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Pubblicazioni recenti - diabetic cardiomyopathy
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Effect of Selenium Nanoparticles and/or Bee Venom against STZ-Induced Diabetic Cardiomyopathy and Nephropathy.
Metabolites2023 Mar;13(3):. doi: 400.
Lotfy Mona M, Dowidar Mohamed F, Ali Haytham A, Ghonimi Wael A M, Al-Farga Ammar, Ahmed Amany I,
Abstract
The main purpose of our study was to examine the role of selenium nanoparticles (SeNPs) and/or bee venom (BV) in ameliorating diabetic cardiomyopathy (DCM) and nephropathy (DN) at the biochemical, histopathological and molecular levels. Fifty male albino rats were used in this experiment, divided into five groups: control, Streptozocin (STZ) diabetic, STZ-diabetic treated with SeNPs, STZ-diabetic treated with BV, and STZ-diabetic treated with SeNPs and BV. Biochemically, STZ injection resulted in a significant increase in serum glucose, BUN, creatinine, CRP, CK-MB, AST, LDH and cardiac troponins with a significant decrease in the serum insulin and albumin concentrations. Histopathologically, STZ injection resulted in diabetes, as revealed by glomerulonephritis, perivascular hemorrhage, inflammatory cell infiltrations and fibrosis, with widening of interstitial spaces of cardiomyocytes, loss of muscle cells continuity and some hyaline degeneration. At the molecular levels, the expression levels of miRNA 328, miRNA-21, TGF?1, TGF?1R, JAK1, STST-3, SMAD-1 and NF?? genes were significantly up-regulated, whereas the expression levels of SMAD-7 were significantly down-regulated. It is concluded that SeNPs and/or BV administration ameliorates the deleterious effects resulting from STZ administration through improving the biochemical, histopathological and molecular effects, suggesting their protective role against the long-term diabetic complications of DCM and DN.
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Embryonic Hyperglycemia Disrupts Myocardial Growth, Morphological Development, and Cellular Organization: An In Vivo Experimental Study.
Life (Basel)2023 Mar;13(3):. doi: 768.
Jaime-Cruz Ricardo, Sánchez-Gómez Concepción, Villavicencio-Guzmán Laura, Lazzarini-Lechuga Roberto, Patiño-Morales Carlos César, García-Lorenzana Mario, Ramírez-Fuentes Tania Cristina, Salazar-García Marcela,
Abstract
Hyperglycemia during gestation can disrupt fetal heart development and increase postnatal cardiovascular disease risk. It is therefore imperative to identify early biomarkers of hyperglycemia during gestation-induced fetal heart damage and elucidate the underlying molecular pathomechanisms. Clinical investigations of diabetic adults with heart dysfunction and transgenic mouse studies have revealed that overexpression or increased expression of TNNI3K, a heart-specific kinase that binds troponin cardiac I, may contribute to abnormal cardiac remodeling, ventricular hypertrophy, and heart failure. Optimal heart function also depends on the precise organization of contractile and excitable tissues conferred by intercellular occlusive, adherent, and communicating junctions. The current study evaluated changes in embryonic heart development and the expression levels of sarcomeric proteins (troponin I, desmin, and TNNI3K), junctional proteins, glucose transporter-1, and Ki-67 under fetal hyperglycemia. Stage 22HH embryos were randomly divided into two groups: a hyperglycemia (HG) group, in which individual embryos were injected with 30 mmol/L glucose solution every 24 h for 10 days, and a no-treatment (NT) control group, in which individual embryos were injected with physiological saline every 24 h for 10 days (stage 36HH). Embryonic blood glucose, height, and weight, as well as heart size, were measured periodically during treatment, followed by histopathological analysis and estimation of sarcomeric and junctional protein expression by western blotting and immunostaining. Hyperglycemic embryos demonstrated delayed heart maturation, with histopathological analysis revealing reduced left and right ventricular wall thickness (-39% and -35% vs. NT). Immunoexpression levels of TNNI3K and troponin 1 increased (by 37% and 39%, respectively), and desmin immunofluorescence reduced (by 23%). Embryo-fetal hyperglycemia may trigger an increase in the expression levels of TNNI3K and troponin I, as well as dysfunction of occlusive and adherent junctions, ultimately inducing abnormal cardiac remodeling.
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Emerging Therapy for Diabetic Cardiomyopathy: From Molecular Mechanism to Clinical Practice.
Biomedicines2023 Feb;11(3):. doi: 662.
Hsuan Chin-Feng, Teng Sean I F, Hsu Chih-Neng, Liao Daniel, Chang Allen Jiun-Wei, Lee Hsiao-Lin, Hee Siow-Wey, Chang Yi-Cheng, Chuang Lee-Ming,
Abstract
Diabetic cardiomyopathy is characterized by abnormal myocardial structure or performance in the absence of coronary artery disease or significant valvular heart disease in patients with diabetes mellitus. The spectrum of diabetic cardiomyopathy ranges from subtle myocardial changes to myocardial fibrosis and diastolic function and finally to symptomatic heart failure. Except for sodium-glucose transport protein 2 inhibitors and possibly bariatric and metabolic surgery, there is currently no specific treatment for this distinct disease entity in patients with diabetes. The molecular mechanism of diabetic cardiomyopathy includes impaired nutrient-sensing signaling, dysregulated autophagy, impaired mitochondrial energetics, altered fuel utilization, oxidative stress and lipid peroxidation, advanced glycation end-products, inflammation, impaired calcium homeostasis, abnormal endothelial function and nitric oxide production, aberrant epidermal growth factor receptor signaling, the activation of the renin-angiotensin-aldosterone system and sympathetic hyperactivity, and extracellular matrix accumulation and fibrosis. Here, we summarize several important emerging treatments for diabetic cardiomyopathy targeting specific molecular mechanisms, with evidence from preclinical studies and clinical trials.
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Inhibition of Pyruvate Dehydrogenase in the Heart as an Initiating Event in the Development of Diabetic Cardiomyopathy.
Antioxidants (Basel)2023 Mar;12(3):. doi: 756.
Elnwasany Abdallah, Ewida Heba A, Szweda Pamela A, Szweda Luke I,
Abstract
Obesity affects a growing fraction of the population and is a risk factor for type 2 diabetes and cardiovascular disease. Even in the absence of hypertension and coronary artery disease, type 2 diabetes can result in a heart disease termed diabetic cardiomyopathy. Diminished glucose oxidation, increased reliance on fatty acid oxidation for energy production, and oxidative stress are believed to play causal roles. However, the progression of metabolic changes and mechanisms by which these changes impact the heart have not been established. Cardiac pyruvate dehydrogenase (PDH), the central regulatory site for glucose oxidation, is rapidly inhibited in mice fed high dietary fat, a model of obesity and diabetes. Increased reliance on fatty acid oxidation for energy production, in turn, enhances mitochondrial pro-oxidant production. Inhibition of PDH may therefore initiate metabolic inflexibility and oxidative stress and precipitate diabetic cardiomyopathy. We discuss evidence from the literature that supports a role for PDH inhibition in loss in energy homeostasis and diastolic function in obese and diabetic humans and in rodent models. Finally, seemingly contradictory findings highlight the complexity of the disease and the need to delineate progressive changes in cardiac metabolism, the impact on myocardial structure and function, and the ability to intercede.
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Aldose reductase inhibition alleviates diabetic cardiomyopathy and is associated with a decrease in myocardial fatty acid oxidation.
Cardiovasc Diabetol2023 Mar;22(1):73. doi: 10.1186/s12933-023-01811-w.
Gopal Keshav, Karwi Qutuba G, Tabatabaei Dakhili Seyed Amirhossein, Wagg Cory S, Zhang Liyan, Sun Qiuyu, Saed Christina T, Panidarapu Sai, Perfetti Riccardo, Ramasamy Ravichandran, Ussher John R, Lopaschuk Gary D,
Abstract
BACKGROUND:
Cardiovascular diseases, including diabetic cardiomyopathy, are major causes of death in people with type 2 diabetes. Aldose reductase activity is enhanced in hyperglycemic conditions, leading to altered cardiac energy metabolism and deterioration of cardiac function with adverse remodeling. Because disturbances in cardiac energy metabolism can promote cardiac inefficiency, we hypothesized that aldose reductase inhibition may mitigate diabetic cardiomyopathy via normalization of cardiac energy metabolism.
METHODS:
Male C57BL/6J mice (8-week-old) were subjected to experimental type 2 diabetes/diabetic cardiomyopathy (high-fat diet [60% kcal from lard] for 10 weeks with a single intraperitoneal injection of streptozotocin (75 mg/kg) at 4 weeks), following which animals were randomized to treatment with either vehicle or AT-001, a next-generation aldose reductase inhibitor (40 mg/kg/day) for 3 weeks. At study completion, hearts were perfused in the isolated working mode to assess energy metabolism.
RESULTS:
Aldose reductase inhibition by AT-001 treatment improved diastolic function and cardiac efficiency in mice subjected to experimental type 2 diabetes. This attenuation of diabetic cardiomyopathy was associated with decreased myocardial fatty acid oxidation rates (1.15?±?0.19 vs 0.5?±?0.1 µmol min g dry wt in the presence of insulin) but no change in glucose oxidation rates compared to the control group. In addition, cardiac fibrosis and hypertrophy were also mitigated via AT-001 treatment in mice with diabetic cardiomyopathy.
CONCLUSIONS:
Inhibiting aldose reductase activity ameliorates diastolic dysfunction in mice with experimental type 2 diabetes, which may be due to the decline in myocardial fatty acid oxidation, indicating that treatment with AT-001 may be a novel approach to alleviate diabetic cardiomyopathy in patients with diabetes.
© 2023. The Author(s).
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Ferroptosis, necroptosis and cuproptosis: Novel forms of regulated cell death in diabetic cardiomyopathy.
Front Cardiovasc Med2023 ;10():1135723. doi: 1135723.
Ke Dan, Zhang Zhen, Liu Jieting, Chen Peijian, Li Jialing, Sun Xinhai, Chu Yanhui, Li Luxin,
Abstract
Diabetes is a common chronic metabolic disease, and its incidence continues to increase year after year. Diabetic patients mainly die from various complications, with the most common being diabetic cardiomyopathy. However, the detection rate of diabetic cardiomyopathy is low in clinical practice, and targeted treatment is lacking. Recently, a large number of studies have confirmed that myocardial cell death in diabetic cardiomyopathy involves pyroptosis, apoptosis, necrosis, ferroptosis, necroptosis, cuproptosis, cellular burial, and other processes. Most importantly, numerous animal studies have shown that the onset and progression of diabetic cardiomyopathy can be mitigated by inhibiting these regulatory cell death processes, such as by utilizing inhibitors, chelators, or genetic manipulation. Therefore, we review the role of ferroptosis, necroptosis, and cuproptosis, three novel forms of cell death in diabetic cardiomyopathy, searching for possible targets, and analyzing the corresponding therapeutic approaches to these targets.
© 2023 Ke, Zhang, Liu, Chen, Li, Sun, Chu and Li.
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Differential changes in cyclic adenosine 3'-5' monophosphate (cAMP) effectors and major Ca handling proteins during diabetic cardiomyopathy.
J Cell Mol Med2023 Mar;():. doi: 10.1111/jcmm.17733.
Chaoul Victoria, Hanna Rita, Hachem Pia, El Hayek Magali Samia, Nour-Eldine Wared, Abou-Khalil Pamela, Abi-Ramia Elias, Vandecasteele Grégoire, Abi-Gerges Aniella,
Abstract
Diabetic cardiomyopathy (DCM) is associated with differential and time-specific regulation of ?-adrenergic receptors and cardiac cyclic nucleotide phosphodiesterases with consequences for total cyclic adenosine 3'-5' monophosphate (cAMP) levels. We aimed to investigate whether these changes are associated with downstream impairments in cAMP and Ca signalling in a type 1 diabetes (T1D)-induced DCM model. T1D was induced in adult male rats by streptozotocin (65?mg/kg) injection. DCM was assessed by cardiac structural and molecular remodelling. We delineated sequential changes affecting the exchange protein (Epac1/2), cAMP-dependent protein kinase A (PKA) and Ca /Calmodulin-dependent kinase II (CaMKII) at 4, 8 and 12?weeks following diabetes, by real-time quantitative PCR and western blot. Expression of Ca ATPase pump (SERCA2a), phospholamban (PLB) and Troponin I (TnI) was also examined. Early upregulation of Epac1 transcripts was noted in diabetic hearts at Week 4, followed by increases in Epac2 mRNA, but not protein levels, at Week 12. Expression of PKA subunits (RI, RII? and C?) remained unchanged regardless of the disease stage, whereas CaMKII increased at Week 12 in DCM. Moreover, PLB transcripts were upregulated in diabetic hearts, whereas SERCA2a and TnI gene expression was unchanged irrespective of the disease evolution. PLB phosphorylation at threonine-17 was increased in DCM, whereas phosphorylation of both PLB at serine-16 and TnI at serine-23/24 was unchanged. We show for the first time differential and time-specific regulations in cardiac cAMP effectors and Ca handling proteins, data that may prove useful in proposing new therapeutic approaches in T1D-induced DCM.
© 2023 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.
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Macrovascular and microvascular type 2 diabetes complications are interrelated in a mouse model.
J Diabetes Complications2023 Mar;37(5):108455. doi: 10.1016/j.jdiacomp.2023.108455.
Cifuentes-Mendiola S E, Solís-Suarez D L, Martínez-Davalos A, García-Hernández A L,
Abstract
AIM:
Evaluate the development of multiple complications, their interactions, and common mechanisms in the same individual with T2D.
MATERIAL AND METHODS:
4-week-old male C57BL/6J mice were divided into: control (n = 6) and T2D (n = 6). T2D was induced through a high-carbohydrate-diet and low doses of streptozotocin. T2D was validated by metabolic parameters. Diabetic neuropathy was evaluated by mechanical and thermal sensitivity tests. We performed a histopathological analysis of the heart, kidney, liver, and parotid salivary glands and changes in bone microarchitecture by ?CT. We calculated the relative risk (RR), odd ratios (OR) and Pearson correlation coefficients between the different complications and metabolic features.
RESULTS:
T2D mice have cardiomyopathy, neuropathy, nephropathy, liver steatosis and fibrosis, structural damage in parotid salivary glands, and bone porosity. RR analysis shows that all complications are interrelated by hyperglycaemia, insulin resistance, obesity, and systemic inflammation.
CONCLUSIONS:
T2D mice develop multiple complications simultaneously, which are related to each other, and this is associated with metabolic alterations. Our findings open up new approaches for the study and new therapeutic approaches of the pathophysiology of T2D and its complications.
Published by Elsevier Inc.
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Hypertrophic cardiomyopathy as the initial presentation of mitochondrial disease in an infant born to a diabetic mother.
Cardiol Young2023 Mar;():1-3. doi: 10.1017/S1047951123000392.
Byun Jun Chul, Choi Hee Joung,
Abstract
In contrast to hypertrophic cardiomyopathy caused by maternal diabetes, neonatal mitochondrial cardiomyopathy is rare and has a poor prognosis. We report an infant born to a mother with maternal diabetes with persistent ventricular hypertrophy, who was diagnosed with mitochondrial disease associated with m.3243A>G mutation in a mitochondrial tRNA leucine 1 gene. The hypertrophic cardiomyopathy was his initial and only clinical presentation.
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Diabetic cardiomyopathy: The role of microRNAs and long non-coding RNAs.
Front Endocrinol (Lausanne)2023 ;14():1124613. doi: 1124613.
Macvanin Mirjana T, Gluvic Zoran, Radovanovic Jelena, Essack Magbubah, Gao Xin, Isenovic Esma R,
Abstract
Diabetes mellitus (DM) is on the rise, necessitating the development of novel therapeutic and preventive strategies to mitigate the disease's debilitating effects. Diabetic cardiomyopathy (DCMP) is among the leading causes of morbidity and mortality in diabetic patients globally. DCMP manifests as cardiomyocyte hypertrophy, apoptosis, and myocardial interstitial fibrosis before progressing to heart failure. Evidence suggests that non-coding RNAs, such as long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), regulate diabetic cardiomyopathy-related processes such as insulin resistance, cardiomyocyte apoptosis and inflammation, emphasizing their heart-protective effects. This paper reviewed the literature data from animal and human studies on the non-trivial roles of miRNAs and lncRNAs in the context of DCMP in diabetes and demonstrated their future potential in DCMP treatment in diabetic patients.
Copyright © 2023 Macvanin, Gluvic, Radovanovic, Essack, Gao and Isenovic.
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Danlou tablet inhibits high-glucose-induced cardiomyocyte apoptosis via the miR-34a-SIRT1 axis.
Heliyon2023 Mar;9(3):e14479. doi: e14479.
Chen Rui, Chen Hongjian, Yang Zijiang, Zhu Liyun, Bei Yihua, Chen Wei, Qiu Yan,
Abstract
Diabetic cardiomyopathy (DCM) is highly prevalent and increases the risk of heart failure and sudden death. Therefore, proper and effective treatments for DCM are in urgent demand. Danlou tablet (Dan) is reported to confer protective effects on several heart diseases. However, to our knowledge, whether Dan provides protection against DCM is unclear. In this study, we explored the effect of Dan on DCM with the DCM model using AC16 cardiomyocytes. We found that Dan treatment significantly reduced cardiomyocyte apoptosis and oxidative stress in high-glucose (HG)-treated cardiomyocytes, as evidenced by decreased Annexin V-FITC+ cardiomyocytes, intracellular reactive oxygen species (ROS) levels, Bax/Bcl2 ratio, and cleaved-Caspase3/Caspase3 ratio. Interestingly, Dan treatment caused a decreased level of microRNA-34a (miR-34a), which could enhance cardiomyocyte apoptosis. Furthermore, miR-34a mimic blocked Dan's effect in apoptosis prevention. Finally, we observed that the miR-34a mimic effectively decreased the level of sirtuin 1 (SIRT1), while the miR-34a inhibitor increased the level of SIRT1. And downregulation of SIRT1 effectively reversed the effect of miR-34a inhibitor on cardiomyocyte apoptosis. Taken together, our study showed that Dan prevented HG-induced cardiomyocyte apoptosis through downregulating miR-34a and upregulating SIRT1. Our study has provided experimental support for the potential use of Dan in treating DCM. Further detailed study of Dan and the underlying mechanisms may shed light on the prevention and treatment of DCM.
© 2023 The Authors. Published by Elsevier Ltd.
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Clinical features of generalized lipodystrophy in Turkey: a cohort analysis.
Diabetes Obes Metab2023 Mar;():. doi: 10.1111/dom.15061.
Yildirim Simsir Ilgin, Tuysuz Beyhan, Ozbek Mehmet Nuri, Tanrikulu Seher, Celik Guler Merve, Karhan Asuman Nur, Denkboy Ongen Yasemin, Gunes Nilay, Soyaltin Utku Erdem, Altay Canan, Nur Banu, Ozalkak Servan, Akgun Dogan Ozlem, Dursun Fatma, Pekkolay Zafer, Eren Mehmet Ali, Usta Yusuf, Ozisik Secil, Ozgen Saydam Basak, Adiyaman Suleyman Cem, Unal Mehmet Cagri, Gungor Semiz Gokcen, Turan Ihsan, Eren Erdal, Kayserili Hulya, Jeru Isabelle, Vigouroux Corinne, Atik Tahir, Onay Huseyin, Ozen Samim, Oral Elif A, Akinci Baris,
Abstract
AIMS:
Without access to leptin replacement, patients with generalized lipodystrophy (GL) are at high risk for severe metabolic disease. Although there is a well-established GL registry in Turkey since the early 2000s, leptin replacement treatment was not available until recently. This gave us a unique opportunity to describe the natural history of GL.
METHODS:
This study reports on 72 patients with GL (47 families) who were registered at different centers in Turkey that cover all regions of the country. The mean ± SD follow-up was 86 ±?78 months.
RESULTS:
Kaplan-Meier estimate of the median time to diagnosis of diabetes and/or prediabetes was 16?years. Hyperglycemia was not controlled in 37 of 45 patients (82.2%) with diabetes. Hypertriglyceridemia developed in 65 patients (90.3%). Kaplan-Meier estimate of the median time to diagnosis of hypertriglyceridemia was 14?years. Hypertriglyceridemia was severe (?500 mg/dL) in 38 patients (52.8%). Seven (9.7%) patients suffered from pancreatitis. Kaplan-Meier estimate of the median time to diagnosis of hepatic steatosis was 15?years. Liver disease progressed to cirrhosis in 9 patients (12.5%). Liver disease was more severe in congenital lipodystrophy type 2 (CGL2). Proteinuric chronic kidney disease (CKD) developed in 32 patients (44.4%) and cardiac disease in 23 patients (31.9%). Kaplan-Meier estimates of the median time to diagnosis of CKD and cardiac disease were 25?years and 45?years, respectively. Females appeared to have a more severe metabolic disease with earlier onset of metabolic abnormalities. Ten patients died during the follow-up period. Causes of death were end-stage renal disease, sepsis (due to recurrent intestinal perforations, coronavirus disease, diabetic foot infection, and following coronary artery bypass graft surgery), myocardial infarction, heart failure due to dilated cardiomyopathy, stroke, liver complications, and angiosarcoma.
CONCLUSIONS:
Standard treatment approaches have only a limited impact and do not prevent the development of severe metabolic abnormalities and early onset of organ complications in GL. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
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Exogenous spermidine alleviates diabetic cardiomyopathy via suppressing ROS, ERS and Pannexin-1-mediated ferroptosis.
Biomol Biomed2023 Mar;():. doi: 10.17305/bb.2022.8846.
Sun Jian, Xu Jiyu, Liu Yong, Lin Yitong, Wang Fengge, Han Yue, Zhang Shumin, Gao Xiaoyan, Xu Changqing, Yuan Hui,
Abstract
Diabetic cardiomyopathy (DCM) is a serious complication and death cause of diabetes mellitus (DM). Recent cardiology studies suggest that spermidine has cardioprotective effects. Here, we verified the hypothesis of spermidine's protective effects on DCM. Therefore, db/db mice and primary neonatal mouse cardiomyocytes were used to observe the effects of spermidine. Immunoblotting showed that ornithine decarboxylase (ODC) and SPD/spermine N1-acetyltransferase (SSAT) were downregulated and upregulated in the myocardium of db/db mice, respectively. We found that diabetic mice showed cardiac dysfunction in 12 weeks. Conversely, exogenous spermidine could improve cardiac functions and reduce the deposition of collagens, myocardial damage, reactive oxygen species (ROS) levels and endoplasmic reticulum stress (ERS) in diabetic mouse hearts. Our results also demonstrated that cardiomyocytes displayed ferroptosis and then activated Pannexin-1 expression, which resulted in the increase of the extracellular adenosine triphosphate (ATP). Subsequently, increased ATP as a paracrine molecule combined to purinergic receptor P2X7 (P2X7) to activate ERK1/2 signaling pathway in cardiomyocytes and activated NCOA4-mediated ferroptinophagy to promote lipid peroxidation and ferroptosis. Interestingly, spermidine could reverse these molecular processes. Our findings indicate an important new mechanism for DCM, and suggest spermidine have potential applicability to protect against deterioration of cardiac function with DCM.
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Glucagon-Like Peptide-1 Receptor Agonist Protects Against Diabetic Cardiomyopathy by Modulating microRNA-29b-3p/SLMAP.
Drug Des Devel Ther2023 ;17():791-806. doi: 10.2147/DDDT.S400249.
Fang Ping, Ye Zhengqin, Li Ran, She Dunmin, Zong Guannan, Zhang Liya, Xue Ying, Zhang Keqin,
Abstract
PURPOSE:
Our aims were to investigate the pathogenesis of diabetic cardiomyopathy (DCM) and to explore the protective effect of glucagon-like peptide-1 receptor agonist (GLP-1RA) on DCM.
METHODS:
After 12 weeks of treatment with exenatide-loaded microspheres, a long-acting GLP-1RA, in DCM mice, cardiac structure and function were evaluated by plasma B-type natriuretic peptide (BNP), echocardiography, H&E, oil red and Sirius staining. The expression of glucagon-like peptide-1 receptor in mouse heart tissue was determined by immunofluorescence staining. The label-free proteomic analysis of cardiac proteins was conducted among control, DCM and DM+GLP-1RA groups. Then, quantitative real-time PCR, Western blotting and dual-luciferase reporter assay were performed to verify the regulation of target protein by the upstream microRNA (miRNA).
RESULTS:
GLP-1RA treatment obviously improved serum BNP, myocardial fibrosis, lipid deposition of the myocardium and echocardiography parameters in DCM mice. Sarcolemmal membrane-associated protein (SLMAP) was one of 61 differentially expressed cardiac proteins found in three groups by proteomic analysis. Up-regulation of microRNA-29b-3p (miR-29b-3p) and down-regulation of SLMAP were found in the ventricular myocardium of GLP-1RA-treated DCM mice. SLMAP was a target of miR-29b-3p, while GLP-1RA regulated SLMAP expression through miR-29b-3p. Furthermore, inhibition of glucagon-like peptide-1 receptor (GLP-1R) in cardiomyocytes reversed the effects of GLP-1RA on miR-29b/SLMAP.
CONCLUSION:
SLMAP may play roles in the pathogenesis of DCM and may be a target of GLP-1RA in protecting against DCM. After binding to myocardial GLP-1R, GLP-1RA can regulate the expression of myocardial SLMAP through miR-29b-3p.
© 2023 Fang et al.
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Impaired myocardial deformation persists at 2 years in offspring of mothers with diabetes mellitus.
Pediatr Res2023 Mar;():. doi: 10.1038/s41390-023-02566-6.
Jacquemyn Xander, Kutty Shelby, Dhanantwari Preeta, Ravekes William J, Kulkarni Aparna,
Abstract
BACKGROUND:
A diabetic intrauterine environment has been proposed as a potential etiological mechanism for in utero programming of cardiac disease, and is associated with impaired fetal cardiac function. We aimed to assess cardiac function in offspring of mothers with diabetes mellitus (ODM) and determine whether fetal cardiac abnormalities persist during follow-up.
METHODS:
Longitudinal observational study to evaluate and compare myocardial function in 40 ODM to age-matched control offspring (CO). Myocardial deformation was measured using speckle-tracking echocardiography (STE).
RESULTS:
Significant differences were detected in global longitudinal strain (-20.9?±?3.1 vs. -23.6?±?2.2%; p?=?0.001), global circumferential strain (-24.4?±?3.9 vs. -26.9?±?2.7%; p?=?0.017), average radial strain (29.0?±?9.8 vs. 37.1?±?7.2%; p?=?0.003), average longitudinal systolic strain rate (-1.24?±?0.25/s vs. -1.47?±?0.30/s; p?=?0.011) and average circumferential systolic strain rate (-1.56?±?0.37/s vs. -1.84?±?0.37/s; p?=?0.013) in comparison to CO up to 2 years of follow-up. Minimal differences were observed within ODM over the 2-year period.
CONCLUSION:
Impaired cardiac function in ODM persists during 2 years follow-up. Functional cardiac assessment might therefore be useful to detect these unfavorable changes, independent of screening for congenital heart disease or hypertrophic cardiomyopathy in this population.
IMPACT:
We demonstrate persistence of subclinical myocardial deformation abnormalities in offspring of mothers with diabetes mellitus from fetal life to early childhood years. These results extend the cellular observations in basic and translational research of developmental programming into the clinical realm. Persistence of subclinical myocardial deformation abnormalities may shed light on the known incidence of early cardiovascular disease in offspring of mother with diabetes. Cardiac myocardial strain assessment can be useful to detect these abnormalities, independent of screening for congenital heart disease or hypertrophic cardiomyopathy in this population.
© 2023. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.
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Regulation of peroxiredoxin-3 gene expression under basal and hyperglycemic conditions: Key roles for transcription factors Sp1, CREB and NF-?B.
Biochim Biophys Acta Mol Basis Dis2023 Mar;():166691. doi: 10.1016/j.bbadis.2023.166691.
Arkat Silpa, Poovitha Sundar, Vijayakumar Anupama, Dhat Rohini, Sitasawad Sandhya L, Mahapatra Nitish R,
Abstract
Peroxiredoxin-3 (Prx-3), a thioredoxin-dependent peroxidase located exclusively in the mitochondrial matrix, catalyses peroxides/peroxinitrites. Altered levels of Prx-3 is associated with diabetic cardiomyopathy (DCM). However, molecular mechanisms of Prx-3 gene regulation remain partially understood. We undertook a systemic analysis of the Prx-3 gene to identify the key motifs and transcriptional regulatory molecules. Transfection of promoter-reporter constructs in the cultured cells identified -191/+20?bp domain as the core promoter region. Stringent in silico analysis of this core promoter revealed putative binding sites for specificity protein 1 (Sp1), cAMP response element-binding protein (CREB) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-?B). Interestingly, while co-transfection of the -191/+20?bp construct with Sp1/CREB plasmid diminished Prx3 promoter-reporter activity, mRNA and protein levels, co-transfection with NF-?B expression plasmid augmented the same. Consistently, inhibition of Sp1/CREB/NF-?B expression reversed the promoter-reporter activity, mRNA and protein levels of Prx-3, thereby confirming their regulatory effects. ChIP assays provided evidence for interactions of Sp1/CREB/NF-?B with the Prx-3 promoter. H9c2 cells treated with high glucose as well as streptozotocin (STZ)-treated diabetic rats showed time-dependent reduction in promoter activity, endogenous transcript and protein levels of Prx-3. Augmentation of Sp1/CREB protein levels and their strong binding with Prx-3 promoter are responsible for diminished Prx-3 levels under hyperglycemia. The activation/increase in the NF-?B expression under hyperglycemia was not sufficient to restore the reduction of endogenous Prx-3 levels owing to its weak binding affinity. Taken together, this study elucidates the previously unknown roles of Sp1/CREB/NF-?B in regulating Prx-3 gene expression under hyperglycemic condition.
Copyright © 2023. Published by Elsevier B.V.
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Cardioprotective and anti-inflammatory effects of Caveolin 1 in experimental diabetic cardiomyopathy.
Clin Sci (Lond)2023 Mar;137(6):511-525. doi: 10.1042/CS20220874.
Gong Wenyan, Jiao Qibin, Yuan Jinghua, Luo Hui, Liu Yingying, Zhang Yuanyuan, Chen Zhen, Xu Xiaoling, Bai Lin, Zhang Xingwei,
Abstract
Previous studies of the Caveolin 1 (Cav1) protein and caveolae, which are lipid raft structures found on the plasma membranes of certain cells, are associated with fat metabolism disorders, inflammation, diabetes, and cardiovascular disease. However, there have been no reports linking Cav1 to diabetic cardiomyopathy (DCM). In the present study, we established a relationship between Cav1 and the development of DCM. We found that compared with Cav1+/+ mice, Cav1-/- diabetic mice exhibited more severe cardiac injury, increased activation of NF-?B signaling, and up-regulation of downstream genes, including hypertrophic factors and inflammatory fibrosis factors in heart tissues. Additionally, in vitro results showed that knocking down Cav1 further activated HG-induced NF-?B signaling, increased the expression of downstream target genes, and decreased the expression of inhibitor ? of NF-?B (i?B?), all of which have been linked to DCM pathogenesis. In contrast, Cav1 overexpression resulted in the opposite effects. Our study suggests that Cav1 knockdown promotes cardiac injury in DCM by activating the NF-?B signaling pathway, and targeting Cav1 may lead to the development of novel treatments for DCM.
© 2023 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.
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Rutaecarpine attenuates high glucose-induced damage in AC16 cardiomyocytes by suppressing the MAPK pathway.
J Appl Toxicol2023 Mar;():. doi: 10.1002/jat.4465.
Lv Jun, Ji Miaomiao, Yang Han, Wang Chao, Zhang Lingyan, Ni Hongzao,
Abstract
Diabetic cardiomyopathy is a common diabetic complication, resulting in heart failure. Rutaecarpine is an active compound with cardiovascular protective effects. However, the function of rutaecarpine in diabetic cardiomyopathy is largely unknown. The aim of this research was to study the effect and action mechanism of rutaecarpine in high glucose (HG)-induced cardiomyocyte damage. The overlapping genes of diabetic cardiomyopathy and rutaecarpine were analyzed according to GeneCards, DisGeNet, and SwissTargetPrediction. Cell damage was investigated by determining apoptosis, oxidative stress, and inflammatory response in HG-stimulated AC16 cells. The expression of proteins involved in the mitogen-activated protein kinase (MAPK) signaling was measured using Western blotting. Totally seven overlapping genes of diabetic cardiomyopathy and rutaecarpine were screened out and predicted to be associated with the MAPK signaling. Rutaecarpine protected against HG-induced cardiomyocyte damage by enhancing cell viability and reducing cell apoptosis, caspase-3 activity, and lactate dehydrogenase (LDH) release. Rutaecarpine mitigated HG-induced oxidative stress in cardiomyocytes through decreasing reactive oxygen species (ROS) formation and malondialdehyde (MDA) level and elevating superoxide dismutase (SOD) activity and glutathione peroxidase (GSH-Px) level. Rutaecarpine alleviated HG-induced inflammatory response via reducing the level of interleukin (IL)-1?, IL-6, tumor necrosis factor (TNF)-?, and IL-8. Moreover, rutaecarpine inhibited HG-induced activation of the MAPK pathway. Treatment with MAPK signaling agonist reversed the suppressive effect of rutaecarpine on HG-induced damage. In conclusion, rutaecarpine alleviated HG-induced cardiomyocyte damage through decreasing apoptosis, oxidative stress, and inflammatory response by inactivating the MAPK pathway.
© 2023 John Wiley & Sons, Ltd.
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Cardiac-specific overexpression of insulin-like growth factor II receptor-? interferes with the regulation of calcium homeostasis in the heart under hyperglycemic conditions.
Mol Biol Rep2023 Mar;():. doi: 10.1007/s11033-023-08327-2.
Lu Shang-Yeh, Tsai Bruce Chi-Kang, Van Thao Dao, Lai Chin-Hu, Chen Michael Yu-Chih, Kuo Wei-Wen, Kuo Chia-Hua, Lin Kuan-Ho, Hsieh Dennis Jine-Yuan, Huang Chih-Yang,
Abstract
BACKGROUND:
Diabetic cardiomyopathy is a progressive disease caused by inexplicit mechanisms, and a novel factor, insulin-like growth factor II receptor-? (IGF-IIR?), may contribute to aggravating its pathogenesis. We hypothesized that IGF-IIR? could intensify diabetic heart injury.
METHODS AND RESULTS:
To demonstrate the potential role of IGF-IIR? in the diabetic heart, we used (SD-TG [IGF-IIR?]) transgenic rat model with cardiac-specific overexpression of IGF-IIR?, along with H9c2 cells, to study the effects of IGF-IIR? in the heart under hyperglycemic conditions. IGF-IIR? was found to remodel calcium homeostasis and intracellular Ca overload-induced autophagy disturbance in the heart during diabetes. IGF-IIR? overexpression induced intracellular Ca alteration by downregulating phosphorylated phospholamban/sarcoplasmic/endoplasmic reticulum calcium-ATPase 2a (PLB/SERCA2a), resulting in the suppression of Ca uptake into the endoplasmic reticulum. Additionally, IGF-IIR? itself contributed to Ca withdrawal from the endoplasmic reticulum by increasing the expression of CaMKII? in the active form. Furthermore, alterations in Ca homeostasis significantly dysregulated autophagy in the heart during diabetes.
CONCLUSIONS:
Our study reveals the novel role of IGF-IIR? in regulating cardiac intracellular Ca homeostasis and its related autophagy interference, which contribute to the development of diabetic cardiomyopathy. In future, the present study findings have implications in the development of appropriate therapy to reduce diabetic cardiomyopathy.
© 2023. The Author(s), under exclusive licence to Springer Nature B.V.
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Grpel2 maintains cardiomyocyte survival in diabetic cardiomyopathy through DLST-mediated mitochondrial dysfunction: a proof-of-concept study.
J Transl Med2023 Mar;21(1):200. doi: 200.
Yang Rongjin, Zhang Xiaomeng, Zhang Yunyun, Wang Yingfan, Li Man, Meng Yuancui, Wang Jianbang, Wen Xue, Yu Jun, Chang Pan,
Abstract
BACKGROUND:
Diabetic cardiomyopathy (DCM) has been considered as a major threat to health in individuals with diabetes. GrpE-like 2 (Grpel2), a nucleotide exchange factor, has been shown to regulate mitochondrial import process to maintain mitochondrial homeostasis. However, the effect and mechanism of Grpel2 in DCM remain unknown.
METHODS:
The streptozotocin (STZ)-induced DCM mice model and high glucose (HG)-treated cardiomyocytes were established. Overexpression of cardiac-specific Grpel2 was performed by intramyocardial injection of adeno-associated virus serotype 9 (AAV9). Bioinformatics analysis, co-immunoprecipitation (co-IP), transcriptomics profiling and functional experiments were used to explore molecular mechanism of Grpel2 in DCM.
RESULTS:
Here, we found that Grpel2 was decreased in DCM induced by STZ. Overexpression of cardiac-specific Grpel2 alleviated cardiac dysfunction and structural remodeling in DCM. In both diabetic hearts and HG-treated cardiomyocytes, Grpel2 overexpression attenuated apoptosis and mitochondrial dysfunction, including decreased mitochondrial ROS production, increased mitochondrial respiratory capacities and increased mitochondrial membrane potential. Mechanistically, Grpel2 interacted with dihydrolipoyl succinyltransferase (DLST), which positively mediated the import process of DLST into mitochondria under HG conditions. Furthermore, the protective effects of Grpel2 overexpression on mitochondrial function and cell survival were blocked by siRNA knockdown of DLST. Moreover, Nr2f6 bond to the Grpel2 promoter region and positively regulated its transcription.
CONCLUSION:
Our study provides for the first time evidence that Grpel2 overexpression exerts a protective effect against mitochondrial dysfunction and apoptosis in DCM by maintaining the import of DLST into mitochondria. These findings suggest that targeting Grpel2 might be a promising therapeutic strategy for the treatment of patients with DCM.
© 2023. The Author(s).
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