Abstract MP211: NAD Redox Imbalance Exacerbates Diabetic Cardiomyopathy

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Chi Fung Lee
Keyword(s):  
Diastolic Dysfunction ◽  
Diabetic Cardiomyopathy ◽  
Calcium Sensitivity ◽  
Redox Balance ◽  
Diabetic Control ◽  
Redox Imbalance ◽  
Nadh Ratio ◽  
Streptozotocin Induced Diabetes ◽  
Systolic And Diastolic Function ◽  
Myofilament Calcium Sensitivity

Diabetes and heart failure are linked to NAD redox imbalance, whose role in diabetic cardiomyopathy has not been directly tested. Streptozotocin-induced diabetes in WT mice for 16 weeks promoted declines in systolic and diastolic function, which associated with lowered cardiac NAD/NADH ratio (NAD redox imbalance). To test the hypothesis that , we employed mouse models with cardiac-specific manipulations of NAD redox states. Cardiac-specific Ndufs4-KO mice (cKO) exhibit lowered cardiac NAD/NADH ratio with normal baseline function, geometry and energetics. Control and cKO mice were challenged with 8-week diabetic stress. Metabolomic analyses of plasma collected after the diabetic stress showed similar hyperglycemia and dyslipidemia stresses in diabetic control and diabetic cKO mice. Chronic diabetic stress promoted systolic and diastolic dysfunctions in control mice, which were further exacerbated in diabetic cKO mice in both male and female cohorts. Collagen levels and transcript analyses of fibrosis and extracellular matrix-dependent pathways showed no change in diabetic cKO hearts, suggesting that cardiomyocyte dysfunction is a likely culprit for the exacerbated dysfunction. Increased protein acetylation, including SOD2-K68Ac, was observed in diabetic cKO hearts. Inhibited antioxidant function by SOD2-K68Ac promoted protein oxidation in diabetic cKO hearts, suggesting oxidative stress as a pathogenic mechanism. We next examined phosphorylation status of myofilament proteins in these diabetic hearts. MyBPC-S282Pi levels are suppressed in failing hearts and remained unchanged in diabetic cKO hearts. TnI-S150Pi increases myofilament calcium sensitivity and prolongs calcium dissociation, while TnI-S23/24Pi imposes the opposite effects. TnI-S150Pi levels were elevated in diabetic cKO hearts, while TnI-S23/24Pi levels unchanged. Therefore, exacerbated diastolic dysfunction in diabetic cKO hearts is due to the selective phosphorylation at TnI-S150. AMPK is activated by energetic stress and phosphorylates TnI-S150. ATP levels decreased, and AMP/ATP ratio increased in diabetic cKO hearts, implicating impaired energetics to promote TnI-S150Pi and dysfunction. Elevation of NAD levels normalized cardiac NAD redox balance in diabetic cKO hearts. Elevated levels of SOD2-K68Ac and TnI-S150Pi, exacerbated systolic and diastolic dysfunction in diabetic cKO hearts were all reversed by elevation of NAD levels. Dysfunction in diabetic control hearts was also ameliorated by elevation of NAD levels. These data collectively conclude that NAD redox imbalance is a positive mediator of the progression of diabetic cardiomyopathy.

Abstract 219: NAD Redox Imbalance Accelerates Diabetic Cardiomyopathy via Protein Acetylation and Oxidative Stress

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Ying Ann Chiao ◽  
Christine Light ◽  
Xiaojian Shi ◽  
Rong Tian ◽  
Junichi Sadoshima ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mouse Models ◽  
Diabetic Cardiomyopathy ◽  
Cardiac Fibrosis ◽  
Redox Balance ◽  
Protein Acetylation ◽  
Redox Imbalance ◽  
Nadh Ratio ◽  
Systolic And Diastolic Function ◽  
And Oxidative Stress

Diabetes is long linked to lowered NAD/NADH ratio, aka NAD redox imbalance, but its causal role to diabetic cardiomyopathy is not established. We used mouse models with latent decrease in cardiac NAD/NADH ratio (cardiac-specific Ndufs4-KO, cKO) and elevated cardiac NAD levels to directly test whether cardiac NAD redox imbalance accelerates diabetic cardiomyopathy. Control and cKO mice were subjected to 8-week T1D stress, and longitudinal cardiac function was measured by echocardiography. Accelerated declines in systolic and diastolic function were observed in T1D cKO mice. Insulin depletion and hyperglycemia were similar in T1D control and T1D cKO mice, and serum metabolomic analyses showed unchanged aqueous and lipid metabolite levels. These metabolite results suggested that T1D control and cKO hearts were stressed under similar diabetic conditions. Importantly, elevation of cardiac NAD levels to attenuate NAD redox imbalance mitigated the accelerated functional declines in T1D cKO hearts. The data from mouse models with manipulated NAD redox states suggested that NAD redox imbalance accelerates diabetic cardiomyopathy. Cardiac fibrosis levels were not different in T1D control and cKO hearts, while transcript levels of fibrotic genes, including Adamts proteinases, integrins, laminins, matrix metalloproteinases and collagens, also showed no difference. Therefore, the accelerated functional declines in T1D cKO hearts are not due to altered extracellular matrix environment, but are rather due to cardiomyocyte dysfunction. We next determined whether the accelerated cardiac dysfunction is mediated via protein acetylation and oxidative stress. NAD-dependent global protein acetylation and inhibitory acetylation of superoxide dismutase 2 were elevated in T1D cKO hearts. Inhibition of SOD2 concomitantly promoted elevation of protein oxidation levels in T1D cKO hearts. The results suggested that NAD redox balance-dependent protein acetylation regulates oxidative stress to promote diabetic cardiomyopathy.

Abstract 17069: NAD+Redox Imbalance in the Heart Exacerbates Diabetic Cardiomyopathy

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Akash Deep D Chakraborty ◽  
Ying Ann Chiao ◽  
Christine M Light ◽  
Rong Tian ◽  
Junichi Sadoshima ◽  
...  
Keyword(s):  
Diabetic Cardiomyopathy ◽  
Cardiac Dysfunction ◽  
Diabetic Control ◽  
Causal Role ◽  
Protein Acetylation ◽  
Specific Expression ◽  
Redox Imbalance ◽  
Nadh Ratio ◽  
Systolic And Diastolic Function

Diabetes is a risk factor of heart failure and leads to cardiac dysfunction, a condition named diabetic cardiomyopathy (DCM). NAD redox imbalance is observed in diabetic tissues. However, whether NAD redox imbalance promotes cardiac dysfunction in DCM remains unknown. The objective of this study is to determine the causal role of NAD redox imbalance in DCM.Type 1 diabetes was induced in C57BL6 mice by streptozotocin (STZ) injections, and DCM was allowed to develop for 16 weeks. Diabetes-induced chronic stress led to systolic and diastolic cardiac dysfunction along with a lowered NAD/NADH ratio. The diabetogenic protocol was applied to control and cardiac-specific Ndufs4-KO mice (cKO), a mouse model with lowered cardiac NAD/NADH without baseline cardiac dysfunction. Analyses of blood glucose and >200 metabolites in plasma showed no significant change in diabetic control and diabetic cKO mice, suggesting that their hearts experienced similar diabetic stress. Diabetic cKO hearts showed lowered NAD/NADH, aggravated contractile and relaxation dysfunction compared to the diabetic control hearts in both sexes. The data suggest that NAD redox imbalance exacerbated DCM. Collagen staining and transcript analyses of fibrosis-related genes showed no change in diabetic cKO hearts, signifying that the exacerbated dysfunction was due to cardiomyocyte dysfunction. A global protein acetylation was promoted in the diabetic cKO hearts with an increase in SOD2 acetylation levels at lysine-68 (SOD2-K68Ac) and enhanced protein oxidation. Diabetic cKO mice displayed enhanced levels of TnI S150 phosphorylation (TnI-S150Pi), but not phosphorylation of TnI-S23/24 or MyBPc-S282. These data suggest that enhanced oxidative stress and altered myofilament Ca 2+ sensitivity via TnI-S150Pi are responsible for the NAD redox imbalance-exacerbated DCM.To confirm the role of NAD redox imbalance in DCM, we elevated cardiac NAD levels in diabetic cKO mice by cardiac-specific expression of NAMPT. Expression of NAMPT in the heart improved cardiac systolic and diastolic function in diabetic cKO hearts. This was due to increased NAD/NADH ratio and reversed pathogenic mechanisms (lowered SOD2-K68Ac and TnI-S150Pi). This study supports the causal role of NAD redox imbalance in DCM.

scholarly journals NAD+ Redox Imbalance in the Heart Exacerbates Diabetic Cardiomyopathy

2020 ◽  
Author(s):  
Ying Ann Chiao ◽  
Akash Deep Chakraborty ◽  
Christine M. Light ◽  
Rong Tian ◽  
Junichi Sadoshima ◽  
...  
Keyword(s):  
Diabetic Cardiomyopathy ◽  
Cardiac Dysfunction ◽  
Troponin I ◽  
Therapeutic Potential ◽  
Redox Balance ◽  
Diabetic Mice ◽  
Nicotinamide Phosphoribosyltransferase ◽  
Redox Imbalance ◽  
Nadh Ratio ◽  
Regulate Protein

AbstractBackgroundDiabetes is a risk factor of heart failure and promotes cardiac dysfunction. Diabetic tissues are associated with NAD+ redox imbalance; however, the hypothesis that NAD+ redox imbalance leads to dysfunction of diabetic hearts has not been tested. In this study, we employed mouse models with altered NAD+ redox balance to test the hypothesis.Methods and ResultsDiabetes was induced in C57BL/6 mice by streptozotocin injections, and diabetic cardiomyopathy (DCM) was allowed to develop for 16 weeks. Diabetic stress led to cardiac dysfunction and lowered NAD+/NADH ratio. This diabetogenic regimen was administered to cardiac-specific knockout mice of complex I subunit Ndufs4 (cKO), a model with lowered cardiac NAD+/NADH ratio without baseline dysfunction. Cardiac NAD+ redox imbalance in cKO hearts exacerbated systolic and diastolic dysfunction of diabetic mice in both sexes. Collagen levels and transcript analyses of fibrosis and extracellular matrix-dependent pathways did not show change in diabetic cKO hearts, suggesting that the exacerbated cardiac dysfunction was likely due to cardiomyocyte dysfunction. We found that cardiac NAD+ redox imbalance promoted superoxide dismutase 2 (SOD2) acetylation, protein oxidation, induced troponin I S150 phosphorylation and impaired energetics in diabetic cKO hearts. Importantly, elevation of cardiac NAD+ levels by nicotinamide phosphoribosyltransferase (NAMPT) normalized NAD+ redox balance, over-expression alleviated cardiac dysfunction and reversed pathogenic mechanisms in diabetic mice.ConclusionOur results show that NAD+ redox imbalance to regulate protein acetylation and phosphorylation is a critical mediator of the progression of DCM, and suggest the therapeutic potential of harnessing NAD+ metabolism in DCM.

scholarly journals NAD + Redox Imbalance in the Heart Exacerbates Diabetic Cardiomyopathy

2021 ◽  
Author(s):  
Ying Ann Chiao ◽  
Akash Deep Chakraborty ◽  
Christine M. Light ◽  
Rong Tian ◽  
Junichi Sadoshima ◽  
...  
Keyword(s):  
Mouse Models ◽  
Diabetic Cardiomyopathy ◽  
Cardiac Dysfunction ◽  
Nicotinamide Adenine Dinucleotide ◽  
Redox Balance ◽  
Diabetic Mice ◽  
Redox Imbalance ◽  
Diastolic Velocity ◽  
Nadh Ratio ◽  
Fractional Shortening

Background: Diabetes is a risk factor for heart failure and promotes cardiac dysfunction. Diabetic tissues are associated with nicotinamide adenine dinucleotide (NAD + ) redox imbalance; however, the hypothesis that NAD + redox imbalance causes diabetic cardiomyopathy has not been tested. This investigation used mouse models with altered NAD + redox balance to test this hypothesis. Methods: Diabetic stress was induced in mice by streptozotocin. Cardiac function was measured by echocardiography. Heart and plasma samples were collected for biochemical, histological, and molecular analyses. Two mouse models with altered NAD + redox states (1, Ndufs4 [NADH:ubiquinone oxidoreductase subunit S4] knockout, cKO, and 2, NAMPT [nicotinamide phosphoribosyltranferase] transgenic mice, NMAPT) were used. Results: Diabetic stress caused cardiac dysfunction and lowered NAD + /NADH ratio (oxidized/reduced ratio of nicotinamide adenine dinucleotide) in wild-type mice. Mice with lowered cardiac NAD + /NADH ratio without baseline dysfunction, cKO mice, were challenged with chronic diabetic stress. NAD + redox imbalance in cKO hearts exacerbated systolic (fractional shortening: 27.6% versus 36.9% at 4 weeks, male cohort P <0.05), and diastolic dysfunction (early-to-late ratio of peak diastolic velocity: 0.99 versus 1.20, P <0.05) of diabetic mice in both sexes. Collagen levels and transcripts of fibrosis and extracellular matrix–dependent pathways did not show changes in diabetic cKO hearts, suggesting that the exacerbated cardiac dysfunction was due to cardiomyocyte dysfunction. NAD + redox imbalance promoted superoxide dismutase 2 acetylation, protein oxidation, troponin I S150 phosphorylation, and impaired energetics in diabetic cKO hearts. Importantly, elevation of cardiac NAD + levels by NAMPT normalized NAD + redox balance, alleviated cardiac dysfunction (fractional shortening: 40.2% versus 24.8% in cKO:NAMPT versus cKO, P <0.05; early-to-late ratio of peak diastolic velocity: 1.32 versus 1.04, P <0.05), and reversed pathogenic mechanisms in diabetic mice. Conclusions: Our results show that NAD + redox imbalance to regulate acetylation and phosphorylation is a critical mediator of the progression of diabetic cardiomyopathy and suggest the therapeutic potential for diabetic cardiomyopathy by harnessing NAD + metabolism.

Abstract 220: Emerging Roles of Altered NAD Metabolism in Diabetic Cardiomyopathy

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Chi Fung Lee
Keyword(s):  
Diastolic Dysfunction ◽  
Diabetic Cardiomyopathy ◽  
Cardiac Dysfunction ◽  
Troponin I ◽  
Redox Balance ◽  
Heart Weight ◽  
Mrna Levels ◽  
Nad Metabolism ◽  
Redox Imbalance ◽  
Nad Synthesis

Diabetes is linked to altered NAD metabolism whose causal roles in cardiac dysfunction are poorly understood. Synthesis, consumption and redox balance of NAD dictate NAD metabolism and its homeostasis, and we here explored their roles in diabetic cardiomyopathy. 16 week of Type 1 diabetes (T1D) to C57BL6N mice was associated with lowered cardiac NAD/NADH, mild systolic and more severe diastolic dysfunction. We next used mouse models with altered NAD metabolism to determine how NAD redox balance impacts diabetic cardiomyopathy. Using cardiac-specific Ndufs4-KO mice (cKO) as a model of latent decrease in cardiac NAD/NADH, we observed accelerated systolic and diastolic dysfunction (lowered fractional shortening, E’/A’ ratio, and increased e/E’ ratio) in male cKO mice stressed with chronic T1D. Cardiac hypertrophy (heart weight/tibia length), insulin depletion and hyperglycemia levels were similar in these mice. Serum metabolomic analyses (~240 metabolites) also showed unchanged aqueous and lipid metabolite levels, suggesting that the diabetic stresses on these hearts were similar. The accelerated dysfunction of T1D cKO hearts was also observed in another female cohort. Importantly, elevation of cardiac NAD levels to attenuate NAD redox imbalance mitigated the accelerated dysfunction of T1D cKO hearts. In another cohort, control and cKO mice were stressed by 16-week high fat diet feeding. Accelerated systolic and diastolic dysfunction, and increased hypertrophy were observed in T2D cKO mice with similar glycemic levels to control mice. The data suggested that NAD redox imbalance is a positive regulator of cardiac dysfunction induced by T1D or T2D. However, NAD-dependent pathogenic mechanism induced by T1D or T2D (e.g. hypertrophy) can be different, and is under further investigation. Tissue fibrosis and mRNA levels of pro-fibrotic genes, including Adamts proteinases, integrins, laminins, matrix metalloproteinases and collagens were unchanged in T1D cKO hearts. Therefore, the accelerated dysfunction of T1D cKO hearts is due to cardiomyocyte dysfunction. We examined how NAD metabolism, other than the redox balance, may alter cardiomyocyte function. Levels of metabolite and mRNA regulating NAD synthesis and consumption pathways were measured. Of 32 transcripts assayed, Nmrk2 levels were uniquely up-regulated in T1D cKO hearts, and lowered by elevation of cardiac NAD levels. NMRK product levels were concomitantly decreased in T1D cKO hearts. NAD-dependent global acetylation and inhibitory superoxide dismutase 2 acetylation were increased in T1D cKO hearts. Protein oxidation levels were concomitantly raised. Hyperacetylation in proteins like CaM kinase was associated with increased phosphorylation in troponin I, not in MyBPC or PLN in T1D cKO hearts. These data support the emerging, multifaceted roles of altered NAD metabolism in the progression of diabetic cardiomyopathy.

scholarly journals Ranolazine Improves Cardiac Diastolic Dysfunction Through Modulation of Myofilament Calcium Sensitivity

2012 ◽  
Vol 110 (6) ◽  
pp. 841-850 ◽  
Author(s):  
Joshua D. Lovelock ◽  
Michelle M. Monasky ◽  
Euy-Myoung Jeong ◽  
Harvey A. Lardin ◽  
Hong Liu ◽  
...  
Keyword(s):  
Diastolic Dysfunction ◽  
Calcium Sensitivity ◽  
Myofilament Calcium Sensitivity

scholarly journals Increased myofilament calcium sensitivity is associated with decreased cardiac troponin I phosphorylation in the diabetic rat heart

2021 ◽  
Author(s):  
Angela Greenman ◽  
Gary M. Diffee ◽  
Amelia Power ◽  
Gerard T. Wilkins ◽  
Olivia M. S. Gold ◽  
...  
Keyword(s):  
Cardiac Troponin ◽  
Troponin I ◽  
Calcium Sensitivity ◽  
Cardiac Troponin I ◽  
Diabetic Heart ◽  
Diabetic Rat ◽  
Zdf Rat ◽  
Regulation Of Contraction ◽  
Systolic And Diastolic Function ◽  
Myofilament Calcium Sensitivity

Abstract Background The diabetic heart has impaired systolic and diastolic function independent of other comorbidities. The availability of calcium is altered, but does not fully explain the cardiac dysfunction seen in the diabetic heart. Thus, we explored if myofilament protein regulation of contraction is altered. Methods Calcium sensitivity (pCa50) was measured in Zucker Diabetic Fatty (ZDF) rat hearts at the initial stage of diabetes (12-week-old) and after 8 weeks of uncontrolled hyperglycaemia (20-week-old) and in non-diabetic (nDM) littermates. Skinned cardiomyocytes were connected to a capacitance-gauge transducer and a torque motor to measure force as a function of pCa (-log[Ca2+]). Fluorescent gel stain (ProQ Diamond) was used to measure total protein phosphorylation. Specific phospho-sites on cardiac troponin I (cTnI) and total cTnI O-GlcNAcylation were quantified using immunoblot. Results pCa50 was greater in both 12- and 20-week-old diabetic (DM) rats compared to nDM littermates (p = 0.0005). Total cTnI and cTnI serine 23/24 phosphorylation were lower in DM rats (p = 0.003 & p = 0.01, respectively), but cTnI O-GlcNAc protein expression was not different. pCa50 is greater in DM rats and corresponds with an overall reduction in cTnI phosphorylation. Conclusions These findings indicate that myofilament calcium sensitivity is increased and cTnI phosphorylation is reduced in ZDF DM rats, which suggests an important role for cTnI phosphorylation in the DM heart.

Inhibition of xanthine oxidase ameliorates functional and metabolic impairment in type 2 diabetic hearts under pressure overload

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
Y Igaki ◽  
A Osanami ◽  
M Tanno ◽  
T Sato ◽  
T Ogawa ◽  
...  
Keyword(s):  
Diastolic Dysfunction ◽  
Xanthine Oxidase ◽  
Adenine Nucleotide ◽  
Vascular Dysfunction ◽  
Pressure Overload ◽  
Diabetic Control ◽  
Funding Source ◽  
National Budget ◽  
Adenine Nucleotide Pool

Abstract Background We recently reported that upregulated AMP deaminase (AMPD), via reduction in the tissue adenine nucleotide pool, contributes to exacerbation of diastolic dysfunction under pressure overload in OLETF, a rat model of obese type 2 diabetes (T2DM). Upregulated AMPD also possibly promotes xanthine oxidase (XO)-mediated ROS production, since AMPD deaminases AMP to IMP, which is further converted to inosine, providing substrates of XO, hypoxanthine and xanthine. Here, we examined the hypothesis that inhibition of XO ameliorates the pressure overload-induced diastolic dysfunction by suppression of ROS-mediated mitochondrial dysfunction and/or vascular dysfunction in T2DM rats. Methods and results Metabolomic analyses revealed that levels of xanthine and uric acid in the LV myocardium were significantly higher by 37% and 51%, respectively, in OLETF than in LETO, non-diabetic control rats, under the condition of phenylephrine-induced pressure overloading (200–230 mmHg). Myocardial XO activity in OLETF was 57.9% higher than that in LETO, which may be attributed to 31% higher level of inosine, a positive regulator of XO, in OLETF than in LETO. The activity of XO was significantly attenuated by administration of topiroxostat, an XO inhibitor at 0.5 mg/kg/day for 14 days. Pressure volume loop analyses showed that the pressure overloading resulted in significantly higher LVEDP in OLETF than in LETO (18.3±1.5 vs. 12.2±1.3 mmHg, p&lt;0.05, n=7), though LVEDPs at baseline were comparable in OLETF and LETO (5.6±0.4 vs. 4.7±0.7 mmHg). Treatment with topiroxostat significantly suppressed the pressure overload-induced elevation of LVEDP in OLETF (18.3±1.5 vs. 11.3±1.1 mmHg, p&lt;0.05) but not in LETO. Under the condition of pressure overloading, Ea/Ees, an index for ventricular-arterial coupling, was higher in OLETF than in LETO (2.3±0.3 vs. 1.6±0.3, p&lt;0.05), and it was also improved by topiroxostat in OLETF (1.2±0.2, p&lt;0.05). Myocardial ATP content was lower in OLETF than in LETO (2966±400 vs. 1818±171 nmol/g wet tissue, p&lt;0.05), and treatment with topiroxostat significantly restored the ATP level (2629±307 nmol/g wet tissue). The LV myocardium of OLETF under pressure overload showed significantly higher level of malondialdehyde and 4-hydroxynonenal, an indicator of lipid peroxidation, than that of LETO. Measurement of oxygen consumption rate by Seahorse XFe96 Analyzer in mitochondria isolated from LV tissues revealed that state 3 respiration was significantly suppressed in OLETF by 43% compared to LETO, and it was restored by treatment with topiroxostat. Conclusion Both activity and substrates of XO are increased in T2DM hearts, in which upregulation of AMPD may play a role. Inhibition of XO ameliorates pressure overload-induced diastolic dysfunction and improves ventricular-arterial coupling in diabetic hearts, most likely through protection of mitochondrial function from ROS-mediated injury. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Grant-in-aid for Scientific Research (#26461132, #17K09584) from the Japanese Society for the Promotion of Science

scholarly journals Transcriptomic analysis of the cardiac left ventricle in a rodent model of diabetic cardiomyopathy: molecular snapshot of a severe myocardial disease

2007 ◽  
Vol 28 (3) ◽  
pp. 284-293 ◽  
Author(s):  
Sarah Glyn-Jones ◽  
Sarah Song ◽  
Michael A. Black ◽  
Anthony R. J. Phillips ◽  
Soon Y. Choong ◽  
...  
Keyword(s):  
Diabetic Cardiomyopathy ◽  
Molecular Basis ◽  
Cardiovascular Complications ◽  
Left Ventricular ◽  
Myocardial Disease ◽  
Chronic Hyperglycemia ◽  
Expression Of Genes ◽  
Streptozotocin Induced Diabetes ◽  
Quantitative Verification ◽  
Disproportionate Number

Heart disease is the major cause of death in diabetes, a disorder characterized by chronic hyperglycemia and cardiovascular complications. Diabetic cardiomyopathy (DCM) is increasingly recognized as a major contributor to diastolic dysfunction and heart failure in diabetes, but its molecular basis has remained obscure, in part because of its multifactorial origins. Here we employed comparative transcriptomic methods with quantitative verification of selected transcripts by reverse transcriptase quantitative PCR to characterize the molecular basis of DCM in rats with streptozotocin-induced diabetes of 16-wk duration. Diabetes caused left ventricular disease that was accompanied by significant changes in the expression of 1,614 genes, 749 of which had functions assignable by Gene Ontology classification. Genes corresponding to proteins expressed in mitochondria accounted for a disproportionate number of those whose expression was significantly modified in DCM, consistent with the idea that the mitochondrion is a key target of the pathogenic processes that cause myocardial disease in diabetes. Diabetes also induced global perturbations in the expression of genes regulating cardiac fatty acid metabolism, whose dysfunction is likely to play a key role in the promotion of oxidative stress, thereby contributing to the pathogenesis of diabetic myocardial disease. In particular, these data point to impaired regulation of mitochondrial β-oxidation as central in the mechanisms that generate DCM pathogenesis. This study provides a comprehensive molecular snapshot of the processes leading to myocardial disease in diabetes.

PKC catalytic subunit and phenylephrine induce a comparable decrease in myofilament calcium sensitivity

2007 ◽  
Vol 42 (6) ◽  
pp. S46
Author(s):  
Judit Barta ◽  
Jolanda van der Velden ◽  
Nicky M. Boontje ◽  
Ruud Zaremba ◽  
Ger J.M. Stienen
Keyword(s):  
Calcium Sensitivity ◽  
Catalytic Subunit ◽  
Myofilament Calcium Sensitivity
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