Diabetic cardiomyopathy: Mechanisms and new treatment strategies targeting antioxidant signaling pathways

Huynh, Karina; Bernardo, Bianca C.; McMullen, Julie R.; Ritchie, Rebecca H

doi:10.1016/j.pharmthera.2014.01.003

Cited by 476 publications

(523 citation statements)

References 751 publications

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“…In its most severe state, diabetic cardiomyopathy is manifested as a ventricular dilation and decreased cardiac output 3, 4, 39. Consistent with our previous results, diabetic mice exhibited left ventricular enlargement and a drop in LVEF.…”

Section: Discussionsupporting

confidence: 91%

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Melatonin activates Parkin translocation and rescues the impaired mitophagy activity of diabetic cardiomyopathy through Mst1 inhibition

Wang

Zhao

Feng

et al. 2018

J Cellular Molecular Medi

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Mitophagy eliminates dysfunctional mitochondria and thus plays a cardinal role in diabetic cardiomyopathy (DCM). We observed the favourable effects of melatonin on cardiomyocyte mitophagy in mice with DCM and elucidated their underlying mechanisms. Electron microscopy and flow cytometric analysis revealed that melatonin reduced the number of impaired mitochondria in the diabetic heart. Other than decreasing mitochondrial biogenesis, melatonin increased the clearance of dysfunctional mitochondria in mice with DCM. Melatonin increased LC3 II expression as well as the colocalization of mitochondria and lysosomes in HG‐treated cardiomyocytes and the number of typical autophagosomes engulfing mitochondria in the DCM heart. These results indicated that melatonin promoted mitophagy. When probing the mechanism, increased Parkin translocation to the mitochondria may be responsible for the up‐regulated mitophagy exerted by melatonin. Parkin knockout counteracted the beneficial effects of melatonin on the cardiac mitochondrial morphology and bioenergetic disorders, thus abolishing the substantial effects of melatonin on cardiac remodelling with DCM. Furthermore, melatonin inhibited Mammalian sterile 20‐like kinase 1 (Mst1) phosphorylation, thus enhancing Parkin‐mediated mitophagy, which contributed to mitochondrial quality control. In summary, this study confirms that melatonin rescues the impaired mitophagy activity of DCM. The underlying mechanism may be attributed to activation of Parkin translocation via inhibition of Mst1.

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Section: Discussionsupporting

confidence: 91%

“…Diabetic cardiomyopathy accounts for a significant increase of mortality in diabetic patients 2. However, current treatment strategies for cardiomyopathy in diabetic patients are the same as in non‐diabetic patients and do not address the underlying causes of cardiac dysfunction 3, 4…”

Section: Introductionmentioning

confidence: 99%

Melatonin activates Parkin translocation and rescues the impaired mitophagy activity of diabetic cardiomyopathy through Mst1 inhibition

Wang

Zhao

Feng

et al. 2018

J Cellular Molecular Medi

View full text Add to dashboard Cite

show abstract

“…Pathological remodelling of the myocardium in diabetic cardiomyopathy is a well‐known phenomenon and is characterized by fibrosis, hypertrophy, increased nitro‐oxidative stress, and cardiomyocyte apoptosis 3. Hyperglycaemia can directly lead to the accumulation of ROS and to the development of severe nitro‐oxidative stress in DM 3.…”

Section: Discussionmentioning

confidence: 99%

“…Diabetic cardiomyopathy is a distinct disease entity that develops in DM regardless of the presence of coronary artery disease and hypertension 3. Several key processes can be attributed to the development of diabetic cardiomyopathy including myocardial fibrosis, hypertrophy, cardiac (mainly diastolic) dysfunction, increased nitro‐oxidative stress, apoptosis, and inflammation 3…”

Section: Introductionmentioning

confidence: 99%

“…Phosphodiesterase‐5A (PDE5A) is specific for cGMP molecules4 and has been described to be upregulated in different types of HF and in diabetic cardiomyopathy in particular 5, 6. Theoretically, the above‐mentioned upregulation of PDEs coupled with the enhanced nitro‐oxidative stress3 could notably contribute to the impaired cGMP–PKG signalling in the myocardium of HFpEF patients 7, 8…”

Section: Introductionmentioning

confidence: 99%

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Prevention of the development of heart failure with preserved ejection fraction by the phosphodiesterase‐5A inhibitor vardenafil in rats with type 2 diabetes

Mátyás

Németh

Oláh

et al. 2016

European J of Heart Fail

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AimsHeart failure with preserved ejection fraction (HFpEF) has a great epidemiological burden. The pathophysiological role of cyclic guanosine monophosphate (cGMP) signalling has been intensively investigated in HFpEF. Elevated levels of cGMP have been shown to exert cardioprotective effects in various cardiovascular diseases, including diabetic cardiomyopathy. We investigated the effect of long‐term preventive application of the phosphodiesterase‐5A (PDE5A) inhibitor vardenafil in diabetic cardiomyopathy‐associated HFpEF.Methods and resultsZucker diabetic fatty (ZDF) rats were used as a model of HFpEF and ZDF lean rats served as controls. Animals received vehicle or 10 mg/kg body weight vardenafil per os from weeks 7 to 32 of age. Cardiac function, morphology was assessed by left ventricular (LV) pressure–volume analysis and echocardiography at week 32. Cardiomyocyte force measurements were performed. The key markers of cGMP signalling, nitro‐oxidative stress, apoptosis, myocardial hypertrophy and fibrosis were examined. The ZDF animals showed diastolic dysfunction (increased LV/cardiomyocyte stiffness, prolonged LV relaxation time), preserved systolic performance, decreased myocardial cGMP level coupled with impaired protein kinase G (PKG) activity, increased nitro‐oxidative stress, enhanced cardiomyocyte apoptosis, and hypertrophic and fibrotic remodelling of the myocardium. Vardenafil effectively prevented the development of HFpEF by maintaining diastolic function (decreased LV/cardiomyocyte stiffness and LV relaxation time), by restoring cGMP levels and PKG activation, by lowering apoptosis and by alleviating nitro‐oxidative stress, myocardial hypertrophy and fibrotic remodelling.ConclusionsWe report that vardenafil successfully prevented the development of diabetes mellitus‐associated HFpEF. Thus, PDE5A inhibition as a preventive approach might be a promising option in the management of HFpEF patients with diabetes mellitus.

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Novel ASK1 inhibitor AGI‐1067 improves AGE‐induced cardiac dysfunction by inhibiting MKKs/p38 MAPK and NF‐κB apoptotic signaling

et al. 2018

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Heart failure has been identified as one of the clinical manifestations of diabetic cardiovascular complications. Excessive myocardium apoptosis characterizes cardiac dysfunctions, which are correlated with an increased level of advanced glycation end products ( AGE s). In this study, we investigated the participation of reactive oxygen species ( ROS ) and the involvements of apoptosis signal‐regulating kinase 1 ( ASK 1)/mitogen‐activated protein kinase ( MAPK ) kinases ( MKK s)/p38 MAPK and nuclear factor κB ( NF ‐κB) pathways in AGE ‐induced apoptosis‐mediated cardiac dysfunctions. The antioxidant and therapeutic effects of a novel ASK 1 inhibitor, AGI ‐1067, were also studied. Myocardium and isolated primary myocytes were exposed to AGE s and treated with AGI ‐1067. Invasive hemodynamic and echocardiographic assessments were used to evaluate the cardiac functions. ROS formation was evaluated by dihydroethidium fluorescence staining. A terminal deoxynucleotidyl transferase dUTP nick end labelling assay was used to detect the apoptotic cells. ASK 1 and NADPH activities were determined by kinase assays. The association between ASK 1 and thioredoxin 1 (Trx1) was assessed by immunoprecipitation. Western blotting was used to evaluate the phosphorylation and expression levels of proteins. Our results showed that AGE exposure significantly activated ASK 1/ MKK s/p38 MAPK , which led to increased cardiac apoptosis and cardiac impairments. AGI ‐1067 administration inhibited the activation of MKK s/p38 MAPK by inhibiting the disassociation of ASK 1 and Trx1, which suppressed the AGE ‐induced myocyte apoptosis. Moreover, the NF ‐κB activation as well as the ROS generation was inhibited. As a result, cardiac functions were improved. Our findings suggested that AGI ‐1067 recovered AGE ‐induced cardiac dysfunction by blocking both ASK 1/ MKK s/p38 and NF ‐κB apoptotic signaling pathways.

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Diabetic cardiomyopathy: Mechanisms and new treatment strategies targeting antioxidant signaling pathways

Cited by 476 publications

References 751 publications

Melatonin activates Parkin translocation and rescues the impaired mitophagy activity of diabetic cardiomyopathy through Mst1 inhibition

Melatonin activates Parkin translocation and rescues the impaired mitophagy activity of diabetic cardiomyopathy through Mst1 inhibition

Prevention of the development of heart failure with preserved ejection fraction by the phosphodiesterase‐5A inhibitor vardenafil in rats with type 2 diabetes

Novel ASK1 inhibitor AGI‐1067 improves AGE‐induced cardiac dysfunction by inhibiting MKKs/p38 MAPK and NF‐κB apoptotic signaling

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