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- W46077950 abstract "Background: Diastolic myocardial dysfunction in metabolic heart disease (e.g. diabetes, obesity) is associated with accumulation of the lipid peroxidation product 4-hydroxynonenal (HNE) in cardiac myocytes. We have shown that reactive oxygen species (ROS) can impair diastolic relaxation via oxidative post-translational modification of sarcoplasmic reticulum Ca(2+)-ATPase (SERCA). It is also known that HNE can uncouple nitric oxide synthase (NOS) producing ROS including hydrogen peroxide (H2O2). Since NOS1 isoform in myocardium is associated with sarcoplasmic reticulum and SERCA, we tested the hypothesis that HNE inhibits SERCA and causes diastolic dysfunction via NOS1-mediated ROS production.Methods and Results: End diastolic pressure (EDP)/volume relationships were determined in isolated Langendorff hearts before and after perfusion with HNE (5microM, 20 min, 37 oC ). HNE caused diastolic dysfunction (Fig. A — EDP curve shifted upwards) and decreased maximal calcium-stimulated SERCA activity in SR membrane preparation from these hearts by 60% (p<0.05, n=4). In cardiac myocytes in vitro, HNE increased H2O2 production measured by dichlorofluorescein assay. To test the role of H2O2 in HNE-induced diastolic dysfunction, hearts with myocyte-specific overexpression of catalase (CAT-TG) were perfused with HNE. CAT-TG completely prevented HNE-induced diastolic dysfunction (Fig. B) and inhibition of SERCA. To test the role of NOS as a source of HNE-induced H2O2, HNE was perfused a) together with the NOS inhibitor L-NAME or b) in hearts from NOS1 −/− mice. HNE-induced diastolic dysfunction was abolished both by L-NAME and in NOS1 −/− mice (Fig. C).Conclusion: HNE inhibits myocardial SERCA and causes diastolic dysfunction via NOS1-mediated H2O2 production. These findings support the thesis that HNE and NOS1 contribute to diastolic dysfunction in metabolic heart disease.![Graphic][1] [1]: /embed/inline-graphic-1.gif" @default.
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- W46077950 date "2010-11-23" @default.
- W46077950 modified "2023-09-23" @default.
- W46077950 title "Abstract 18251: Nitric Oxide Synthase-1 Mediates Hydroxynonenal-Induced Inhibition of SERCA and Diastolic Dysfunction in the Heart" @default.
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!["Background: Diastolic myocardial dysfunction in metabolic heart disease (e.g. diabetes, obesity) is associated with accumulation of the lipid peroxidation product 4-hydroxynonenal (HNE) in cardiac myocytes. We have shown that reactive oxygen species (ROS) can impair diastolic relaxation via oxidative post-translational modification of sarcoplasmic reticulum Ca(2+)-ATPase (SERCA). It is also known that HNE can uncouple nitric oxide synthase (NOS) producing ROS including hydrogen peroxide (H2O2). Since NOS1 isoform in myocardium is associated with sarcoplasmic reticulum and SERCA, we tested the hypothesis that HNE inhibits SERCA and causes diastolic dysfunction via NOS1-mediated ROS production.Methods and Results: End diastolic pressure (EDP)/volume relationships were determined in isolated Langendorff hearts before and after perfusion with HNE (5microM, 20 min, 37 oC ). HNE caused diastolic dysfunction (Fig. A — EDP curve shifted upwards) and decreased maximal calcium-stimulated SERCA activity in SR membrane preparation from these hearts by 60% (p<0.05, n=4). In cardiac myocytes in vitro, HNE increased H2O2 production measured by dichlorofluorescein assay. To test the role of H2O2 in HNE-induced diastolic dysfunction, hearts with myocyte-specific overexpression of catalase (CAT-TG) were perfused with HNE. CAT-TG completely prevented HNE-induced diastolic dysfunction (Fig. B) and inhibition of SERCA. To test the role of NOS as a source of HNE-induced H2O2, HNE was perfused a) together with the NOS inhibitor L-NAME or b) in hearts from NOS1 −/− mice. HNE-induced diastolic dysfunction was abolished both by L-NAME and in NOS1 −/− mice (Fig. C).Conclusion: HNE inhibits myocardial SERCA and causes diastolic dysfunction via NOS1-mediated H2O2 production. These findings support the thesis that HNE and NOS1 contribute to diastolic dysfunction in metabolic heart disease.![Graphic][1] [1]: /embed/inline-graphic-1.gif"](?object=%22Background%3A%20Diastolic%20myocardial%20dysfunction%20in%20metabolic%20heart%20disease%20(e.g.%20diabetes%2C%20obesity)%20is%20associated%20with%20accumulation%20of%20the%20lipid%20peroxidation%20product%204-hydroxynonenal%20(HNE)%20in%20cardiac%20myocytes.%20We%20have%20shown%20that%20reactive%20oxygen%20species%20(ROS)%20can%20impair%20diastolic%20relaxation%20via%20oxidative%20post-translational%20modification%20of%20sarcoplasmic%20reticulum%20Ca(2%2B)-ATPase%20(SERCA).%20It%20is%20also%20known%20that%20HNE%20can%20uncouple%20nitric%20oxide%20synthase%20(NOS)%20producing%20ROS%20including%20hydrogen%20peroxide%20(H2O2).%20Since%20NOS1%20isoform%20in%20myocardium%20is%20associated%20with%20sarcoplasmic%20reticulum%20and%20SERCA%2C%20we%20tested%20the%20hypothesis%20that%20HNE%20inhibits%20SERCA%20and%20causes%20diastolic%20dysfunction%20via%20NOS1-mediated%20ROS%20production.Methods%20and%20Results%3A%20End%20diastolic%20pressure%20(EDP)%2Fvolume%20relationships%20were%20determined%20in%20isolated%20Langendorff%20hearts%20before%20and%20after%20perfusion%20with%20HNE%20(5microM%2C%2020%20min%2C%2037%20oC%20).%20HNE%20caused%20diastolic%20dysfunction%20(Fig.%20A%20%E2%80%94%20EDP%20curve%20shifted%20upwards)%20and%20decreased%20maximal%20calcium-stimulated%20SERCA%20activity%20in%20SR%20membrane%20preparation%20from%20these%20hearts%20by%2060%25%20(p%3C0.05%2C%20n%3D4).%20In%20cardiac%20myocytes%20in%20vitro%2C%20HNE%20increased%20H2O2%20production%20measured%20by%20dichlorofluorescein%20assay.%20To%20test%20the%20role%20of%20H2O2%20in%20HNE-induced%20diastolic%20dysfunction%2C%20hearts%20with%20myocyte-specific%20overexpression%20of%20catalase%20(CAT-TG)%20were%20perfused%20with%20HNE.%20CAT-TG%20completely%20prevented%20HNE-induced%20diastolic%20dysfunction%20(Fig.%20B)%20and%20inhibition%20of%20SERCA.%20To%20test%20the%20role%20of%20NOS%20as%20a%20source%20of%20HNE-induced%20H2O2%2C%20HNE%20was%20perfused%20a)%20together%20with%20the%20NOS%20inhibitor%20L-NAME%20or%20b)%20in%20hearts%20from%20NOS1%20%E2%88%92%2F%E2%88%92%20mice.%20HNE-induced%20diastolic%20dysfunction%20was%20abolished%20both%20by%20L-NAME%20and%20in%20NOS1%20%E2%88%92%2F%E2%88%92%20mice%20(Fig.%20C).Conclusion%3A%20HNE%20inhibits%20myocardial%20SERCA%20and%20causes%20diastolic%20dysfunction%20via%20NOS1-mediated%20H2O2%20production.%20These%20findings%20support%20the%20thesis%20that%20HNE%20and%20NOS1%20contribute%20to%20diastolic%20dysfunction%20in%20metabolic%20heart%20disease.!%5BGraphic%5D%5B1%5D%20%5B1%5D%3A%20%2Fembed%2Finline-graphic-1.gif%22){kind=link}