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Pubblicazioni recenti - diabetic cardiomyopathy
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Heart failure and diabetes: role of ATM.
Curr Opin Pharmacol2020 Jul;54():27-35. doi: S1471-4892(20)30037-0.
Wingard Mary C, Frasier Chad R, Singh Mahipal, Singh Krishna,
Abstract
Heart failure is a leading cause of death in the United States. Diabetes, also known as diabetes mellitus (DM), exponentially increases the risk of heart failure. The increase in oxidative stress and metabolic dysfunction caused by DM can lead to DNA damage and the development of diabetic cardiomyopathy. Ataxia telangiectasia mutated kinase (ATM) is a DNA damage response protein with a primary nuclear function to regulate cell cycle progression in response to double-strand DNA breaks, acts as a redox sensor, and facilitates DNA repair. ATM deficiency associates with the development of insulin resistance and DM. Consequently, patients with Ataxia telangiectasia, a rare autosomal recessive disorder, have an increased risk of developing heart failure. The main objective of this review is to summarize the shared metabolic and cardiac abnormalities associated with DM and ATM deficiency, with a focus on the development of heart failure.
Published by Elsevier Ltd.
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SIRT3 is a downstream target of PPAR-? implicated in high glucose-induced cardiomyocyte injury in AC16 cells.
Exp Ther Med2020 Aug;20(2):1261-1268. doi: 10.3892/etm.2020.8860.
Zong Xiaojuan, Cheng Kuan, Yin Guizhi, Wu Zhaodi, Su Qian, Yu Dong, Liao Pengfei, Hu Wei, Chen Yueguang,
Abstract
Diabetic cardiomyopathy (DCM) is a worldwide public health concern that continues to display rapid growth trends. This study investigated the function of sirtuin 3 (SIRT3), a primary mitochondrial deacetylase with important roles in antioxidant defense and oxidative metabolism, during high glucose-induced cardiomyocyte (AC16 cell) injury. Peroxisome proliferator-activated receptor-? (PPAR-?) is directly related to the occurrence of DCM. Hence, we further examined the relationship between SIRT3 and PPAR-?. AC16 cells were treated with various concentrations of glucose. Relative mRNA expression and protein levels were detected by RT-qPCR and western blot analysis, respectively. Cell proliferation and apoptosis were assessed using CCK8 and Annexin V-FITC apoptosis detection kits, respectively. DCFH-DA assay was used to measure reactive oxygen species (ROS) accumulation. The results indicated that high glucose treatment reduced the expression of mRNA and protein of SIRT3 and PPAR-? in AC16 cells. Moreover, high glucose inhibited cell proliferation, as well as induced apoptosis, intracellular hydrogen peroxide production, and JNK1/2 phosphorylation. These effects were antagonized by SIRT3 overexpression or treatment with the PPAR-? agonist, Wy14643. Conversely, inhibition of SIRT3 via 3-TYP led to similar phenomena as those induced by high glucose treatment in AC16 cells, which were blocked by Wy14643. Lastly, chromatin immunoprecipitation (ChIP) and luciferase assays demonstrated SIRT3 as a direct target of PPAR-?. Taken together, the results provide evidence for an important role of SIRT3 in high glucose-induced cardiomyocyte injury and regulation of JNK1/2 signaling. Further, SIRT3 is a direct downstream target of PPAR-?.
Copyright: © Zong et al.
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Sustaining Circulating Regulatory T Cell Subset Contributes to the Therapeutic Effect of Paroxetine on Mice With Diabetic Cardiomyopathy.
Circ J2020 Aug;():. doi: 10.1253/circj.CJ-19-1182.
Han Yongsheng, Lai Jiacheng, Tao Juan, Tai Yu, Zhou Weijie, Guo Paipai, Wang Zhen, Wang Manman, Wang Qingtong,
Abstract
BACKGROUND:
G protein coupled receptor kinase 2 (GRK2) inhibitor, paroxetine, has been approved to ameliorate diabetic cardiomyopathy (DCM). GRK2 is also involved in regulating T cell functions; the potential modifications of paroxetine on the immune response to DCM is unclear.Methods?and?Results:DCM mouse was induced by high-fat diet (HFD) feeding. A remarkable reduction in the regulatory T (Treg) cell subset in DCM mouse was found by flow cytometry, with impaired cardiac function evaluated by echocardiography. The inhibited Treg differentiation was attributable to insulin chronic stimulation in a GRK2-PI3K-Akt signaling-dependent manner. The selective GRK2 inhibitor, paroxetine, rescued Treg differentiation in vitro and in vivo. Furthermore, heart function, as well as the activation of excitation-contraction coupling proteins such as phospholamban (PLB) and troponin I (TnI) was effectively promoted in paroxetine-treated DCM mice compared with vehicle-treated DCM mice. Blockade of FoxP3 expression sufficiently inhibited the proportion of Treg cells, abolished the protective effect of paroxetine on heart function as well as PLB and TnI activation in HFD-fed mice. Neither paroxetine nor carvedilol could effectively ameliorate the metabolic disorder of HFD mice.
CONCLUSIONS:
The impaired systolic heart function of DCM mice was effectively improved by paroxetine therapy, partially through restoring the population of circulating Treg cells by targeting the GRK2-PI3K-Akt pathway.
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Paradoxical effect of fat diet in matrix metalloproteinases induced mitochondrial dysfunction in diabetic cardiomyopathy.
J Cardiovasc Med (Hagerstown)2020 Jul;():. doi: 10.2459/JCM.0000000000001046.
Gliozzi Micaela, Scarano Federica, Musolino Vincenzo, Carresi Cristina, Scarcella Antonino, Nucera Saverio, Scicchitano Miriam, Ruga Stefano, Bosco Francesca, Maiuolo Jessica, Macrì Roberta, Zito Maria Caterina, Oppedisano Francesca, Guarnieri Lorenza, Mollace Rocco, Palma Ernesto, Muscoli Carolina, Mollace Vincenzo,
Abstract
AIMS:
Diabetic cardiomyopathy represents the main cause of death among diabetic people. Despite this evidence, the molecular mechanisms triggered by impaired glucose and lipid metabolism inducing heart damage remain unclear. The aim of our study was to investigate the effect of altered metabolism on the early stages of cardiac injury in experimental diabetes.
METHODS:
For this purpose, rats were fed a normocaloric diet (NPD) or a high fat diet (HFD) for up to 12 weeks. After the fourth week, streptozocin (35?mg/kg) was administered in a subgroup of both NPD and HFD rats to induce diabetes. Cardiac function was analysed by echocardiography. Matrix metalloproteinases (MMPs) activity and intracellular localization were assessed through zymography and immunofluorescence, whereas apoptotic and oxidative markers by immunohistochemistry and western blot.
RESULTS:
Hyperglycaemia or hyperlipidaemia reduced ejection fraction and fractional shortening as compared with control. Unexpectedly, cardiac dysfunction was less marked in diabetic rats fed a hyperlipidaemic diet, suggesting an adaptive response of the myocardium to hyperglycaemia-induced injury. This response was characterized by the inhibition of N-terminal truncated-MMP-2 translocation from endoplasmic reticulum into mitochondria and by superoxide anion overproduction observed in cardiomyocytes under hyperglycaemia.
CONCLUSION:
Overall, these findings suggest novel therapeutic targets aimed to counteract mitochondrial dysfunction in the onset of diabetic cardiomyopathy.
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Diabetic Cardiomyopathy: From Mechanism to Management in a Nutshell.
Endocr Metab Immune Disord Drug Targets2020 Jul;():. doi: 10.2174/1871530320666200731174724.
Khan Shahzad, Ahmad Syed S, Kamal Mohammad A,
Abstract
Diabetic cardiomyopathy (DCM) is a significant complication of diabetes mellitus characterized by gradual failing heart with detrimental cardiac remodellings such as fibrosis and diastolic and systolic dysfunction, which is not directly attributable to coronary artery disease. Insulin resistance and resulting hyperglycemia is the main trigger involved in the initiation of diabetic cardiomyopathy. There is a constellation of many pathophysiological events such as lipotoxicity, oxidative stress, inflammation, inappropriate activation of the renin-angiotensin-aldosterone system, dysfunctional immune modulation promoting increased rate of cardiac cell injury, apoptosis, and necrosis which ultimately culminates into interstitial fibrosis, cardiac stiffness, diastolic dysfunction initially and later systolic dysfunction too. These events finally lead to clinical heart failure of DCM. Herein, we have briefly discussed the pathophysiology of DCM. We have also briefly mentioned potential therapeutic strategies currently used for DCM.
Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.
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Silencing of peroxisome proliferator-activated receptor-alpha alleviates myocardial injury in diabetic cardiomyopathy by downregulating 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2 expression.
IUBMB Life2020 Jul;():. doi: 10.1002/iub.2337.
Wang Li, Bi Xintong, Han Jiarui,
Abstract
Diabetic cardiomyopathy (DCM) is a cardiac disorder, which affects around 12% diabetic patients, resulting in overt heart death. Our initial bioinformatic analysis identified the differentially expressed gene 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2 (HMGCS2) in DCM, which may be activated by peroxisome proliferator-activated receptor-alpha (PPAR?) based on previous evidence. Therefore, the present study aims to explore the effect of PPAR? on the development of DCM through regulating HMGCS2. The expression of PPAR? and HMGCS2 was detected by reverse transcription quantitative polymerase chain reaction in cardiomyocytes and high-glucose-cultured cardiomyocytes. The proliferation and apoptosis of cardiomyocytes were examined by 5-ethynyl-2'-deoxyuridine assay and flow cytometry, separately. Mitoehondrial membrane potential (MMP) and intracellular reactive oxygen species (ROS) levels were determined. Then, the protein levels of B-cell lymphoma 2, Bcl-2-associated X protein, and cleaved Caspase-3 were detected by Western blot analysis. The myocardial apoptosis index, heart weight, and serum lipids of rats were examined. At last, the expressions of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), transforming growth factor ?1 (TGF?1), peroxisome proliferator activator receptor gamma coactivator-1 alpha (PGC1?), nuclear respiratory factor (NRF)-1, NRF-2, NAD(P)H oxidase 1, and superoxide dismutase-1 were examined. HMGCS2 was the most differentially expressed gene in DCM. The levels of HMGCS2 and PPAR? were upregulated in patients with DCM. HMGCS2 silencing was shown to inhibit HMGCS2 expression to suppress the apoptosis of high-glucose-induced cardiomyocytes and the loss of MMP, reduce the accumulation of ROS, and promote cardiomyocyte proliferation. Silencing of HMGCS2 and PPAR? alleviated myocardial injury, decreased blood glucose, and lipid in DCM rats, downregulated the expression of ANP, BNP, and TGF?1 to reduce myocardial injury, and elevated PGC1?, NRF-1, and NRF-2 levels to enhance oxidative stress levels. Our results demonstrated that silencing of PPAR? could alleviate cardiomyocyte injury and oxidative stress via a mechanism related to the downregulation of HMGCS2, which could provide a novel target for DCM treatment.
© 2020 International Union of Biochemistry and Molecular Biology.
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Syringaresinol Protects against Type 1 Diabetic Cardiomyopathy by Alleviating Inflammation Responses, Cardiac Fibrosis and Oxidative Stress.
Mol Nutr Food Res2020 Jul;():e2000231. doi: 10.1002/mnfr.202000231.
Li Guangru, Yang Lei, Feng Lifeng, Yang Jiu, Li Yafei, An Jiale, Li Dihua, Xu Yang, Gao Yang, Li Jing, Liu Jie, Yang Liang, Qi Zhi,
Abstract
BACKGROUND:
Syringaresinol (SYR) is a phenolic compound, which could be found in various cereals and medicinal plants. It exerts both anti-inflammatory and antioxidant pharmacological properties. However, little is known about the effect of SYR on modulating diabetic cardiomyopathy. The present study aimed to investigate the pharmacodynamic effect of SYR on diabetic cardiomyopathy and the underlying molecular mechanism.
METHODS AND RESULTS:
In STZ-induced type 1 diabetic mice, orally administration with SYR in every other day for 8 weeks significantly improved cardiac dysfunction and prevented cardiac hypertrophy and fibrosis. The macrophage infiltration and oxidative stress biomarkers were also suppressed by SYR distinctly without affecting hyperglycemia and body weight. In neonatal cardiomyocytes, high glucose-induced cell apoptosis and fibrosis were potently decreased by SYR, and the inflammatory response and oxidant stress were also alleviated by SYR incubation. Mechanistically, SYR may exert its protective effects by restoring suppression of antioxidant Keap1/Nrf2 system and abnormal activation of TGF-?/Smad signaling pathway both in vitro and in vivo.
CONCLUSION:
The results indicated that SYR could be a potential therapeutic agent for the treatment of diabetic cardiomyopathy by inhibiting inflammation, fibrosis and oxidative stress. The signaling pathway of Keap1/Nrf2 and TGF-?/Smad could be used as therapeutic targets for diabetic complications. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
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Tom70 protects against diabetic cardiomyopathy through its antioxidant and antiapoptotic properties.
Hypertens Res2020 Jul;():. doi: 10.1038/s41440-020-0518-x.
Wang Peijian, Wang Dan, Yang Yi, Hou Jixin, Wan Jindong, Ran Fei, Dai Xiaozhen, Zhou Peng, Yang Yongjian,
Abstract
Mitochondrial dysfunction plays a critical role in the pathogenesis of diabetic cardiomyopathy. Translocase of mitochondrial outer membrane 70 (Tom70) primarily facilitates the import of mitochondrial preproteins that may be involved in the regulation of oxidative stress and mitochondrial function. This study aimed to investigate the role of Tom70 in the development of myocardial injury in leptin receptor-deficient (db/db) diabetic mice. Tom70 siRNA or an overexpressing lentivirus was intramuscularly injected into mouse hearts or used to treat cultured neonatal cardiomyocytes. We found that Tom70 was downregulated in the diabetic hearts compared with the level in the wild-type hearts and that knocking down Tom70 exacerbated cardiac hypertrophy, fibrosis, and ventricular dysfunction in the db/db mice. Similarly, the in vitro data demonstrated that silencing Tom70 enhanced high-glucose and high-fat (HGHF) medium treatment-induced mitochondrial superoxide production, decreased ATP production and the mitochondrial membrane potential, and enhanced cell apoptosis in neonatal cardiomyocytes. Importantly, overexpression of Tom70 alleviated HGHF medium-induced oxidative stress, mitochondrial dysfunction, and cell apoptosis. Furthermore, in vivo data confirmed that reconstitution of Tom70 ameliorated cardiac hypertrophy, interstitial fibrosis, and ventricular dysfunction in the db/db mice. In addition, Tom70 overexpression mitigated mitochondrial fragmentation and dysfunction in the hearts of the db/db mice. Taken together, these findings suggest that downregulation of Tom70 contributes to the development of diabetic cardiomyopathy and that reconstitution of Tom70 may be a new therapeutic strategy for the prevention and treatment of diabetic cardiomyopathy.
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Value of circulating miRNA-21 in the diagnosis of subclinical diabetic cardiomyopathy.
Mol Cell Endocrinol2020 Jul;():110944. doi: S0303-7207(20)30244-6.
Tao Lichan, Huang Xiaoli, Xu Min, Qin Zihan, Zhang Feifei, Hua Fei, Jiang Xiaohong, Wang Yuetao,
Abstract
BACKGROUND:
Diabetic cardiomyopathy (DCM) is a type of cardiac dysfunction that affects approximately 12% of diabetic patients, ultimately leading to heart failure or even death. However, there is currently no efficient or specific biomarker for DCM diagnosis.
METHODS:
A total of 266 subjects with type II diabetes (T2DM) were enrolled in this study and were divided into the T2DM with cardiac dysfunction (DCM) group and T2DM without cardiac dysfunction (non-DCM) group. The diagnostic efficacy of miR-21 was determined and compared with that of serum hemoglobin A1c% (HbA1c%). Db/db mice and H9c2 cells stimulated with high glucose (HG)/high fatty acid (PA) were used as in vivo and in vitro models of DCM, respectively.
RESULTS:
Through echocardiography and gated-myocardial perfusion imaging (gated-MPI), 49 patients were selected to be enrolled in the DCM group, with 49 matched controls in the non-DCM group. The circulating miR-21 levels were significantly decreased in the DCM group compared to the non-DCM group (P?
CONCLUSIONS:
Our findings identify circulating miR-21 as a novel biomarker in the diagnosis of DCM and provide an underlying mechanism for miRNA-based therapy for the treatment of DCM.
TRIAL REGISTRATION:
The study was approved by the Ethics Committee of the Third Affiliated Hospital of Soochow University and has been registered in the Chinese Clinical Trial Registry (ChiCTR1900027080).
Copyright © 2020. Published by Elsevier B.V.
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Activation of calcium?sensing receptor?mediated autophagy in high glucose?induced cardiac fibrosis in vitro.
Mol Med Rep2020 Sep;22(3):2021-2031. doi: 10.3892/mmr.2020.11277.
Yuan Hui, Xu Jiyu, Zhu Yanfei, Li Li, Wang Qi, Yu Yaquan, Zhou Bin, Liu Yi, Xu Xiaoyi, Wang Zhilong,
Abstract
Myocardial fibrosis is a major complication of diabetic cardiomyopathy (DCM) that is primarily caused by cardiac fibroblasts that are highly activated by persistent hyperglycemic stimulation, resulting in excessive collagen deposition. Calcium sensing receptor (CaSR) is a member of the G protein?coupled receptor superfamily and regulates intracellular calcium concentrations, which are associated with numerous diseases, including myocardial infarction, tumors and pulmonary hypertension. However, whether CaSR participates in the pathological process of myocardial fibrosis in DCM remains unknown. The present study aimed to investigate the mechanism via which CaSR regulates high glucose (HG)?induced cardiac fibrosis in vitro. HG treated?cardiac fibroblast (CFs) were used and western blotting, immunoprecipitation, Cell Counting Kit?8 assay, ELISA and transfection technology were performed to examine the role of CaSR. In the HG group, treatment with HG increased CaSR, ??smooth muscle actin, collagen I/III and matrix metalloproteinase 2/9 expression and enhanced autophagosome generation and CF proliferation. Furthermore, CaSR activation upregulated the expression of Smad ubiquitin regulatory factor 2 (Smurf2), which led to increased intracellular Ca2+ concentrations, increased ubiquitination levels of SKI like proto?oncogene and Smad7 and autophagy activation. Furthermore, the CaSR agonist (R568) or the CaSR inhibitor (Calhex231) and Smurf2?small interfering RNA promoted or inhibited HG?induced alterations, including the enhanced and weakened effects, respectively. Taken together, the results from the present study suggested that increased CaSR expression in CFs activated the Smurf2?ubiquitin proteasome and autophagy, causing excessive CF proliferation and extensive collagen deposition, which resulted in HG?induced myocardial fibrosis. These findings indicated a novel pathogenesis of DCM and may provide a novel strategy for the diagnosis and treatment of DCM.
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Expression profiling of circular RNAs and their potential role in early?stage diabetic cardiomyopathy.
Mol Med Rep2020 Sep;22(3):1958-1968. doi: 10.3892/mmr.2020.11248.
Dong Shengzhong, Tu Chunyan, Ye Xing, Li Liliang, Zhang Mingchang, Xue Aimin, Chen Shangheng, Zhao Ziqin, Cong Bin, Lin Junyi, Shen Yiwen,
Abstract
Diabetic cardiomyopathy (DCM) is a severe cardiovascular complication of diabetes mellitus (DM). Detecting DCM during the early stages of the disease remains a challenge, as the molecular mechanisms underlying early?stage DCM are not clearly understood. Circular RNA (circRNA), a type of non?coding RNA, has been confirmed to be associated with numerous diseases. However, it is still unclear how circRNAs are involved in early?stage DCM. In the present study, heart tissues harvested from BKS?db/db knock?out mice were identified through high?throughput RNA sequencing technology. A total of 58 significantly differentially expressed circRNAs were identified in the db/db sample. Among these, six upregulated circRNAs and seven downregulated circRNAs were detected by reverse transcription?quantitative PCR and analyzed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. Furthermore, based on the predicted binding site with microRNAs (miRNAs) involved in DCM, five circRNAs (mmu_circ_0000652, mmu_circ_0000547, mmu_circ_0001058, mmu_circ_0000680 and novel_circ_0004285) were shown to serve as competing endogenous (ce)RNAs. The corresponding miRNAs and mRNAs of the ceRNAs were also verified, and two promising circRNA?miRNA?mRNA regulatory networks were determined. Finally, internal ribosome entry site prediction combined with open reading frame prediction indicated that it was highly possible that mmu_circ_0001160 encoded a protein. In the present study, a comprehensive analysis of the circRNA expression profile during the early phase of DCM was performed, and two promising circRNA?miRNA?mRNA regulatory networks were identified. These results lay the foundation for unravelling the underlying pathogenesis of DCM, and highlight potential biomarkers and therapeutic targets for the treatment of DCM at an early stage.
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Identification of potential biomarkers for predicting the early onset of diabetic cardiomyopathy in a mouse model.
Sci Rep2020 Jul;10(1):12352. doi: 10.1038/s41598-020-69254-x.
Johnson Rabia, Nxele Xolisa, Cour Martin, Sangweni Nonhlakanipho, Jooste Tracey, Hadebe Nkanyiso, Samodien Ebrahim, Benjeddou Mongi, Mazino Mikateko, Louw Johan, Lecour Sandrine,
Abstract
Type 2 diabetes (T2D) is characterized by metabolic derangements that cause a shift in substrate preference, inducing cardiac interstitial fibrosis. Interstitial fibrosis plays a key role in aggravating left ventricular diastolic dysfunction (LVDD), which has previously been associated with the asymptomatic onset of heart failure. The latter is responsible for 80% of deaths among diabetic patients and has been termed diabetic cardiomyopathy (DCM). Through in silico prediction and subsequent detection in a leptin receptor-deficient db/db mice model (db/db), we confirmed the presence of previously identified potential biomarkers to detect the early onset of DCM. Differential expression of Lysyl Oxidase Like 2 (LOXL2) and Electron Transfer Flavoprotein Beta Subunit (ETF?), in both serum and heart tissue of 6-16-week-old db/db mice, correlated with a reduced left-ventricular diastolic dysfunction as assessed by high-resolution Doppler echocardiography. Principal component analysis of the combined biomarkers, LOXL2 and ETF?, further displayed a significant difference between wild type and db/db mice from as early as 9 weeks of age. Knockdown in H9c2 cells, utilising siRNA of either LOXL2 or ETF?, revealed a decrease in the expression of Collagen Type I Alpha1 (COL1A1), a marker known to contribute to enhanced myocardial fibrosis. Additionally, receiver-operating curve (ROC) analysis of the proposed diagnostic profile showed that the combination of LOXL2 and ETF? resulted in an area under the curve (AUC) of 0.813, with a cut-off point of 0.824, thus suggesting the favorable positive predictive power of the model and further supporting the use of LOXL2 and ETF? as possible early predictive DCM biomarkers.
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BH4 activates CaMKK2 and rescues the cardiomyopathic phenotype in rodent models of diabetes.
Life Sci Alliance2020 Sep;3(9):. doi: e201900619.
Kim Hyoung Kyu, Ko Tae Hee, Song In-Sung, Jeong Yu Jeong, Heo Hye Jin, Jeong Seung Hun, Kim Min, Park Nam Mi, Seo Dae Yun, Kha Pham Trong, Kim Sun-Woo, Lee Sung Ryul, Cho Sung Woo, Won Jong Chul, Youm Jae Boum, Ko Kyung Soo, Rhee Byoung Doo, Kim Nari, Cho Kyoung Im, Shimizu Ippei, Minamino Tohru, Ha Nam-Chul, Park Young Shik, Nilius Bernd, Han Jin,
Abstract
Diabetic cardiomyopathy (DCM) is a major cause of mortality/morbidity in diabetes mellitus patients. Although tetrahydrobiopterin (BH4) shows therapeutic potential as an endogenous cardiovascular target, its effect on myocardial cells and mitochondria in DCM and the underlying mechanisms remain unknown. Here, we determined the involvement of BH4 deficiency in DCM and the therapeutic potential of BH4 supplementation in a rodent DCM model. We observed a decreased BH4:total biopterin ratio in heart and mitochondria accompanied by cardiac remodeling, lower cardiac contractility, and mitochondrial dysfunction. Prolonged BH4 supplementation improved cardiac function, corrected morphological abnormalities in cardiac muscle, and increased mitochondrial activity. Proteomics analysis revealed oxidative phosphorylation (OXPHOS) as the BH4-targeted biological pathway in diabetic hearts as well as BH4-mediated rescue of down-regulated peroxisome proliferator-activated receptor-? coactivator 1-? (PGC-1?) signaling as a key modulator of OXPHOS and mitochondrial biogenesis. Mechanistically, BH4 bound to calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) and activated downstream AMP-activated protein kinase/cAMP response element binding protein/PGC-1? signaling to rescue mitochondrial and cardiac dysfunction in DCM. These results suggest BH4 as a novel endogenous activator of CaMKK2.
© 2020 Kim et al.
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Ca-Dependent NOX5 (NADPH Oxidase 5) Exaggerates Cardiac Hypertrophy Through Reactive Oxygen Species Production.
Hypertension2020 Jul;():HYPERTENSIONAHA12015558. doi: 10.1161/HYPERTENSIONAHA.120.15558.
Zhao Guo-Jun, Zhao Chang-Ling, Ouyang Shan, Deng Ke-Qiong, Zhu Lihua, Montezano Augusto C, Zhang Changjiang, Hu Fengjiao, Zhu Xue-Yong, Tian Song, Liu Xiaolan, Ji Yan-Xiao, Zhang Peng, Zhang Xiao-Jing, She Zhi-Gang, Touyz Rhian M, Li Hongliang,
Abstract
NOX5 (NADPH oxidase 5) is a homolog of the gp91 subunit of the phagocyte NOX, which generates reactive oxygen species. NOX5 is involved in sperm motility and vascular contraction and has been implicated in diabetic nephropathy, atherosclerosis, and stroke. The function of NOX5 in the cardiac hypertrophy is unknown. Because NOX5 is a Ca-sensitive, procontractile NOX isoform, we questioned whether it plays a role in cardiac hypertrophy. Studies were performed in (1) cardiac tissue from patients undergoing heart transplant for cardiomyopathy and heart failure, (2) NOX5-expressing rat cardiomyocytes, and (3) mice expressing human NOX5 in a cardiomyocyte-specific manner. Cardiac hypertrophy was induced in mice by transverse aorta coarctation and Ang II (angiotensin II) infusion. NOX5 expression was increased in human failing hearts. Rat cardiomyocytes infected with adenoviral vector encoding human NOX5 cDNA exhibited elevated reactive oxygen species levels with significant enlargement and associated increased expression of ANP (atrial natriuretic peptides) and ?-MHC (?-myosin heavy chain) and prohypertrophic genes (, , and ) under Ang II stimulation. These effects were reduced by N-acetylcysteine and diltiazem. Pressure overload and Ang II infusion induced left ventricular hypertrophy, interstitial fibrosis, and contractile dysfunction, responses that were exaggerated in cardiac-specific trangenic mice. These phenomena were associated with increased reactive oxygen species levels and activation of redox-sensitive MAPK (mitogen-activated protein kinase). N-acetylcysteine treatment reduced cardiac oxidative stress and attenuated cardiac hypertrophy in trangenic. Our study defines Ca-regulated NOX5 as an important NOX isoform involved in oxidative stress- and MAPK-mediated cardiac hypertrophy and contractile dysfunction.
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Palmitate-induced toxicity is associated with impaired mitochondrial respiration and accelerated oxidative stress in cultured cardiomyocytes: The critical role of coenzyme Q.
Toxicol In Vitro2020 Jul;68():104948. doi: S0887-2333(20)30498-7.
Dludla Phiwayinkosi V, Silvestri Sonia, Orlando Patrick, Mazibuko-Mbeje Sithandiwe E, Johnson Rabia, Marcheggiani Fabio, Cirilli Ilenia, Muller Christo J F, Louw Johan, Chellan Nireshni, Obonye Nnini, Nkambule Bongani B, Tiano Luca,
Abstract
Impaired mitochondrial function concomitant to enhanced oxidative stress-induced damage are well established mechanisms involved in hyperlipidemia-induced cardiotoxicity. Currently, limited information is available on the direct effect of myocardial lipid overload on endogenous coenzyme Q (CoQ) levels in association with mitochondrial respiration and oxidative stress status. Here, such effects were explored by exposing H9c2 cardiomyocytes to various doses (0.15 to 1 mM) of palmitate for 24 h. The results demonstrated that palmitate doses ?0.25 mM are enough to impair mitochondrial respiration and cause oxidative stress. Although endogenous CoQ levels are enhanced by palmitate doses ?0.5 mM, this is not enough to counteract oxidative stress, but is sufficient to maintain cell viability of cardiomyocytes. Palmitate doses >0.5 mM caused severe mitochondrial toxicity, including reduction of cell viability. Interestingly, enhancement of CoQ levels with the lowest dose of palmitate (0.15 mM) was accompanied by a significantly reduction of CoQ oxidation status, as well as low cytosolic production of reactive oxygen species. From the overall findings, it appears that CoQ response may be crucial to improve mitochondrial function in conditions linked to hyperlipidemia-induced insult. Confirmation of such findings in relevant in vivo models remains essential to better understand the cardioprotective effects in association with improving endogenous CoQ content.
Copyright © 2020 Elsevier Ltd. All rights reserved.
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The Mitochondria: A Target of Polyphenols in the Treatment of Diabetic Cardiomyopathy.
Int J Mol Sci2020 Jul;21(14):. doi: E4962.
Bhagani Humna, Nasser Suzanne A, Dakroub Ali, El-Yazbi Ahmed F, Eid Assaad A, Kobeissy Firas, Pintus Gianfranco, Eid Ali H,
Abstract
Diabetic cardiomyopathy (DCM) is a constellation of symptoms consisting of ventricular dysfunction and cardiomyocyte disarray in the presence of diabetes. The exact cause of this type of cardiomyopathy is still unknown; however, several processes involving the mitochondria, such as lipid and glucose metabolism, reactive oxygen species (ROS) production, apoptosis, autophagy and mitochondrial biogenesis have been implicated. In addition, polyphenols have been shown to improve the progression of diabetes. In this review, we discuss some of the mechanisms by which polyphenols, particularly resveratrol, play a role in slowing the progression of DCM. The most important intermediates by which polyphenols exert their protective effect include Bcl-2, UCP2, SIRT-1, AMPK and JNK1. Bcl-2 acts to attenuate apoptosis, UCP2 decreases oxidative stress, SIRT-1 increases mitochondrial biogenesis and decreases oxidative stress, AMPK increases autophagy, and JNK1 decreases apoptosis and increases autophagy. Our dissection of these molecular players aims to provide potential therapeutic targets for the treatment of DCM.
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Examining the Relationship and Prognostic Implication of Diabetic Status and Extracellular Matrix Expansion by Cardiac Magnetic Resonance.
Circ Cardiovasc Imaging2020 Jul;13(7):e011000. doi: 10.1161/CIRCIMAGING.120.011000.
Khan Mohammad A, Yang Eric Y, Nguyen Duc T, Nabi Faisal, Hinojosa Jeremy, Jabel Maria, Nagueh Sherif F, Graviss Edward A, Shah Dipan J,
Abstract
BACKGROUND:
Although not fully understood, diabetes mellitus is thought to be associated with cardiac fibrosis and stiffness due to alteration of myocardial extracellular matrix. Newer cardiac magnetic resonance techniques may be able to identify extracellular matrix expansion by measuring extracellular volume fraction (ECV). We used cardiac magnetic resonance to evaluate the association of alteration in the extracellular matrix with diabetic status and its implications on incident heart failure events and all-cause mortality.
METHODS:
We studied 442 patients who underwent comprehensive contrast cardiac magnetic resonance to assess cardiac morphology and function, left ventricular replacement fibrosis, and pre-post contrast T1 mapping to quantify ECV. The cohort did not have coexisting pathologies associated with ECV alteration. We categorized our final cohort based on diabetic status using criteria from the American Diabetic Association. Subsequent heart failure hospitalization and all-cause death were ascertained.
RESULTS:
Our patients were predominantly white with a median age of 57 with 48% being men. Compared with nondiabetes mellitus, diabetes mellitus was significantly associated with elevated ECV after adjusting for clinical and imaging covariates: ? coefficient 1.33 (95% CI, 0.22-2.44); =0.02. Over a median follow-up of 24.5 (interquartile range, 14.8-33.4) months, 52 deaths and 24 heart failure events occurred. Patients with diabetes mellitus and elevated ECV had the worst outcomes compared with patients with diabetes mellitus and normal ECV or nondiabetics. Elevated ECV remained an independent predictor of outcomes (hazard ratio, 3.31 [95% CI, 1.93-5.67]; <0.001) after adjusting for covariates.
CONCLUSIONS:
Elevated ECV is an independent predictor of mortality among patients with diabetes mellitus and may have an additive effect with diabetes mellitus on outcomes. ECV may represent a novel noninvasive biomarker to evaluate severity of diabetic heart disease.
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Autophagy, Myocarditis, and Cardiomyopathy.
Adv Exp Med Biol2020 ;1207():229-235. doi: 10.1007/978-981-15-4272-5_17.
Du Jie, Liu Yan, Fu Jintao,
Abstract
Direct damage and immune responses after viral infection lead to myocarditis. Autophagy is involved in both viral clearance and replication. In this chapter, we will briefly describe the role of autophagy in viral myocarditis. In addition, we will discuss the role of autophagy in dilated cardiomyopathy, hypertrophic cardiomyopathy, and diabetic cardiomyopathy.
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Effects of diabetes on nitric oxide synthase in rat uterus.
Biotech Histochem2020 Jul;():1-8. doi: 10.1080/10520295.2020.1788161.
Karabulut Derya, Sonmez Mehmet Fatih,
Abstract
Diabetes mellitus (DM) is a common metabolic disorder with complications including nephropathy, cardiomyopathy, neuropathy and infertility. We investigated nitric oxide synthase (NOS) expression in uterine tissue of diabetic rats. The rats were assigned randomly to four groups of ten: group C, control; group 1, diabetic for 1 month; group 2, diabetic for 2 months; group 3, diabetic for 3 months. DM was induced by streptozotocin injection. nNOS, iNOS, eNOS expressions and TUNEL staining were assessed in uterine tissue and luteinizing hormone (LH), follicle stimulating hormone (FSH) and estrogen were measured in blood samples. The uterine epithelium, connective tissue of the endometrium, myometrium wall thickness and number of apoptotic cells were decreased in groups 1 - 3 compared to group C. nNOS and eNOS expression was increased in diabetic groups, but iNOS expression was similar to group 1. FSH was increased in group 2, but serum LH and estrogen levels were unchanged among groups. DM damages uterine tissue, and NOS, especially nNOS and eNOS, contributes to this damage.
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Differential effect of cardiac resynchronization therapy in patients with diabetes mellitus: a long-term retrospective cohort study.
ESC Heart Fail2020 Jul;():. doi: 10.1002/ehf2.12876.
Kahr Peter C, Trenson Sander, Schindler Matthias, Kuster Joël, Kaufmann Philippe, Tonko Johanna, Hofer Daniel, Inderbitzin Devdas T, Breitenstein Alexander, Saguner Ardan M, Flammer Andreas J, Ruschitzka Frank, Steffel Jan, Winnik Stephan,
Abstract
AIMS:
Cardiac resynchronization therapy (CRT) has become an important therapy in patients with heart failure with reduced left ventricular ejection fraction (LVEF). The effect of diabetes on long-term outcome in these patients is controversial. We assessed the effect of diabetes on long-term outcome in CRT patients and investigated the role of diabetes in ischaemic and non-ischaemic cardiomyopathy.
METHODS AND RESULTS:
All patients undergoing CRT implantation at our institution between November 2000 and January 2015 were enrolled. The study endpoints were (i) a composite of ventricular assist device (VAD) implantation, heart transplantation, or all-cause mortality; and (ii) reverse remodelling (improvement of LVEF ? 10% or reduction of left ventricular end-systolic volume ? 15%). Median follow-up of the 418 patients (age 64.6 ± 11.6 years, 22.5% female, 25.1% diabetes) was 4.8 years [inter-quartile range: 2.8;7.4]. Diabetic patients had an increased risk to reach the composite endpoint [adjusted hazard ratio (aHR) 1.48 [95% CI 1.12-2.16], P = 0.041]. Other factors associated with an increased risk to reach the composite endpoint were a lower body mass index or baseline LVEF (aHR 0.95 [0.91; 0.98] and 0.97 [0.95; 0.99], P < 0.01 each), and a higher New York Heart Association functional class or creatinine level (aHR 2.14 [1.38; 3.30] and 1.04 [1.01; 1.05], P < 0.05 each). Early response to CRT, defined as LVEF improvement ? 10%, was associated with a lower risk to reach the composite endpoint (aHR 0.60 [0.40; 0.89], P = 0.011). Reverse remodelling did not differ between diabetic and non-diabetic patients with respect to LVEF improvement ? 10% (aHR 0.60 [0.32; 1.14], P = 0.118). However, diabetes was associated with decreased reverse remodelling with respect to a reduction of left ventricular end-systolic volume ? 15% (aHR 0.45 [0.21; 0.97], P = 0.043). In patients with ischaemic cardiomyopathy, survival rates were not significantly different between diabetic and non-diabetic patients (HR 1.28 [0.83-1.97], P = 0.101), whereas in patients with non-ischaemic cardiomyopathy, diabetic patients had a higher risk of reaching the composite endpoint (HR 1.65 [1.06-2.58], P = 0.027). The latter effect was dependent on other risk factors (aHR 1.47 [0.83-2.61], P = 0.451). The risk of insulin-dependent patients was not significantly higher than in patients under oral antidiabetic drugs (HR 1.55 [95% CI 0.92-2.61], P = 0.102).
CONCLUSIONS:
Long-term follow-up revealed diabetes mellitus as independent risk factor for all-cause mortality, heart transplantation, or VAD in heart failure patients undergoing CRT. The detrimental effect of diabetes appeared to weigh heavier in patients with non-ischaemic compared with ischaemic cardiomyopathy.
© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.
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