Superoxide production by NAD(P)H oxidase and mitochondria is increased in genetically obese and hyperglycemic rat heart and aorta before the development of cardiac dysfunction. The role of glucose-6-phosphate dehydrogenase-derived NADPH

Increased oxidative stress is a known cause of cardiac dysfunction in animals and patients with diabetes, but the sources of reactive oxygen species [e.g., superoxide anion (O2−)] and the mechanisms underlying O2− production in diabetic hearts are not clearly understood. Our aim was to determine whether NADPH oxidase (Nox) is a source of O2− and whether glucose-6-phosphate dehydrogenase (G6PD)-derived NADPH plays a role in augmenting O2− generation in diabetes. We assessed cardiac function, Nox and G6PD activities, NADPH levels, and the activities of antioxidant enzymes in heart homogenates from young (9–11 wk old) Zucker lean and obese (fa/fa) rats. We found that myocardial G6PD activity was significantly higher in fa/fa than in lean rats, whereas superoxide dismutase and glutathione peroxidase activities were decreased ( P < 0.05). O2− levels were elevated (70–90%; P < 0.05) in the diabetic heart, and this elevation was blocked by the Nox inhibitor gp-91ds-tat (50 μM) or by the mitochondrial respiratory chain inhibitors antimycin (10 μM) and rotenone (50 μM). Inhibition of G6PD by 6-aminonicotinamide (5 mM) and dihydroepiandrosterone (100 μM) also reduced ( P < 0.05) O2− production. Notably, the activities of Nox and G6PD in the fa/fa rat heart were inhibited by chelerythrine, a protein kinase C inhibitor. Although we detected no changes in stroke volume, cardiac output, or ejection fraction, left ventricular diameter was slightly increased during diastole and systole, and left ventricular posterior wall thickness was decreased during systole ( P < 0.05) in Zucker fa/fa rats. Our findings suggest that in a model of severe hyperlipidema and hyperglycemia Nox-derived O2− generation in the myocardium is fueled by elevated levels of G6PD-derived NADPH. Similar mechanisms were found to activate O2− production and induce endothelial dysfunction in aorta. Thus G6PD may be a useful therapeutic target for treating the cardiovascular disease associated with type 2 diabetes, if second-generation drugs specifically reducing the activity of G6PD to near normal levels are developed.

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Fgl2 deficiency causes neonatal death and cardiac dysfunction during embryonic and postnatal development in mice

Physiological Genomics ◽

10.1152/physiolgenomics.00026.2007 ◽

2007 ◽

Vol 31 (1) ◽

pp. 53-62 ◽

Cited By ~ 16

Author(s):

Junwu Mu ◽

Dawei Qu ◽

Agata Bartczak ◽

M. James Phillips ◽

Justin Manuel ◽

...

Keyword(s):

Postnatal Development ◽

Cardiac Dysfunction ◽

Neonatal Death ◽

Posterior Wall ◽

Ultrasound Biomicroscopy ◽

Left Ventricular ◽

Mode Analysis ◽

Posterior Wall Thickness ◽

Perinatal Lethality ◽

And Function

We hypothesized that cardiac dysfunction was responsible for the high perinatal lethality that we previously reported in fibrinogen-like protein 2 ( Fgl2) knockout (KO) mice. We therefore used ultrasound biomicroscopy to assess left ventricular (LV) cardiac structure and function during development in Fgl2 KO and wild-type (WT) mice. The only deaths observed between embryonic day (E)8.5 (onset of heart beating) and postnatal day (P)28 (weaning) were within 3 days after birth, when 33% of Fgl2 KO pups died. Histopathology and Doppler assessments suggested that death was due to acute congestive cardiac failure without evidence of valvular or other obvious cardiac structural abnormalities. Heart rates in Fgl2 KO embryos were significantly reduced at E8.5 and E17.5, and irregular heart rhythms were significantly more common in Fgl2 KO (21/26) than WT (2/21) embryos at E13.5. Indexes of systolic and/or diastolic cardiac function were also abnormal in KO mice at E13.5 and E17.5, in postnatal mice studied at P1, and in KO mice surviving to P28. M-mode analysis showed no difference in LV diastolic chamber dimension, although posterior wall thickness was thinner at P7 and P28 in Fgl2 KO mice. We conclude that Fgl2 deficiency is not associated with obvious structural cardiac defects but is associated with a high incidence of neonatal death as well as contractile dysfunction and rhythm abnormalities during embryonic and postnatal development in mice.

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Cardiac dysfunction following spinal irradiation during childhood.

Journal of Clinical Oncology ◽

10.1200/jco.1993.11.6.1033 ◽

1993 ◽

Vol 11 (6) ◽

pp. 1033-1038 ◽

Cited By ~ 67

Author(s):

R I Jakacki ◽

J W Goldwein ◽

R L Larsen ◽

G Barber ◽

J H Silber

Keyword(s):

Radiation Field ◽

Cardiac Dysfunction ◽

Wall Stress ◽

Posterior Wall ◽

Left Ventricular ◽

Internal Diameter ◽

Asymmetric Distribution ◽

Natural Logarithm ◽

Posterior Wall Thickness

PURPOSE Although spinal irradiation used in the treatment of CNS malignancies includes a portion of the heart in the radiation field, cardiac effects have not been previously reported. PATIENTS AND METHODS We compared patients treated for malignancy in childhood with spinal irradiation (n = 26) with patients treated with mediastinal/flank irradiation (n = 47) that included the heart in the radiation field. All patients were more than 1 year from completion of radiation therapy. Patients underwent at least two of the following cardiac evaluations: (1) ECG; (2) 24-hour ambulatory ECG; (3) echocardiogram; and (4) exercise-testing using cycle ergometry. RESULTS Twelve of 16 patients (75%) in the spinal irradiation group with an assessable exercise test achieved a maximal cardiac index (MCI) below the fifth percentile as compared with 13 of 40 patients (32%) who had received mediastinal/flank irradiation (P = .007). Furthermore, after adjusting for normal heart growth, radiation and anthracycline doses, and follow-up time, the group of patients who received spinal irradiation had significantly higher estimated posterior wall stress (P = .002), expressed as the natural logarithm of the ratio of end-diastolic left ventricular internal diameter (LVID) to left ventricular posterior wall thickness (LVPWT), than the group who had received mediastinal/flank irradiation. Finally, eight of 26 patients (31%) in the spinal group had pathologic Q-waves in the inferior leads versus three of 47 (6.4%) in the mediastinal/flank group (P = .001). CONCLUSION Patients who have received spinal irradiation for pediatric malignancies appear to be at risk for significant cardiac dysfunction. The asymmetric distribution of radiation to a growing heart, as given with spinal irradiation, may be the cause of these findings.

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Abstract 15352: Plasma Levels of BNP are Lower in Patients With Heart failure With Preserved EF (HFpEF) as Compared With Those With Reduced EF (HFrEF)

Circulation ◽

10.1161/circ.132.suppl_3.15352 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Eisaku Harada ◽

Yuji Mizuno ◽

Makoto Shono ◽

Hiroyuki Maeda ◽

Naotsugu Yano ◽

...

Keyword(s):

Heart Failure ◽

Plasma Levels ◽

Left Atrial ◽

Female Gender ◽

Posterior Wall ◽

Left Ventricular ◽

Posterior Wall Thickness ◽

Lv Mass ◽

Echocardiographic Parameters

Introduction: Heart failure with preserved ejection fraction (HFpEF) is increasing in prevalence and causes substantial morbidity, mortality, and resource utilization in the aging population. The plasma level of B-type natriuretic peptide (BNP) is used as a marker of HF with reduced EF (HFrEF). However, the role of BNP in HFpEF is not well known. The purpose of the present study was to compare the levels of BNP together with the echocardiographic findings between HFpEF and HFrEF. Methods: The study subjects consisted of 1574 patients with HF and early diastolic flow velocity (E)/velocity of early diastolic mitral annular motion (e′) or E/e′≥15 (as a measure of elevated left atrial pressure) (574 men and 1000 women, mean age 78.8±10.7) admitted at our hospital. They were divided into 1238 patients with HFpEF (373 men and 865 women, mean age 79.7±10.2) [left ventricular (LV) EF≥50% and E/e′≥15] and 336 patients with HFrEF (201 men and 135 women, mean age 75.4±11.8) (LVEF<50%). Echocardiographic parameters, age, gender, and BNP were examined. Results: The levels of BNP were lower [107(47, 225) pg/ml vs. 296(121, 626) pg/ml, P<0.001] in the HFpEF group than in the HFrEF group. The frequencies of female gender, age, EF, LV posterior wall thickness were higher (all P<0.001, respectively) and LV mass, LV end-diastolic diameter (LVDd), LV end-systolic diameter (LVDs) and left atrial diameter (LAD) were lower (all P<0.001, respectively) in the HFpEF group than in the HFrEF group. A multiple regression analysis revealed EF (t=-17.0), age (t=11.2), E/e′ (t=10.5), LAD (t=9.0), LV mass (t=7.9), and LVDd (t=-5.3) were independent predictors (all P<0.001, respectively) for the BNP level (P<0.001, R2=0.40) in this order. Conclusions: HFpEF was associated with lower levels of BNP and smaller heart and was more prevalent in the elders and women as compared with HFrEF. Predictors for the levels of BNP were EF, age, and E/e′ in this order. These findings imply that the plasma levels of BNP reflect LVEF more than LV diastolic function (E/e′) and thus are lower in the HFpEF group than in the HFrEF group. These findings suggest that the role of BNP in HF may be different between HFpEF and HFrEF.

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Abstract 174: Role of Cardiomyocyte-Localized Nuclear Factor (NF)-κB in Diet-Induced Diabetic Cardiomyopathy

Circulation Research ◽

10.1161/res.115.suppl_1.174 ◽

2014 ◽

Vol 115 (suppl_1) ◽

Author(s):

Mehak Goel ◽

Mohamed A Ismahil ◽

Tariq Hamid ◽

Sumanth D Prabhu

Keyword(s):

Insulin Resistance ◽

Body Weight ◽

Diabetic Cardiomyopathy ◽

Control Diet ◽

Fasting Blood Glucose ◽

Posterior Wall ◽

Mononuclear Phagocyte ◽

Left Ventricular ◽

Posterior Wall Thickness

Role of Inflammatory signaling in the development of obesity- and type 2 diabetes (T2D)-associated cardiomyopathy remains unclear. We hypothesized that cardiomyocyte-specific inflammatory activation, independent of systemic inflammation, is sufficient for the genesis of diabetic cardiomyopathy. Wild-type (WT) and transgenic (Tg) C57BL/6 mice with myocyte-restricted overexpression of phosphorylation-resistant IκBα (IκBαS32A,S36A) were fed a high fat (HFD, 45% kcal fat) or control diet (CD, 10% kcal fat) for 28 weeks to induce obesity and T2D. These Tg mice exhibit attenuated NF-kB activation, a central regulator of inflammation. After 28 weeks of feeding, WT HFD mice exhibited increased body weight, hyperglycemia, hyperinsulinemia, insulin resistance, and glucose intolerance. In contrast, although HFD-fed Tg mice exhibited significantly (p < 0.05) increased body weight, the mice still maintained normal fasting blood glucose, insulin levels, and insulin sensitivity compared to CD Tg mice, indicating absence of overt T2D. Echocardiography revealed that both HFD-fed WT and Tg mice developed concentric left ventricular (LV) hypertrophy with increased septal and posterior wall thickness, decreased LV end-diastolic diameter and had unchanged LV ejection fraction suggesting development of LV hypertrophy in both strains regardless of the severity of the metabolic disorder. Analysis of mononuclear phagocyte cell profiles revealed similar trends in WT and IκB Tg mice. HFD fed mice had higher levels of pro-inflammatory (CD11b+Ly6chi) and anti-inflammatory (CD11b+Ly6clo) monocytes in the blood, heart, spleen and adipose tissue compared to CD fed mice. Analysis of antigen presenting cells indicated that HFD fed mice in both genotypes had significantly increased levels of both classical (CD11c+CD45R–) and plasmacytoid (CD11cintCD45R+) dendritic cells in blood, heart, spleen and adipose tissues compared to respective CD fed mice. Thus, we conclude that cardiomyocyte inflammation is central to the development of metabolic abnormalities related to obesity, whereas neither cardiomyocyte-specific nor systemic insulin resistance is required for the development of the hypertrophic cardiomyopathic phenotype.

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Investigating Insulin Resistance in Pediatric Cardiomyopathy - A Pilot Study

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.1348 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A660-A661

Author(s):

Daniel Mak ◽

Kaitlin A Ryan ◽

Joan C Han

Keyword(s):

Insulin Resistance ◽

Dilated Cardiomyopathy ◽

Wall Thickness ◽

Cardiac Dysfunction ◽

Posterior Wall ◽

Left Ventricular ◽

Inverse Association ◽

Septal Thickness ◽

Posterior Wall Thickness ◽

Pediatric Cardiomyopathy

Abstract Children with cardiomyopathy are a vulnerable population and understanding the factors that contribute to cardiac dysfunction are of great importance. At the biochemical level, energy utilization by cardiomyocytes during stress may provide insight into the progression of cardiomyopathy. There is a large body of literature that describes insulin resistance in adults with cardiomyopathy (1,2). Extensive literature on the topic in adult individuals exists however investigation in the pediatric population is sparse. The pathophysiology of disease in children and adolescents is unique. To study the role of insulin resistance in pediatric cardiomyopathy, we measured the homeostasis model assessment-estimated insulin resistance (HOMA-IR) at baseline in pre-pubertal patients (age 13-18 years old; mean 16 years old; n = 8) with either hypertrophic cardiomyopathy (HCM) or dilated cardiomyopathy (DCM). In patients with HCM, greater insulin resistance was positively correlated with greater left ventricular (LV) septal thickness (r = 0.55; p = 0.33; n = 5) and LV posterior wall thickness (r = 0.7; p = 0.19; n = 5) during diastole. As expected, insulin resistance was strongly correlated with BMI (r = 0.84; p = 0.08; n = 5) though greater BMI was not as strongly associated with LV septal thickness (r = 0.59; p = 0.3; n = 5) or posterior wall thickness (r = 0.59; p = 0.3; n = 5). In patients with DCM, insulin resistance was positively correlated with LV end diastolic volume (r = 0.59; p = 0.59; n = 3). Interestingly, there was an observed inverse association between insulin resistance and BMI in DCM (r = -0.85; p = 0.34; n =3). Though our sample population is limited, thus affecting statistical significance, results showed that there was a trend towards greater insulin resistance in patients with poorer cardiac measurements. These findings are consistent with adult literature and the proposition that cardiac dysfunction is an insulin resistant state. References: (1) Riehle C, Abel ED. Insulin Signaling and Heart Failure. Circulation research. 2016;118(7):1151-1169. (2) Shah A, Shannon RP. Insulin resistance in dilated cardiomyopathy. Reviews in cardiovascular medicine. 2003;4 Suppl 6:S50-57

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Combination of Huangqi Granule and Rosuvastatin Improves the Cardiac Function in Heart Failure

Current Topics in Nutraceutical Research ◽

10.37290/ctnr2641-452x.19:181-187 ◽

2020 ◽

Vol 19 (2) ◽

pp. 181-187

Author(s):

Jing Li ◽

Yun Zhang ◽

Weizhong Huangfu ◽

Yuhong Ma

Keyword(s):

Heart Failure ◽

Left Ventricular Ejection Fraction ◽

Ejection Fraction ◽

Wall Thickness ◽

Posterior Wall ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Model Group ◽

Ventricular Ejection Fraction ◽

Posterior Wall Thickness

Using rat models of heart failure, we evaluated the effects of rosuvastatin and Huangqi granule alone and in combination on left ventricular end-diastolic dimension, left ventricular end-systolic dimension, left ventricular ejection fraction, left ventricular posterior wall thickness at end-diastole, and left ventricular posterior wall thickness at end-systole. Results showed that left ventricular end-diastolic dimension, left ventricular end-systolic dimension in the rosuvastatin + Huangqi granule group were significantly decreased (P ‹ 0.01), while left ventricular ejection fraction, left ventricular posterior wall thickness at end-diastole and left ventricular posterior wall thickness at end-systole were significantly increased (P ‹ 0.05). The serum IL-2, IFN-β, and TNF-α in rosuvastatin + Huangqi granule group were significantly lower than those in model group (P ‹ 0.05). However, the levels of S-methylglutathione and superoxide dismutase in rosuvastatin + Huangqi granule group were significantly higher, while nitric oxide was significantly lower than that in the model group (P ‹ 0.05). Also, compared to the model group, the apoptosis rate, and the autophagy protein LC3-II in the cardiomyocytes of rosuvastatin + Huangqi granule group was significantly decreased (P ‹ 0.01), while the level of p62 protein was significantly increased (P ‹ 0.01). The levels of AMPK and p-AMPK in cardiomyocytes were significantly lower in rosuvastatin + Huangqi granule group; however, the levels of mTOR and p-mTOR showed an opposite trend (P ‹ 0.05). To sum up, rosuvastatin + Huangqi granule could improve the cardiac function, decrease the level of oxidative stress, and inflammatory cytokines in rats with HF. The possible underlying mechanism might be inhibition of autophagy and reduced apoptosis in cardiomyocytes by regulating AMPK-mTOR signaling pathway.

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Left ventricular geometric patterns and cardiac function in patients with chronic renal failure undergoing hemodialysis

Monaldi Archives for Chest Disease ◽

10.4081/monaldi.2005.608 ◽

2005 ◽

Vol 64 (1) ◽

Cited By ~ 3

Author(s):

Maria Teresa Manes ◽

Manlio Gagliardi ◽

Gianfranco Misuraca ◽

Stefania Rossi ◽

Mario Chiatto

Keyword(s):

Left Ventricular Hypertrophy ◽

Diastolic Dysfunction ◽

Cardiac Troponin ◽

Ventricular Hypertrophy ◽

Interventricular Septum ◽

Myocardial Damage ◽

Posterior Wall ◽

Left Ventricular ◽

Posterior Wall Thickness ◽

Significant Difference

The aim of this study was to estimate the impact and prevalence of left ventricular geometric alterations and systolic and diastolic dysfunction in hemodialysis patients, as well as the relationship with cardiac troponin as a marker of myocardial damage. Methods: 31 patients (pts), 19 males and 12 females, age 58.1±16.4 (26 on hemodialysis, 5 on peritoneal dialysis) and 31 healthy normal controls were enrolled. Echocardiography measurements were carried out according to the American Society of Echocardiography recommendations. Left ventricular mass was calculated, according to the Devereux formula and indexed to height and weight 2.7. Doppler echocardiography was performed to study diastolic function by measurements of isovolumetric relaxation period (IVRT), E wave deceleretion time (DTE) and E/A ratio. Cardiac troponin was measured by a third generation electrochemiluminescence immunoassay. Statistical analysis was performed using the t-test for between-group comparisons and the Pearson and Spearman’s tests to investigate correlations; p values of <0.05 were considered statistically significant. Results: Eccentric hypertrophy was the most frequent pattern (n=17; 55%), followed by normal cardiac geometry (n=7; 23%), and concentric hypertrophy (n=5; 16%). Only 6% of pts (n=2) showed concentric remodelling. Systolic dysfunction was present in terms of endocardial parameters in 3 pts (9%) (fractional shartening <25%, EF<50%), but in terms of midwall myocardial shortening in 51% (n=16). Diastolic dysfunction was present in 87% (n=27) with a pattern of impaired relaxation (in 5 without left ventricular hypertrophy). E/A was negatively correlated with age (r=-0.41, p=0.02); DTE was positively correlated with posterior wall thickness (r=0.36, p=0.05) and interventricular septum thickness (r=0.45, p=0.01); cardiac troponin was positively correlated with age (r=0.50, p=0.00), left ventricular mass (r=0.41, p=0.02), posterior wall thickness (r=0.41; p=0.02) and interventricular septum thickness (r=0.39, p=0.03) but not with diastolic dysfunction parameters. No significant difference was found in terms of duration of dialysis between patients with normal left ventricular geometry and those with left ventricular hypertrophy, but a significant difference in age was found (p=0.03). Pts with diastolic dysfunction had more frequent hypotensive episodes during dialysis (p <0.01). Conclusion: Impaired geometry and cardiac function is frequently observed in pts undergoing hemodialysis. Diastolic dysfuction is associated to a geometric pattern of left ventricular hypetrophy, although it can be an isolated initial manifestation of myocardial damage. Depressed midwall myocardial shortening can discriminate left ventricular dysfunction better than traditional endocardial systolic indexes.

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The impact of obesity on left ventricular mass and left ventricular systolic function in children

Paediatrica Indonesiana ◽

10.14238/pi45.4.2005.171-6 ◽

2016 ◽

Vol 45 (4) ◽

pp. 171

Author(s):

Ria Nova ◽

Bambang Madiyono ◽

Sudigdo Sastroasmoro ◽

Damayanti R Sjarif

Keyword(s):

Wall Thickness ◽

Systolic Function ◽

Posterior Wall ◽

Left Ventricular ◽

Internal Diameter ◽

Obese Children ◽

Normal Children ◽

Posterior Wall Thickness ◽

Lv Mass ◽

Lv Systolic Function

Background Obesity causes cardiovascular disturbances. Theincidence of cardiovascular disease is higher even in mildly obesepatients than in lean subjects.Objectives The purpose of this study was to compare left ven-tricular (LV) mass, LV internal dimensions, and LV systolic func-tion between obese and normal children; and to determine the as-sociation of the degree of obesity with LV mass and LV systolicfunction.Methods This cross-sectional study was conducted on elemen-tary school students in Jakarta from February to April 2003. Wemeasured the subjects’ body weight and height, and performedlipid profile and echocardiography examinations. Measurementsof LV mass, LV internal dimensions with regard to septum thick-ness, LV internal diameter, and LV posterior wall thickness; andLV systolic function as indicated by shortening fraction and ejec-tion fraction, were performed echocardiographically. The differ-ences in measurements between obese and normal children aswell as between obese children with and without lipid abnormalitywere analyzed. The correlation between the degree of obesity withLV size and systolic function was determined.Results Twenty-eight normal children and 62 obese children wereenrolled in the study. Mean LV mass was 35.7 (SD 5.16) g/cm 3 inobese children versus 24.0 (SD 3.80) g/cm 3 in normal children(P<0.0001). Mean septum thickness was 0.8 (SD 0.14) mm inobese children versus 0.6 (SD 7.90) mm in normal children (P<0.0001). Mean posterior wall thickness was 0.9 (SD 0.14) mm inobese children versus 0.6 (SD 9.97) mm in normal children(P<0.0001). Mean LV internal diameter was 4.0 (SD 0.34) mm inobese children versus 3.9 (SD 0.29) mm in normal children(P=0.300). There was strong correlation between the degree ofobesity and LV mass (r=0.838, P<0.0001). LV systolic function(shortening fraction) was 37.1 (SD 4.20) percent in obese childrenversus 35.8 (SD 4.99) percent in normal children (P=0.19). Ejec-tion fraction was 67.4 (SD 5.32) percent in obese children versus65.5 (SD 6.29) percent in normal children (P=0.13). There wasweak correlation between LV systolic function and the degree ofobesity (shortening fraction r=0.219, P=0.038; ejection fractionr=0.239, P=0.023).Conclusions Obese children had significantly greater LV mass,septum thickness, and posterior wall thickness than normal chil-Backgrounddren. Such significant difference was absent for LV internal diam-eter and measures of LV systolic function. There was no signifi-cant difference in LV mass and LV systolic function between obesechildren with or without abnormality of lipid profile. A strong corre-lation exists between the degree of obesity and LV mass, but thecorrelation between degree of obesity and LV systolic function wasweak

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Low Plasma Hydrogen Sulfide Is Associated with Impaired Renal Function and Cardiac Dysfunction

American Journal of Nephrology ◽

10.1159/000489606 ◽

2018 ◽

Vol 47 (5) ◽

pp. 361-371 ◽

Cited By ~ 7

Author(s):

Qing Kuang ◽

Ning Xue ◽

Jing Chen ◽

Ziyan Shen ◽

Xiaomeng Cui ◽

...

Keyword(s):

Renal Function ◽

Hydrogen Sulfide ◽

Cardiac Dysfunction ◽

Mononuclear Cells ◽

Troponin T ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Mrna Levels ◽

Ventricular Ejection Fraction

Background: Chronic kidney disease (CKD) has been proposed to associate with decreased hydrogen sulfide (H2S) level. Nevertheless, the role of H2S in the pathogenesis of CKD has not been fully investigated. Our study aimed to investigate the plasma level of endogenous H2S in patients with different stages of CKD, and to identify the role of H2S in the progression of CKD and its relationship with cardiovascular diseases. Methods: A total of 157 non-dialysis CKD patients were recruited in our study, with 37 age- and sex-matched healthy individuals as control. Plasma concentration of H2S was measured with spectrophotometry. Sulfhemoglobin, the integration of H2S and hemoglobin, was characterized and measured by dual wavelength spectrophotometry. Serum levels of homocysteine (Hcy), cardiac troponin T (cTnT), and N-terminal pro B type natriuretic peptide were measured using automated analyzers. Conventional transthoracic echocardiography was performed and left ventricular ejection fraction (LVEF) was analyzed as a sensitive parameter of cardiac dysfunction. Results: The plasma H2S level (μmol/L) in CKD patients was significantly lower than those in healthy controls (7.32 ± 4.02 vs. 14.11 ± 5.24 μmol/L, p < 0.01). Plasma H2S level was positively associated with estimated glomerular filtration rate (eGFR; ρ = 0.577, p < 0.01) and negatively associated with plasma indoxyl sulfate concentration (ρ = –0.554, p < 0.01). The mRNA levels of cystathionine β-synthase and cystathionine γ-lyase, 2 catalytic enzymes of H2S formation, were significantly lower in blood mononuclear cells of CKD patients with respect to controls; however, the mRNA level of 3-mercaptopyruvate sulfurtransferase, as another H2S-producing enzyme, was significantly higher in CKD patients. The serum concentration of Hcy, acting as the substrate of H2S synthetase, was higher in the CKD group (p < 0.01). Specifically, the content of serum Hcy in CKD stages 3–5 patients was significantly higher than that in CKD stages 1–2, indicating an increasing trend of serum Hcy with the decline of renal function. Examination of ultrasonic cardiogram revealed a negative correlation between plasma H2S level and LVEF (ρ = –0.204, p < 0.05) in CKD patients. The H2S level also correlated negatively with cTnT concentration (ρ = –0.249, p < 0.01). Conclusions: Plasma H2S level decreased with the decline of eGFR, which may contribute to the cardiac dysfunction in CKD patients.

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Abstract P050: Novel Mechanism of Ser-496 ERK5 Phosphorylation and Association with p90RSK Is Critical for Regulating C Terminus of Hsc70-Interacting Protein (CHIP) Ubiquitin E3 Ligase Activity in Diabetes-Mediated Exacerbation of Cardiomyocyte Apoptosis and Left Ventricular Dysfunction After Myocardial Infarction

Circulation Research ◽

10.1161/res.109.suppl_1.ap050 ◽

2011 ◽

Vol 109 (suppl_1) ◽

Author(s):

Nhat-Tu Le ◽

Yuichiro Takei ◽

Chang-Hoon Woo ◽

Tetsuro Shishido ◽

Yan Lu ◽

...

Keyword(s):

Transgenic Mice ◽

Cardiac Dysfunction ◽

Critical Role ◽

Active Form ◽

E3 Ligase ◽

Left Ventricular ◽

Ang Ii ◽

Lv Dysfunction ◽

On Chip

Rationale: Cardiac dysfunction is accelerated in DM patients after MI. Previously, we reported the critical role of ERK5 and CHIP association on CHIP Ub E3 ligase activity, which inhibits inducible cAMP early repressor (ICER)-mediated apoptosis and left ventricle (LV) dysfunction after MI in DM (DM + MI). Yet the regulatory mechanism of ERK5-CHIP has not been established. Objective: Since we found that p90RSK activation was increased in DM heart, we investigated whether p90RSK activation may inhibit ERK5-mediated CHIP activation, and subsequent ICER induction and apoptosis. Methods and Results: The inhibition of p90RSK activation prevented the reduction of ERK5-CHIP binding, CHIP activity, as well as ICER induction and cardiac apoptosis both in vitro after angiotensin II (ang II) stimulation and in vivo after DM + MI. p90RSK and CHIP share a same binding site with ERK5 C-terminal domain (aa571–807), and overexpression of both p90RSK and ERK5 (aa571–807) fragment, but not kinase dead mutant of p90RSK, inhibited ERK5-CHIP association, suggesting the critical role of p90RSK activation on ERK5-CHIP interaction, and competitive nature of p90RSK and CHIP against ERK5 association. Furthermore. LC-MS/MS analysis identified ERK5-S496 as being directly phosphorylated by p90RSK, and ERK5 S496A mutant significantly impaired ang II-mediated inhibition of CHIP Ub ligase activity, suggesting the critical role of Ser-496 phoaphorylation of ERK5 on CHIP activity. Therefore, p90RSK activation is critical for both p90RSK-ERK5 association as well as ERK5-Ser496 phosphorylation, and following disruption of ERK5-CHIP interaction and subsequent inhibition of CHIP Ub ligase activity. The reduction of CHIP Ub ligase activity and LV dysfunction were accelerated both in cardio-specific ERK5 knock out and wild type p90RSK transgenic mice (WT-p90RSK-Tg). Furthermore, double transgenic mice of WT-p90RSK and constitutively active form of MEK5α (specific ERK5 activator) inhibited single WT-p90RSK-Tg-medaited reduction of CHIP Ub ligase activity, LV dysfunction, and improved mortality after MI. Conclusions: These data strongly suggested that p90RSK activation accelerated cardiac dysfunction and apoptosis after DM + MI via inhibiting ERK5-CHIP module.

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