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Elevated levels of DNA damage due to oxidative stress in serum and myocardium of patients with heart failure
The 8th Annual Scientific Meeting
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JHFS
S163
O-033
O-035
Elevated Levels of DNA Damage Due to Oxidative Stress in Serum and Myocardium of Patients with Heart Failure
Combined Therapy with PPAR Alpha Agonist and Carnitine Supplementation Rescues the Detrimental Cardiomyopathy with Energy Metabolism Disorder ASAI TORU, TAKAHASHI RYOTARO, MURAKAMI HISASHI, MURAKAMI RYUICHIRO, NUMAGUCHI YASUSHI, MATSUI HIDEO, OKUMURA KENJI, MUROHARA TOYOAKI Department of Cardiology, Nagoya University, Graduate School of Medicine, Nagoya, Japan
NAKAMURA KAZUFUMI, KUSANO KENGO, MIURA AYA, NISHII NOBUHIRO, NAGASE SATOSHI, MIYAJI KATSUMASA, SAITO HIRONORI, KOHNO YASUYUKI, HARAOKA KAYO, OHE TOHRU Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan Background: We hypothesized that oxidative damage to DNA might be associated with progression of heart failure. We investigated whether the levels of 8-hydroxy-2-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage, were elevated in serum and myocardium of patients with cardiomyopathies. Methods and Results: Serum levels of 8-OHdG were measured by enzyme immunoassay in 58 patients with dilated cardiomyopathy (DCM) and 23 patients with hypertrophic cardiomyopathy (HCM) and in 20 control subjects. DCM patients had significantly elevated serum levels of 8-OHdG compared with those in control subjects and HCM patients (DCM: 5.2 ⫾ 2.9 ng/mL vs. control: 3.0 ⫾ 1.5 ng/mL, P ⫽ 0.0004; DCM vs. HCM: 2.6 ⫾ 0.8 ng/mL, P ⬍ 0.0001). The serum levels were significantly correlated with left ventricular end-diastolic diameter determined by echocardiography (P ⫽ 0.0009). The levels were significantly inversely correlated with left ventricular ejection fraction determined by left ventriculography (P ⫽ 0.0002). Endomyocardial biopsy samples obtained from 12 DCM patients and 5 control subjects with normal cardiac function were studied immunohistochemically for the expression of 8-OHdG. Positive 8-OHdG staining was found in the nuclei of cardiac myocytes of samples from DCM patients but not in those from control subjects. After treatment with carvedilol, the serum levels of 8-OHdG in DCM patients decreased by 19% (P ⬍ 0.05) along with amelioration of heart failure. Conclusion: These results indicate that DNA damage due to oxidative stress is implicated in progression of heart failure.
The juvenile visceral steatosis (JVS) mouse, a murine model of systemic carnitine deficiency (SCD), causes disorder of fatty acid oxidation and develops cardiac hypertrophy with lipid accumulation. We investigated the effect of fenofibrate, a PPARalpha agonist, in addition to carnitine supplementation on the hypertrophied heart in JVS mice. JVS mice were fed a normal chow, 0.1% carnitine/kg containing chow (CA), or 0.1% carnitine/kg and 0.2% fenofibrate/kg containing chow (CA ⫹ FE) from 4 weeks of age. At 8 weeks, the ventricular hypertrophy in JVS mice was more attenuated by CA ⫹ FE than by CA alone. CA ⫹ FE normalized the content of myocardial ATP and triglycerides to control levels, and prevented the deterioration of left ventricular function. Combined therapy with PPARalpha agonist and carnitine supplementation may be beneficial in treating the cardiomyopathy due to SCD.
O-034
O-036
Suppressed Expression of GTP Cyclohydrolase I mRNA in Endomyocardial Biopsy Specimens From Patients with Dilated Cardiomyopathy OHTSUKI MASATSUGU, MORIMOTO SHIN-ICHIRO, HIRAMITSU SHINYA, UEMURA AKIHISA, KATOH SHIGERU, SUGIURA ATSUSHI, MIYAGISHIMA KENJI, MORI NAMI, SHIMOKUBO JUNKO, HISHIDA HITOSHI Department of Internal Medicine, Fujita Health University, School of Medicine, Toyoake, Japan
Effects of Statins on Progression of Glucose Intolerance and Diastolic Dysfunction in a Model of Type-2 Diabetes Mellitus OHMORI KOJI1, CHEN YAN1, SHINOMIYA KAORI1, YOSHIDA JUNJI1, FUJITA NORIHIRO1, MIZUSHIGE KATSUFUMI1, KOSAKA HIROAKI2, KOHNO MASAKAZU1 1 Second Department of Internal Medicine, Kagawa University School of Medicine, Kagawa, Japan, 2Department of Cardiovascular Physiology, Kagawa University School of Medicine
Background: Tetrahydrobiopterin (BH4) is an essential cofactor of nitric oxide synthase, and GTP cyclohydrolase I (GCHI) is a rate-limiting enzyme in the biosynthesis of BH4. The expression of nitric oxide synthase was earlier demonstrated in the ventricles of patients with dilated cardiomyopathy (DCM), although that of GCHI was not clarified. The present study was designed to determine the GCHI mRNA expression in endomyocardial biopsy specimens from patients with DCM. Methods: Clinical details were assessed in 19 patients with DCM and in 9 control subjects. Patients with arrhythmia and whose biopsy samples were histologically normal and free from organic cardiovascular findings were used as the control. The real-time reverse transcription polymerase chain reaction was performed on total RNA extracted from endomyocardial biopsy specimens. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) mRNA was quantified for use as an internal control. Results: GCHI/GAPDH for the DCM samples was reduced to 31.1% of the control (P ⬍ 0.05). BH4 levels were not determined because of limitations of the amount of the sample. However, it is reasonable to assume that BH4 production in the DCM heart would be markedly reduced under the condition of decreased GCHI mRNA expression in the tissue. Conclusions: In the present study, we show for the first time that the GCHI mRNA level was suppressed in endomyocardial biopsy specimens from patients with DCM.
Purposes: Preventive effects of statins on the population prone to develop diabetes mellitus (DM) remain to be fully examined. Therefore, we examined how early treatment with statins affects the progressions of glucose intolerance and diastolic dysfunction in a model of spontaneous type-2 DM (OLETF rats). Methods: In OLETF rats, pravastatin or atorvastatin (100mg/kg/day) was started at 6W of age. We repeated OGTT and Doppler measurements of LV inflow velocity. NO production was estimated by measuring plasma concentration of end products of NO (NOx) with the Griess method. Results were compared among the two treated groups (Prav-gr and Atorv-gr), untreated OLETF (OLE-gr), and normal rats (LET-gr). Results: In OLE-gr, 42% and 75% of rats were diabetic at 20 and 30W, respectively. Although the prevalence was similar in Atorv-gr (33% and 73%), it was limited in Prav-gr (0% and 17%). E/A ratio was gradually reduced and deceleration-time of E-wave was increased in OLE-gr (1.8 ⫾ 0.3 and 48 ⫾ 4msec at 30W), which was found prevented in Prav-gr (2.1 ⫾ 0.3 and 40 ⫾ 5msec) but unaffected in Atorv-gr (1.8 ⫾ 0.3 and 46 ⫾ 5msec). Although plasma NOx at 30W, which was 19 ⫾ 4 micromol/L in LET-gr, was reduced both in OLE-gr (14 ⫾ 3) and Atorv-gr (16 ⫾ 2), it remained unchanged in Prav-gr (18 ⫾ 3). Conclusions: Pravastatin but not atorvastatin prevented new-onset DM and progressive diastolic dysfunction in OLETF rats, which was accompanied by preserved NO production.
•
JHFS
S163
O-033
O-035
Elevated Levels of DNA Damage Due to Oxidative Stress in Serum and Myocardium of Patients with Heart Failure
Combined Therapy with PPAR Alpha Agonist and Carnitine Supplementation Rescues the Detrimental Cardiomyopathy with Energy Metabolism Disorder ASAI TORU, TAKAHASHI RYOTARO, MURAKAMI HISASHI, MURAKAMI RYUICHIRO, NUMAGUCHI YASUSHI, MATSUI HIDEO, OKUMURA KENJI, MUROHARA TOYOAKI Department of Cardiology, Nagoya University, Graduate School of Medicine, Nagoya, Japan
NAKAMURA KAZUFUMI, KUSANO KENGO, MIURA AYA, NISHII NOBUHIRO, NAGASE SATOSHI, MIYAJI KATSUMASA, SAITO HIRONORI, KOHNO YASUYUKI, HARAOKA KAYO, OHE TOHRU Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan Background: We hypothesized that oxidative damage to DNA might be associated with progression of heart failure. We investigated whether the levels of 8-hydroxy-2-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage, were elevated in serum and myocardium of patients with cardiomyopathies. Methods and Results: Serum levels of 8-OHdG were measured by enzyme immunoassay in 58 patients with dilated cardiomyopathy (DCM) and 23 patients with hypertrophic cardiomyopathy (HCM) and in 20 control subjects. DCM patients had significantly elevated serum levels of 8-OHdG compared with those in control subjects and HCM patients (DCM: 5.2 ⫾ 2.9 ng/mL vs. control: 3.0 ⫾ 1.5 ng/mL, P ⫽ 0.0004; DCM vs. HCM: 2.6 ⫾ 0.8 ng/mL, P ⬍ 0.0001). The serum levels were significantly correlated with left ventricular end-diastolic diameter determined by echocardiography (P ⫽ 0.0009). The levels were significantly inversely correlated with left ventricular ejection fraction determined by left ventriculography (P ⫽ 0.0002). Endomyocardial biopsy samples obtained from 12 DCM patients and 5 control subjects with normal cardiac function were studied immunohistochemically for the expression of 8-OHdG. Positive 8-OHdG staining was found in the nuclei of cardiac myocytes of samples from DCM patients but not in those from control subjects. After treatment with carvedilol, the serum levels of 8-OHdG in DCM patients decreased by 19% (P ⬍ 0.05) along with amelioration of heart failure. Conclusion: These results indicate that DNA damage due to oxidative stress is implicated in progression of heart failure.
The juvenile visceral steatosis (JVS) mouse, a murine model of systemic carnitine deficiency (SCD), causes disorder of fatty acid oxidation and develops cardiac hypertrophy with lipid accumulation. We investigated the effect of fenofibrate, a PPARalpha agonist, in addition to carnitine supplementation on the hypertrophied heart in JVS mice. JVS mice were fed a normal chow, 0.1% carnitine/kg containing chow (CA), or 0.1% carnitine/kg and 0.2% fenofibrate/kg containing chow (CA ⫹ FE) from 4 weeks of age. At 8 weeks, the ventricular hypertrophy in JVS mice was more attenuated by CA ⫹ FE than by CA alone. CA ⫹ FE normalized the content of myocardial ATP and triglycerides to control levels, and prevented the deterioration of left ventricular function. Combined therapy with PPARalpha agonist and carnitine supplementation may be beneficial in treating the cardiomyopathy due to SCD.
O-034
O-036
Suppressed Expression of GTP Cyclohydrolase I mRNA in Endomyocardial Biopsy Specimens From Patients with Dilated Cardiomyopathy OHTSUKI MASATSUGU, MORIMOTO SHIN-ICHIRO, HIRAMITSU SHINYA, UEMURA AKIHISA, KATOH SHIGERU, SUGIURA ATSUSHI, MIYAGISHIMA KENJI, MORI NAMI, SHIMOKUBO JUNKO, HISHIDA HITOSHI Department of Internal Medicine, Fujita Health University, School of Medicine, Toyoake, Japan
Effects of Statins on Progression of Glucose Intolerance and Diastolic Dysfunction in a Model of Type-2 Diabetes Mellitus OHMORI KOJI1, CHEN YAN1, SHINOMIYA KAORI1, YOSHIDA JUNJI1, FUJITA NORIHIRO1, MIZUSHIGE KATSUFUMI1, KOSAKA HIROAKI2, KOHNO MASAKAZU1 1 Second Department of Internal Medicine, Kagawa University School of Medicine, Kagawa, Japan, 2Department of Cardiovascular Physiology, Kagawa University School of Medicine
Background: Tetrahydrobiopterin (BH4) is an essential cofactor of nitric oxide synthase, and GTP cyclohydrolase I (GCHI) is a rate-limiting enzyme in the biosynthesis of BH4. The expression of nitric oxide synthase was earlier demonstrated in the ventricles of patients with dilated cardiomyopathy (DCM), although that of GCHI was not clarified. The present study was designed to determine the GCHI mRNA expression in endomyocardial biopsy specimens from patients with DCM. Methods: Clinical details were assessed in 19 patients with DCM and in 9 control subjects. Patients with arrhythmia and whose biopsy samples were histologically normal and free from organic cardiovascular findings were used as the control. The real-time reverse transcription polymerase chain reaction was performed on total RNA extracted from endomyocardial biopsy specimens. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) mRNA was quantified for use as an internal control. Results: GCHI/GAPDH for the DCM samples was reduced to 31.1% of the control (P ⬍ 0.05). BH4 levels were not determined because of limitations of the amount of the sample. However, it is reasonable to assume that BH4 production in the DCM heart would be markedly reduced under the condition of decreased GCHI mRNA expression in the tissue. Conclusions: In the present study, we show for the first time that the GCHI mRNA level was suppressed in endomyocardial biopsy specimens from patients with DCM.
Purposes: Preventive effects of statins on the population prone to develop diabetes mellitus (DM) remain to be fully examined. Therefore, we examined how early treatment with statins affects the progressions of glucose intolerance and diastolic dysfunction in a model of spontaneous type-2 DM (OLETF rats). Methods: In OLETF rats, pravastatin or atorvastatin (100mg/kg/day) was started at 6W of age. We repeated OGTT and Doppler measurements of LV inflow velocity. NO production was estimated by measuring plasma concentration of end products of NO (NOx) with the Griess method. Results were compared among the two treated groups (Prav-gr and Atorv-gr), untreated OLETF (OLE-gr), and normal rats (LET-gr). Results: In OLE-gr, 42% and 75% of rats were diabetic at 20 and 30W, respectively. Although the prevalence was similar in Atorv-gr (33% and 73%), it was limited in Prav-gr (0% and 17%). E/A ratio was gradually reduced and deceleration-time of E-wave was increased in OLE-gr (1.8 ⫾ 0.3 and 48 ⫾ 4msec at 30W), which was found prevented in Prav-gr (2.1 ⫾ 0.3 and 40 ⫾ 5msec) but unaffected in Atorv-gr (1.8 ⫾ 0.3 and 46 ⫾ 5msec). Although plasma NOx at 30W, which was 19 ⫾ 4 micromol/L in LET-gr, was reduced both in OLE-gr (14 ⫾ 3) and Atorv-gr (16 ⫾ 2), it remained unchanged in Prav-gr (18 ⫾ 3). Conclusions: Pravastatin but not atorvastatin prevented new-onset DM and progressive diastolic dysfunction in OLETF rats, which was accompanied by preserved NO production.