF) patients. For prognostic evaluation from different aspects, the utility of combined measurement of the 3 biomarkers in patients with CHF was examined in the present study.
Levels of BNP (associated with left ventricular dysfunction, positive if >200 pg/ml), H-FABP (marker of myocardial damage, positive if >4.1 ng/ml), and PTX3 (marker of inflammation, positive if >4.0 ng/ml) were measured in 164 consecutive CHF patients, and patients were prospectively followed with endpoints of cardiac death or rehospitalization. When patients were categorized on the basis of the number of elevated biomarkers, patients with 1, 2, and 3 elevated biomarkers had a 5.4-fold (not significant), 11.2-old (p<0.05), and 34.6-fold increase (p<0.01), respectively, in the risk of adverse cardiac events compared with those without elevated biomarkers. Kaplan-Meier analysis revealed that patients with 3 elevated biomarkers had a significantly higher cardiac event rate than patients with a lower number of elevated biomarkers.
The combination of these 3 biomarkers could reliably risk-stratify CHF patients for prediction of cardiac events.
[show abstract][hide abstract] ABSTRACT: Heat shock protein (HSP) 60 is induced by a variety of stressors, including oxidative stress and inflammation, and it plays a protective role against stress-induced cardiomyocyte injury. Recently, it has been reported that HSP 60 exists in the circulation. Chronic heart failure (CHF) is characterized by systemic abnormalities, and the myocardium is exposed to various stressors. However, the clinical significance of serum HSP 60 has not been examined in CHF. Therefore, the purpose of this study was to examine whether HSP 60 is correlated with the severity of CHF and whether HSP 60 can predict clinical outcomes in patients with CHF. Serum HSP 60 levels were measured in 112 patients with CHF and 62 control subjects. Serum HSP 60 levels were higher in patients with CHF than in control subjects and increased with advancing New York Heart Association functional class. There were 37 cardiac events during a mean follow-up period of 569 +/- 476 days (range 17 to 1,986). Serum HSP 60 levels were higher in patients with cardiac events than in event-free patients. Patients were divided into 4 groups on the basis of HSP 60 level. Cox proportional-hazards regression analysis and Kaplan-Meier analysis revealed that the fourth quartile was associated with the greatest risk for cardiac events. In conclusion, serum HSP 60 level was related to the severity of CHF and associated with a high risk for adverse cardiac events in patients CHF.
The American Journal of Cardiology 10/2008; 102(5):606-10. · 3.21 Impact Factor
[show abstract][hide abstract] ABSTRACT: Galpha(q) protein-coupled receptor (GPCR) signaling pathway, which includes diacylglycerol (DAG) and protein kinase C (PKC), plays a critical role in cardiac hypertrophy. DAG kinase (DGK) catalyzes DAG phosphorylation and controls cellular DAG levels, thus acting as a regulator of GPCR signaling. It has been reported that DGKepsilon acts specifically on DAG produced by inositol cycling. In this study, we examined whether DGKepsilon prevents cardiac hypertrophy and progression to heart failure under chronic pressure overload. We generated transgenic mice with cardiac-specific overexpression of DGKepsilon (DGKepsilon-TG) using an alpha-myosin heavy chain promoter. There were no differences in cardiac morphology and function between wild-type (WT) and DGKepsilon-TG mice at the basal condition. Either continuous phenylephrine infusion or thoracic transverse aortic constriction (TAC) was performed in WT and DGKepsilon-TG mice. Increases in heart weight after phenylephrine infusion and TAC were abolished in DGKepsilon-TG mice compared with WT mice. Cardiac dysfunction after TAC was prevented in DGKepsilon-TG mice, and the survival rate after TAC was higher in DGKepsilon-TG mice than in WT mice. Phenylephrine- and TAC-induced DAG accumulation, the translocation of PKC isoforms, and the induction of fetal genes were blocked in DGKepsilon-TG mouse hearts. The upregulation of transient receptor potential channel (TRPC)-6 expression after TAC was attenuated in DGKepsilon-TG mice. In conclusion, these results demonstrate the first evidence that DGKepsilon restores cardiac dysfunction and improves survival under chronic pressure overload by controlling cellular DAG levels and TRPC-6 expression. DGKepsilon may be a novel therapeutic target to prevent cardiac hypertrophy and progression to heart failure.
[show abstract][hide abstract] ABSTRACT: We recently reported that serum levels of pentosidine, one of the well-defined advanced glycation end products (AGE), was an independent prognostic factor for heart failure. Receptor for AGEs (RAGE) is expressed in a variety of tissues, and RAGE has a C-truncated secretory isoform of the receptor protein, termed soluble RAGE. In the present study, we measured serum soluble RAGE levels in patients and examined whether serum soluble RAGE predicts prognosis in patients with heart failure.
Serum soluble RAGE concentration was measured in 160 patients with heart failure by a competitive enzyme-linked immunosorbent assay. Patients were prospectively followed during a median follow-up period of 872 days with end points of cardiac death or rehospitalization. Serum soluble RAGE level increased with advancing New York Heart Association functional class. Serum soluble RAGE level was also higher in patients with cardiac events than in event free patients. From the receiver operating characteristic curve analysis, the cutoff value of serum soluble RAGE level was determined as 1220 pg/mL. Kaplan-Meier analysis clearly demonstrated that the high soluble RAGE group had a significantly higher incidence of cardiac events than occurred in the low serum soluble RAGE group (P = .0004). In the multivariate Cox proportional hazard analysis, soluble RAGE and serum pentosidine were independent risk factors for cardiac events (soluble RAGE: HR 1.90, 95% CI 1.16-3.09, P = .010; pentosidine: HR 1.59, 95% CI 1.11-2.29, P = .012).
Serum soluble RAGE level is an independent prognostic factor for heart failure, and this novel marker may be useful for risk stratification of patients with heart failure.
Journal of cardiac failure 04/2008; 14(2):133-9. · 3.25 Impact Factor
[show abstract][hide abstract] ABSTRACT: The G alpha q protein-coupled receptor (GPCR) signaling pathway, which includes diacylglycerol (DAG) and protein kinase C (PKC), plays a critical role in the development of cardiac hypertrophy and heart failure (HF). It has been reported that the expression of a constitutively active mutant of the G protein alpha q subunit in the hearts of transgenic mice (G alpha q-TG) induces cardiac hypertrophy and lethal HF. DAG kinase (DGK) catalyzes DAG and controls its cellular levels, thus acting as a regulator of GPCR signaling. It has been found that transgenic mice with cardiac-specific overexpression of DGK zeta (DGK zeta-TG) inhibit GPCR agonist-induced activation of the DAG-PKC signaling and subsequent cardiac hypertrophy, so this study tested the hypothesis that DGK zeta could rescue G alpha q-TG mice from developing HF.
Double transgenic mice (G alpha q/DGK zeta-TG) with cardiac-specific overexpression of both DGK zeta and G alpha q were generated by crossing G alpha q-TG with DGK zeta-TG mice, and the pathophysiological consequences were analyzed. DGK zeta prevented cardiac dysfunction, determined by dilatation of left ventricular (LV) dimensions, reduction of LV fractional shortening, and marked increases in LV end-diastolic pressure in G alpha q-TG mice. Translocation of PKC isoforms, phosphorylation activity of c-jun N-terminal kinase and p38 mitogen-activated protein kinase in G alpha q-TG mice were attenuated by DGK zeta. DGK zeta improved the survival rate of G alpha q-TG mice.
These results demonstrate the first evidence that DGK zeta blocks cardiac dysfunction and progression to lethal HF by activated G alpha q protein without detectable adverse effects in the in-vivo heart and suggest that DGK zeta is a novel therapeutic target for HF.
[show abstract][hide abstract] ABSTRACT: Heart-type fatty acid-binding protein (H-FABP) is a small cytosolic protein that is released into the circulation when the myocardium is injured. This study examined whether serial measurement of the H-FABP level provides additional prognostic information.
Serum H-FABP levels were measured in 113 consecutive chronic heart failure (CHF) patients at both admission and discharge. The following 3 patterns of changes were identified. In 41 patients, H-FABP levels (<4.3 ng/ml) at both admission and discharge were normal (Group 1). The remaining 72 patients had high initial H-FABP levels (> or =4.3 ng/ml) at admission, and in 21 of them (29%), H-FABP decreased to the normal range at discharge (Group 2), whereas 51 had persistently high H-FABP levels despite improvement in symptoms and signs of CHF (Group 3). There were 33 cardiac events (29%) during the follow-up period, and Group 3 had significantly higher cardiac event rates than Groups 1 and 2 (p=0.0002). Group 3 had the highest cardiac risk among the groups (hazard ratio 5.68, p=0.012).
Serial measurement of the H-FABP level is a new monitoring tool that provides information to guide optimal therapy and management of CHF patients.
[show abstract][hide abstract] ABSTRACT: Activation of the diacylglycerol (DAG)-protein kinase C (PKC) pathway has been implicated in the pathogenesis of a number of diabetic complications. Diacylglycerol kinase (DGK) converts DAG to phosphatidic acid and acts as an endogenous regulator of PKC activity. Akt/PKB is associated with a downstream insulin signaling, and PKCbeta attenuates insulin-stimulated Akt phosphorylation.
We examined transgenic mice with cardiac-specific overexpression of DGKzeta (DGKzeta-TG) compared to wild type (WT) mice in streptozotocin-induced (STZ, 150 mg/kg) diabetic and nondiabetic conditions. After 8 weeks, decreases in heart weight and heart weight/body weight ratio in diabetic WT mice were inhibited in DGKzeta-TG mice. Echocardiography at 8 weeks after STZ-injection demonstrated that decreases in left ventricular end-diastolic diameter and fractional shortening observed in WT mice were attenuated in DGKzeta-TG mice. Thinning of the interventricular septum and the posterior wall in diabetic WT hearts were blocked in DGKzeta-TG mice. Reduction of transverse diameter of cardiomyocytes isolated from the left ventricle in diabetic WT mice was attenuated in DGKzeta-TG mice. Cardiac fibrosis was much less in diabetic DGKzeta-TG than in diabetic WT mice. Western blots showed translocation of PKCbeta and delta isoforms to membrane fraction and decreased Akt/PKB phosphorylation in diabetic WT mouse hearts. However in diabetic DGKzeta-TG mice, neither translocation of PKC nor changes Akt/PKB phosphorylation was observed.
DGKzeta modulates intracellular signaling and improves the course of diabetic cardiomyopathy. These data may suggest that DGKzeta is a new therapeutic target to prevent or reverse diabetic cardiomyopathy.
[show abstract][hide abstract] ABSTRACT: Aim: High-mobility group box 1 (HMGB1) is a nuclear DNA-binding protein and is released from necrotic cells, inducing inflammatory responses and promoting tissue repair and angiogenesis. To test the hypothesis that HMGB1 enhances angiogenesis and restores cardiac function after myocardial infarction, we generated transgenic mice with cardiac specific overexpression of HMGB1 (HMGB1-Tg) using α-myosin heavy chain (MHC) promoter. Methods and Results: The left anterior descending coronary artery was ligated in HMGB1-Tg and wild-type littermate (Wt) mice. After coronary artery ligation, HMGB1 was released into circulation from the necrotic cardiomyocytes of HMGB1 overexpressing hearts. The size of myocardial infarction was smaller in HMGB1-Tg than in Wt mice. Echocardiography and cardiac catheterization demonstrated that cardiac remodeling and dysfunction after myocardial infarction were prevented in HMGB1-Tg mice compared to Wt mice. Furthermore, survival rate after myocardial infarction of HMGB1-Tg mice was higher than that of Wt mice. Immunohistochemical staining revealed that capillary and arteriole formations after myocardial infarction were enhanced in HMGB1-Tg mice. Conclusions: We demonstrated the first in vivo evidence that HMGB1 enhances angiogenesis, restores cardiac function, and improves survival after myocardial infarction. These results may provide a novel therapeutic approach for left ventricular dysfunction after myocardial infarction.