Pubblicazioni recenti - diabetic cardiomyopathy
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A comprehensive review of the novel therapeutic targets for the treatment of diabetic cardiomyopathy.
Ther Adv Cardiovasc Dis2023 ;17():17539447231210170. doi: 10.1177/17539447231210170.
Dhar Arti, Venkadakrishnan Jegadheeswari, Roy Utsa, Vedam Sahithi, Lalwani Nikita, Ramos Kenneth S, Pandita Tej K, Bhat Audesh,
Abstract
Diabetic cardiomyopathy (DCM) is characterized by structural and functional abnormalities in the myocardium affecting people with diabetes. Treatment of DCM focuses on glucose control, blood pressure management, lipid-lowering, and lifestyle changes. Due to limited therapeutic options, DCM remains a significant cause of morbidity and mortality in patients with diabetes, thus emphasizing the need to develop new therapeutic strategies. Ongoing research is aimed at understanding the underlying molecular mechanism(s) involved in the development and progression of DCM, including oxidative stress, inflammation, and metabolic dysregulation. The goal is to develope innovative pharmaceutical therapeutics, offering significant improvements in the clinical management of DCM. Some of these approaches include the effective targeting of impaired insulin signaling, cardiac stiffness, glucotoxicity, lipotoxicity, inflammation, oxidative stress, cardiac hypertrophy, and fibrosis. This review focuses on the latest developments in understanding the underlying causes of DCM and the therapeutic landscape of DCM treatment.
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Cardioprotective and Antifibrotic Effects of Low-Dose Renin-Angiotensin-Aldosterone System Inhibitors in Type 1 Diabetic Rat Model.
Int J Mol Sci2023 Dec;24(23):. doi: 17043.
Balogh Dora B, Molnar Agnes, Degi Arianna, Toth Akos, Lenart Lilla, Saeed Adar, Barczi Adrienn, Szabo Attila J, Wagner Laszlo J, Reusz Gyorgy, Fekete Andrea,
Abstract
Diabetic cardiovascular complications are associated with up to 50% mortality, and current therapies are not effective enough. Renin-angiotensin-aldosterone system inhibitors (RAASis) are the standard of care for diabetic patients with hypertension and albuminuria. Based on our previous studies reporting the renoprotective effects of low-dose RAASis, here, we hypothesized that low-dose RAASi treatment has cardioprotective and antifibrotic benefits in type 1 diabetes mellitus (T1DM). After five weeks of T1DM, adult male Wistar rats received low doses of ramipril, losartan, or eplerenone for two weeks. Heart rate, blood pressure, and pulse wave velocity (PWV) were recorded. Aortic intima-media thickness (IMT), collagen accumulation, and myocardial fibrosis were assessed. All RAASis reduced PWV elevation, prevented the progression of myocardial fibrosis, and normalized B-type natriuretic peptide, troponin I, and fibroblast growth factor 23 levels without affecting blood pressure. Interestingly, only eplerenone reversed the decline in Klotho levels and reduced IMT and fibrosis in the media of the aorta. Our comparative analysis suggests that mineralocorticoid receptor antagonists, particularly eplerenone, may offer superior efficacy in halting both the arterial and the myocardial injuries in T1DM compared to angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor blockers.
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Ginsenoside Rg3 Protects against Diabetic Cardiomyopathy and Promotes Adiponectin Signaling via Activation of PPAR-?.
Int J Mol Sci2023 Nov;24(23):. doi: 16736.
Zhang Chenyang, Yu Huifang, Ye Jingxue, Tong Hongna, Wang Min, Sun Guibo,
Abstract
Ginsenoside Rg3 extracted from has therapeutic effects on diabetes and heart diseases. However, the underlying mechanism of ginsenoside Rg3 on diabetic cardiomyopathy (DCM) remains unclear. 24-week-old diabetic db/db mice were treated with ginsenoside Rg3 for 12 weeks, then body weight, serum lipids, adiponectin levels, as well as cardiac function and pathological morphology, were measured. The targets of ginsenoside Rg3 and its regulation of the adiponectin pathway were also evaluated on 3T3-L1 or H9c2 cells. Ginsenoside Rg3 directly bound to PPAR-?, improving adiponectin secretion and promoting adiponectin signaling. Significantly attenuated overweight, hyperglycemia, and hyperlipidemia, as well as alleviated lipid accumulation and dysfunction in adipose, liver, and heart tissues, were observed in the ginsenoside Rg3-treated group. Ginsenoside Rg3 could be a promising drug targeting PPAR-? to treat diabetic cardiomyopathy.
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Gasdermin D-Mediated Pyroptosis in Diabetic Cardiomyopathy: Molecular Mechanisms and Pharmacological Implications.
Molecules2023 Nov;28(23):. doi: 7813.
Liu Zhou, Chen Yifan, Mei Yu, Yan Meiling, Liang Haihai,
Abstract
Diabetic cardiomyopathy (DCM) is a pathophysiological condition triggered by diabetes mellitus (DM), which can lead to heart failure (HF). One of the most important cellular processes associated with DCM is the death of cardiomyocytes. Gasdermin D (GSDMD) plays a key role in mediating pyroptosis, a type of programmed cell death closely associated with inflammasome activation. Recent studies have revealed that pyroptosis is induced during hyperglycemia, which is crucial to the development of DCM. Although the effects of pyroptosis on DCM have been discussed, the relationship between DCM and GSDMD is not fully clarified. Recent studies gave us the impetus for clarifying the meaning of GSDMD in DCM. The purpose of this review is to summarize new and emerging insights, mainly discussing the structures of GSDMD and the mechanism of pore formation, activation pathways, molecular mechanisms of GSDMD-mediated pyroptosis, and the therapeutic potential of GSDMD in DCM. The implications of this review will pave the way for a new therapeutic target in DCM.
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Prevalence and Predictors of Subclinical Cardiomyopathy in Patients With Type 2 Diabetes in a Health System.
J Diabetes Sci Technol2023 Dec;():19322968231212219. doi: 10.1177/19322968231212219.
Nagori Aditya, Segar Matthew W, Keshvani Neil, Patel Lajjaben, Patel Kershaw V, Chandra Alvin, Willett DuWayne, Pandey Ambarish,
Abstract
INTRODUCTION:
Diabetic cardiomyopathy (DbCM) is characterized by subclinical abnormalities in cardiac structure/function and is associated with a higher risk of overt heart failure (HF). However, there are limited data on optimal strategies to identify individuals with DbCM in contemporary health systems. The aim of this study was to evaluate the prevalence of DbCM in a health system using existing data from the electronic health record (EHR).
METHODS:
Adult patients with type 2 diabetes mellitus free of cardiovascular disease (CVD) with available data on HF risk in a single-center EHR were included. The presence of DbCM was defined using different definitions: (1) least restrictive: ?1 echocardiographic abnormality (left atrial enlargement, left ventricle hypertrophy, diastolic dysfunction); (2) intermediate restrictive: ?2 echocardiographic abnormalities; (3) most restrictive: 3 echocardiographic abnormalities. DbCM prevalence was compared across age, sex, race, and ethnicity-based subgroups, with differences assessed using the chi-squared test. Adjusted logistic regression models were constructed to evaluate significant predictors of DbCM.
RESULTS:
Among 1921 individuals with type 2 diabetes mellitus, the prevalence of DbCM in the overall cohort was 8.7% and 64.4% in the most and least restrictive definitions, respectively. Across all definitions, older age and Hispanic ethnicity were associated with a higher proportion of DbCM. Females had a higher prevalence than males only in the most restrictive definition. In multivariable-adjusted logistic regression, higher systolic blood pressure, higher creatinine, and longer QRS duration were associated with a higher risk of DbCM across all definitions.
CONCLUSIONS:
In this single-center, EHR cohort, the prevalence of DbCM varies from 9% to 64%, with a higher prevalence with older age and Hispanic ethnicity.
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Understanding One Half of the Sex Difference Equation: The Modulatory Effects of Testosterone on Diabetic Cardiomyopathy.
Am J Pathol2023 Dec;():. doi: S0002-9440(23)00448-0.
Visanji Mika'il, Venegas-Pino Daniel E, Werstuck Geoff H,
Abstract
Diabetes is a prevalent disease, primarily characterized by high blood sugar (hyperglycemia). Significantly higher rates of myocardial dysfunction have been noted in individuals with diabetes, even in those without coronary artery disease or high blood pressure (hypertension). Numerous molecular mechanisms have been identified, through which diabetes contributes to the pathology of diabetic cardiomyopathy, which presents as cardiac hypertrophy and fibrosis. At the cellular level, oxidative stress and inflammation in cardiomyocytes are triggered by hyperglycemia. While males are generally more likely to develop cardiovascular disease than females, diabetic males are less likely to develop diabetic cardiomyopathy than are diabetic females. One reason for these differences may be the higher levels of serum testosterone in males compared to females. While testosterone appears to protect against cardiomyocyte oxidative stress and exacerbate hypertrophy, its role in inflammation and fibrosis are much less clear. Additional pre-clinical and clinical studies will be required to delineate testosterone's effect on the diabetic heart.
Copyright © 2023. Published by Elsevier Inc.
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Upregulation of NF-?B by USP24 aggravates ferroptosis in diabetic cardiomyopathy.
Free Radic Biol Med2023 Dec;210():352-366. doi: 10.1016/j.freeradbiomed.2023.11.032.
Wu Shenglin, Zhou Yueran, Liang Jiaquan, Ying Pengxiang, Situ Qiwei, Tan Xuerui, Zhu Jinxiu,
Abstract
BACKGROUND:
Recent investigations have proposed a potential causal association between the occurrence of ferroptosis, nuclear factor kappa B (NF-?B) and ubiquitin-specific protease 24 (USP24). Nevertheless, the mechanism of USP24 and NF-?B regulation of ferroptosis in the context of diabetic cardiomyopathy (DCM) remain unclear.
METHODS:
In this study, a high-fat diet and a streptozotocin-induced mouse DCM model were established, and high glucose and palmitic acid treatment of H9c2 cells and neonatal mouse primary cardiomyocytes (NMPCs) was used as an in vitro DCM models. Utilizing both the in vivo and in vitro DCM models, we assessed of USP24, NF-?B, and ferroptosis levels, and explored the relationship among them.
RESULTS:
In in vivo and in vitro DCM models, increased expression of USP24, NF-?B, phosphorylated NF-?B (p-NF-?B) and fatty acid-CoA ligase 4 (FACL4) were detected, along with accumulated iron, as well as reduced ferritin heavy chain 1 (FTH1), solute carrier family 7 member 11 (SLC7A11) and antioxidant capacity. Knockdown of USP24 resulted in a reduction of NF-?B levels, while knockdown of NF-?B did not lead to a decrease in USP24 expression. Moreover, in H9c2 cells, knockdown of USP24 and NF-?B separately resulted in reduced levels of FACL4, increased levels of SLC7A11 and FTH1, as well as improved antioxidant capacity and cell viability. In shUSP24 knockdown H9c2 cells, administration of phorbol 12-myristate 13-acetate (PMA) activated NF-?B, subsequently reversing the previously observed effect caused by USP24 knockdown.
CONCLUSIONS:
These findings show that USP24 upregulates NF-?B to promote ferroptosis in DCM.
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.
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Deletion of the muscle enriched lncRNA Oip5os1 induces atrial dysfunction in male mice with diabetes.
Physiol Rep2023 Dec;11(23):e15869. doi: e15869.
Zhuang Aowen, Tan Yanie, Liu Yingying, Yang Christine, Kiriazis Helen, Grigolon Kyah, Walker Shannen, Bond Simon T, McMullen Julie R, Calkin Anna C, Drew Brian G,
Abstract
Long ncRNAs (lncRNAs) have been shown to play a biological and physiological role in various tissues including the heart. We and others have previously established that the lncRNA Oip5os1 (1700020I14Rik, OIP5-AS1, Cyrano) is enriched in striated muscles, and its deletion in mice leads to defects in both skeletal and cardiac muscle function. In the present study, we investigated the impact of global Oip5os1 deletion on cardiac function in the setting of streptozotocin (STZ)-induced diabetes. Specifically, we studied male WT and KO mice with or without diabetes for 24?weeks, and phenotyped animals for metabolic and cardiac endpoints. Independent of genotype, diabetes was associated with left ventricular diastolic dysfunction based on a fall in E'/A' ratio. Deletion of Oip5os1 in a setting of diabetes had no significant impact on ventricular function or ventricular weight, but was associated with left atrial dysfunction (reduced fractional shortening) and myopathy which was associated with anesthesia intolerance and premature death in the majority of KO mice tested during cardiac functional assessment. This atrial phenotype was not observed in WT diabetic mice. The most striking molecular difference was a reduction in the metabolic regulator ERRalpha in the atria of KO mice compared with WT mice. There was also a trend for a reduction in Serca2a. These findings highlight Oip5os1 as a gene of interest in aspects of atrial function in the setting of diabetes, highlighting an additional functional role for this lncRNA in cardiac pathological settings.
© 2023 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.
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Ubiquitin-conjugating enzyme E2 for regulating autophagy in diabetic cardiomyopathy: A mini-review.
J Diabetes2023 Dec;():. doi: 10.1111/1753-0407.13511.
Zhou Yueran, Zheng Zequn, Wu Shenglin, Zhu Jinxiu,
Abstract
The prevalence of diabetic cardiomyopathy (DCM) increases year by year with the increase in the prevalence of diabetes mellitus (DM), which is one of the most serious cardiovascular complications of DM and a major cause of death in diabetic patients. Although the pathological molecular features of DCM have not been fully elucidated, increasing evidence suggests that impaired autophagy in cardiomyocytes plays a nonnegligible role in the development of DCM. It has been shown that SUMOylation [SUMO = small ubiquitin-like modifier], a post-translational modification of proteins, and its associated ubiquitin-proteasome system mediates protein quality control in the heart and plays an important role in the proteotoxic environment of the heart. Specifically, the expression of ubiquitin-conjugating enzyme E2 (Ubc9), the only SUMO-E2 enzyme, exerts a positive regulatory effect on autophagy in cardiomyocytes with potential cardioprotective effects. This review focuses on the role that autophagy plays in DCM and the potential for Ubc9-regulated autophagy pathways to ameliorate DCM, highlighting the potential of Ubc9 as an interventional target in DCM and providing new insights into the pathogenesis of the disease.
© 2023 The Authors. Journal of Diabetes published by Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.
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RTA 408 ameliorates diabetic cardiomyopathy by activating Nrf2 to regulate mitochondrial fission and fusion and inhibiting NF-?B-mediated inflammation.
Am J Physiol Cell Physiol2023 Dec;():. doi: 10.1152/ajpcell.00467.2023.
Hao Jinjin, Zhou Jiedong, Hu Songqing, Zhang Peipei, Wu Haowei, Yang Juntao, Zhao Bingjie, Liu Hanxuan, Lin Hui, Chi Jufang, Lou Dajun,
Abstract
Diabetic cardiomyopathy (dCM) is a major complication of diabetes; however, specific treatments for dCM are currently lacking. RTA 408, a semisynthetic triterpenoid, has shown therapeutic potential against various diseases by activating the Nrf2 (Nuclear factor erythroid 2-related factor 2) signaling pathway. We established and models using high-glucose toxicity and db/db mice, respectively, to simulate dCM. Our results demonstrated that RTA 408 activated Nrf2 and alleviated various dCM-related cardiac dysfunctions, both and . Additionally, it was found that silencing the Nrf2 gene eliminated the cardioprotective effect of RTA 408. RTA 408 ameliorated oxidative stress in dCM mice and HG-exposed H9C2 cells by activating Nrf2, inhibiting mitochondrial fission, exerting anti-inflammatory effects through the Nrf2/NF-?B axis, and ultimately suppressing apoptosis, thereby providing cardiac protection against dCM. These findings provide valuable insights for potential dCM treatments.
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Loss of cardiac PFKFB2 drives Metabolic, Functional, and Electrophysiological Remodeling in the Heart.
bioRxiv2023 Nov;():. doi: 2023.11.22.568379.
Harold Kylene M, Matsuzaki Satoshi, Pranay Atul, Loveland Brooke L, Batushansky Albert, Mendez Garcia Maria F, Eyster Craig, Stavrakis Stavros, Chiao Ying Ann, Kinter Michael, Humphries Kenneth M,
Abstract
BACKGROUND:
Phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2) is a critical glycolytic regulator responsible for upregulation of glycolysis in response to insulin and adrenergic signaling. PFKFB2, the cardiac isoform of PFK-2, is degraded in the heart in the absence of insulin signaling, contributing to diabetes-induced cardiac metabolic inflexibility. However, previous studies have not examined how the loss of PFKFB2 affects global cardiac metabolism and function.
METHODS:
To address this, we have generated a mouse model with a cardiomyocyte-specific knockout of PFKFB2 (cKO). Using 9-month-old cKO and control (CON) mice, we characterized impacts of PFKFB2 on cardiac metabolism, function, and electrophysiology.
RESULTS:
cKO mice have a shortened lifespan of 9 months. Metabolically, cKO mice are characterized by increased glycolytic enzyme abundance and pyruvate dehydrogenase (PDH) activity, as well as decreased mitochondrial abundance and beta oxidation, suggesting a shift toward glucose metabolism. This was supported by a decrease in the ratio of palmitoyl carnitine to pyruvate-dependent mitochondrial respiration in cKO relative to CON animals. Metabolomic, proteomic, and western blot data support the activation of ancillary glucose metabolism, including pentose phosphate and hexosamine biosynthesis pathways. Physiologically, cKO animals exhibited impaired systolic function and left ventricular (LV) dilation, represented by reduced fractional shortening and increased LV internal diameter, respectively. This was accompanied by electrophysiological alterations including increased QT interval and other metrics of delayed ventricular conduction.
CONCLUSIONS:
Loss of PFKFB2 results in metabolic remodeling marked by cardiac ancillary pathway activation. This could delineate an underpinning of pathologic changes to mechanical and electrical function in the heart.
CLINICAL PERSPECTIVE:
We have generated a novel cardiomyocyte-specific knockout model of PFKFB2, the cardiac isoform of the primary glycolytic regulator Phosphofructokinase-2 (cKO).The cKO model demonstrates that loss of cardiac PFKFB2 drives metabolic reprogramming and shunting of glucose metabolites to ancillary metabolic pathways.The loss of cardiac PFKFB2 promotes electrophysiological and functional remodeling in the cKO heart. PFKFB2 is degraded in the absence of insulin signaling, making its loss particularly relevant to diabetes and the pathophysiology of diabetic cardiomyopathy.Changes which we observe in the cKO model are consistent with those often observed in diabetes and heart failure of other etiologies.Defining PFKFB2 loss as a driver of cardiac pathogenesis identifies it as a target for future investigation and potential therapeutic intervention.
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Diabetes and vascular disease: New therapeutic avenues.
Vascul Pharmacol2023 Nov;():107247. doi: 10.1016/j.vph.2023.107247.
Del Prato Stefano,
Abstract
Vascular disease remains a major burden for people with type 2 diabetes due to the syndromic nature of the disease. Therefore, strategies that go beyond the mere glycemic control need to be enacted. Recent evidence has been gathered showing the cardiorenal potential of medications such as glucagon-like peptide1-receptor agonists (GLP1RA) and sodium-glucose transporter 2-inhibitors (SGLT2i). Even greater are the expectations for the new dual glucose-dependent insulinotropic-peptide (GIP) and GLP1 agonists. Along with these new diabetes drugs, opportunities are now provided for renal protecting agents like finerenone. Finally, new pharmacologic venues are currently under investigation for treating diabetic cardiomyopathy, a cause for heart failure in diabetes.
Copyright © 2023. Published by Elsevier Inc.
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Shengmai injection inhibits palmitic acid-induced myocardial cell inflammatory death via regulating NLRP3 inflammasome activation.
Heliyon2023 Nov;9(11):e21522. doi: e21522.
Yin Gang, Hu Zi-Qing, Li Jing-Ya, Wen Zhong-Yu, Du Yong-Qin, Zhou Peng, Wang Liang,
Abstract
OBJECTIVE:
To determine the protective effect of Shengmai injection (SMI) on myocardial injury in diabetic rats and its mechanism based on NLRP3/Caspase1 signaling pathway.
MATERIALS AND METHODS:
Rat H9c2 cardiomyocytes were cultured , and the cell survival rate of different concentrations of palmitate acid (PA) and different concentrations of SMI were detected by CCK-8. The myocardial injury cell model was induced with PA, treated with SMI, and combined with NLRP3 specific inhibitor (MCC950) to interfere with the high-fat-induced rat H9c2 myocardial cell injury model. The cell changes were observed by Hoechst/PI staining and the expression levels of MDA, SOD, and ROS in each group were detected. The protein and gene changes of the NLRP3/Caspase-1 signaling pathway were detected by Western blot and RT-qPCR, respectively.
RESULTS:
200 ?mol/L of PA were selected to induce the myocardial injury cell model and 25 ?L/mL of SMI was selected for intervention concentration. SMI could significantly reduce MDA expression, increase SOD level, and decrease ROS production. SMI could decrease the gene expression levels of NLRP3, ASC, Caspase-1, and GSDMD, and the protein expressions of NLRP3, ASC, Cleaved Caspase-1, GSDMD, and GSDMD-N.
CONCLUSION:
SMI can inhibit the high-fat-induced activation of the NLRP3/Caspase-1 signaling pathway, intervene in cardiomyocyte pyroptosis, and prevent diabetic cardiomyopathy.
© 2023 The Authors. Published by Elsevier Ltd.
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Dynamic changes in cardiac morphology, function, and diffuse myocardial fibrosis duration of diabetes in type 1 and type 2 diabetic mice models using 7.0 T CMR and echocardiography.
Front Endocrinol (Lausanne)2023 ;14():1278619. doi: 1278619.
Zhang Hong-Kai, Shi Chun-Yan, Liu Dong-Ting, Gao Hui-Qiang, Zhao Qian-Qian, Zhang Nan, Yang Lin, Li Guo-Qi, Wang Yue-Li, Du Yu, Li Qing, Bo Kai-Rui, Zhuang Baiyan, Fan Zhan-Ming, Sun Zhong-Hua, Xu Lei,
Abstract
BACKGROUND:
Diabetes mellitus (DM) is associated with an increased risk of cardiovascular disease (CVD). Hence, early detection of cardiac changes by imaging is crucial to reducing cardiovascular complications.
PURPOSE:
Early detection of cardiac changes is crucial to reducing cardiovascular complications. The study aimed to detect the dynamic change in cardiac morphology, function, and diffuse myocardial fibrosis(DMF) associated with T1DM and T2DM mice models.
MATERIALS AND METHODS:
4-week-old C57Bl/6J male mice were randomly divided into control (n=30), T1DM (n=30), and T2DM (n=30) groups. A longitudinal study was conducted every 4 weeks using serial 7.0T CMR and echocardiography imaging. Left ventricular ejection fraction (LV EF), tissue tracking parameters, and DMF were measured by cine CMR and extracellular volume fraction (ECV). Global peak circumferential strain (GCPS), peak systolic strain rate (GCPSSR) values were acquired by CMR feature tracking. LV diastolic function parameter (E/E') was acquired by echocardiography. The correlations between the ECV and cardiac function parameters were assessed by Pearson's test.
RESULTS:
A total of 6 mice were included every 4 weeks in control, T1DM, and T2DM groups for analysis. Compared to control group, an increase was detected in the LV mass and E/E' ratio, while the values of GCPS, GCPSSR decreased mildly in DM. Compared to T2DM group, GCPS and GCPSSR decreased earlier in T1DM(GCPS 12W,P=0.004; GCPSSR 12W,P=0.04). ECV values showed a significant correlation with GCPS and GCPSSR in DM groups. Moreover, ECV values showed a strong positive correlation with E/E'(T1DM,r=0.757,P
CONCLUSION:
The combination of ECV and cardiac mechanical parameters provide imaging biomakers for pathophysiology, early diagnosis of cardiac morphology, function and early intervention in diabetic cardiomyopathy in the future.
Copyright © 2023 Zhang, Shi, Liu, Gao, Zhao, Zhang, Yang, Li, Wang, Du, Li, Bo, Zhuang, Fan, Sun and Xu.
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Chinese herbal medicine and active ingredients for diabetic cardiomyopathy: molecular mechanisms regulating endoplasmic reticulum stress.
Front Pharmacol2023 ;14():1290023. doi: 1290023.
Ao Lianjun, Chen Zhengtao, Yin Jiacheng, Leng Yulin, Luo Yue, Fu Xiaoxu, Liu Hanyu, Liu Xiaoke, Gao Hong, Xie Chunguang,
Abstract
Diabetic cardiomyopathy (DCM) is one of the serious microvascular complications of diabetes mellitus. It is often associated with clinical manifestations such as arrhythmias and heart failure, and significantly reduces the quality of life and years of survival of patients. Endoplasmic reticulum stress (ERS) is the removal of unfolded and misfolded proteins and is an important mechanism for the maintenance of cellular homeostasis. ERS plays an important role in the pathogenesis of DCM by causing cardiomyocyte apoptosis, insulin resistance, calcium imbalance, myocardial hypertrophy and fibrosis. Targeting ERS is a new direction in the treatment of DCM. A large number of studies have shown that Chinese herbal medicine and active ingredients can significantly improve the clinical outcome of DCM patients through intervention in ERS and effects on myocardial structure and function, which has become one of the hot research directions. The aim of this review is to elucidate and summarize the roles and mechanisms of Chinese herbal medicine and active ingredients that have the potential to modulate endoplasmic reticulum stress, thereby contributing to better management of DCM. Databases such as PubMed, Web of Science, China National Knowledge Internet, and Wanfang Data Knowledge Service Platform were used to search, analyze, and collect literature, in order to review the mechanisms by which phytochemicals inhibit the progression of DCM by targeting the ERS and its key signaling pathways. Keywords used included "diabetic cardiomyopathy" and "endoplasmic reticulum stress." This review found that Chinese herbs and their active ingredients can regulate ERS through IRE1, ATF6, and PERK pathways to reduce cardiomyocyte apoptosis, ameliorate myocardial fibrosis, and attenuate myocardial hypertrophy for the treatment of DCM. A comprehensive source of information on potential ERS inhibitors is provided in this review. The analysis of the literature suggests that Chinese herbal medicine and its active ingredients can be used as potential drug candidates for the treatment of DCM. In short, we cannot ignore the role of traditional Chinese medicine in regulating ERS and treating DCM, and look forward to more research and new drugs to come.
Copyright © 2023 Ao, Chen, Yin, Leng, Luo, Fu, Liu, Liu, Gao and Xie.
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Mitochondrial quality control in health and cardiovascular diseases.
Front Cell Dev Biol2023 ;11():1290046. doi: 1290046.
Atici Asli E, Crother Timothy R, Noval Rivas Magali,
Abstract
Cardiovascular diseases (CVDs) are one of the primary causes of mortality worldwide. An optimal mitochondrial function is central to supplying tissues with high energy demand, such as the cardiovascular system. In addition to producing ATP as a power source, mitochondria are also heavily involved in adaptation to environmental stress and fine-tuning tissue functions. Mitochondrial quality control (MQC) through fission, fusion, mitophagy, and biogenesis ensures the clearance of dysfunctional mitochondria and preserves mitochondrial homeostasis in cardiovascular tissues. Furthermore, mitochondria generate reactive oxygen species (ROS), which trigger the production of pro-inflammatory cytokines and regulate cell survival. Mitochondrial dysfunction has been implicated in multiple CVDs, including ischemia-reperfusion (I/R), atherosclerosis, heart failure, cardiac hypertrophy, hypertension, diabetic and genetic cardiomyopathies, and Kawasaki Disease (KD). Thus, MQC is pivotal in promoting cardiovascular health. Here, we outline the mechanisms of MQC and discuss the current literature on mitochondrial adaptation in CVDs.
Copyright © 2023 Atici, Crother and Noval Rivas.
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Proteomic and Phosphoproteomic Analysis of Right Ventricular Hypertrophy in the Pulmonary Hypertension Rat Model.
J Proteome Res2023 Nov;():. doi: 10.1021/acs.jproteome.3c00546.
Luo Ang, Jia Yangfan, Hao Rongrong, Zhou Xia, Bao Changlei, Yang Lei, Gu Chenxin, Tang Haiyang, Chu Ai-Ai,
Abstract
Pulmonary arterial hypertension (PAH) is a progressive disease that affects both the lungs and heart. Right ventricle (RV) hypertrophy is a primary pathological feature of PAH; however, its underlying molecular mechanisms remain insufficiently studied. In this study, we employed tandem mass tag (TMT)-based quantitative proteomics for the integrative analysis of the proteome and phosphoproteome of the RV derived from monocrotaline-induced PAH model rats. Compared with control samples, 564 significantly upregulated proteins, 616 downregulated proteins, 622 downregulated phosphopeptides, and 683 upregulated phosphopeptides were identified ( log 1.2) in the MCT samples. The quantitative real-time polymerase chain reaction (qRT-PCR) validated the expression levels of top 20 significantly altered proteins, including Nppa (natriuretic peptides A), latent TGF-? binding protein 2 (Ltbp2), periostin, connective tissue growth factor 2 (Ccn2), Ncam1 (neural cell adhesion molecule), quinone reductase 2 (Nqo2), and tropomodulin 4 (Tmod4). Western blotting confirmed the upregulation of Ncam1 and downregulation of Nqo2 and Tmod4 in both MCT-induced and hypoxia-induced PH rat models. Pathway enrichment analyses indicated that the altered proteins are associated with pathways, such as vesicle-mediated transport, actin cytoskeleton organization, TCA cycle, and respiratory electron transport. These significantly changed phosphoproteins were enriched in pathways such as diabetic cardiomyopathy, hypertrophic cardiomyopathy, glycolysis/gluconeogenesis, and cardiac muscle contraction. In summary, this study provides an initial analysis of the RV proteome and phosphoproteome in the progression of PAH, highlighting several RV dysfunction-associated proteins and pathways.
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Scutellarin Alleviates Diabetic Retinopathy via the Suppression of Nucleotide-Binding Oligomerization Domain (NOD)-Like Receptor Pyrin Domain Containing Protein 3 Inflammasome Activation.
Curr Eye Res2023 Nov;():1-8. doi: 10.1080/02713683.2023.2273777.
Yang Lina, Li Zheming, Fang Jian,
Abstract
PURPOSE:
Diabetic retinopathy, a prevalent complication of diabetes, represents the leading cause of vision loss and blindness among middle-aged and elderly populations. Recent research has demonstrated the ameliorating effects of scutellarin on diabetes-associated complications such as diabetic retinopathy and type 2 diabetic cardiomyopathy. However, investigations into its protective impact and underlying mechanisms on diabetic retinopathy are scant. This study aims to explore the therapeutic potential of scutellarin in diabetic retinopathy treatment.
METHODS:
Diabetic retinopathy was induced in rats through intraperitoneal injections of streptozotocin (STZ, 60?mg/kg) administered daily for three consecutive days. Following this, diabetic retinopathy rats received daily intragastric administration of scutellarin (40?mg/kg) for 42?days.
RESULTS:
Our findings suggest that scutellarin alleviates histological damage in the retinal tissues of streptozotocin-challenged rats. Furthermore, scutellarin effectively enhances total retinal thickness and increases the number of ganglion cell layer (GCL) cells in the retinal tissues of streptozotocin-treated rats. Scutellarin also demonstrated anti-inflammatory and antioxidant effects in the retinal tissues of STZ-induced rats, as indicated by reduced levels of tumor necrosis factor-?, interleukin-1?, and interleukin-6, and elevated levels of glutathione peroxidase, superoxide dismutase, and catalase. Additionally, scutellarin effectively inhibited the expression of NOD-like receptor pyrin domain containing protein 3 inflammasome-related markers in the retinal tissues of streptozotocin-administered rats.
CONCLUSIONS:
Collectively, our results indicate that scutellarin significantly reduces streptozotocin-induced retinal inflammation, an effect that may be partially attributed to the suppression of NLRP3 inflammasome activation.
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The essential role of glutamine metabolism in diabetic cardiomyopathy: A review.
Medicine (Baltimore)2023 Nov;102(47):e36299. doi: e36299.
Zhang Yiying,
Abstract
Diabetic cardiomyopathy (DCM) is a pathophysiological condition caused by diabetes mellitus and is the leading cause of diabetes mellitus-related mortality. The pathophysiology of DCM involves various processes, such as oxidative stress, inflammation, ferroptosis, and abnormal protein modification. New evidence indicates that dysfunction of glutamine (Gln) metabolism contributes to the pathogenesis of DCM by regulating these pathophysiological mechanisms. Gln is a conditionally essential amino acid in the human body, playing a vital role in maintaining cell function. Although the precise molecular mechanisms of Gln in DCM have yet to be fully elucidated, recent studies have shown that supplementing with Gln improves cardiac function in diabetic hearts. However, excessive Gln may worsen myocardial injury in DCM by generating a large amount of glutamates or increasing O-GlcNacylation. To highlight the potential therapeutic method targeting Gln metabolism and its downstream pathophysiological mechanisms, this article aims to review the regulatory function of Gln in the pathophysiological mechanisms of DCM.
Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.
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Echocardiographic Changes in Saudi Patients with Type 2 Diabetes Mellitus.
Medicina (Kaunas)2023 Nov;59(11):. doi: 1985.
Almigbal Turky H, Almunif Dina S, Aburisheh Khaled H, Barhoush Mazen M, Aldhahi Reem A, Anabi Mohammed J, Alotaibi Obeed A,
Abstract
: Cardiovascular disease is one of the leading causes of morbidity and mortality among the diabetic population. Given the high prevalence of diabetes mellitus (DM) in Saudi Arabia and the high prevalence of heart failure in the diabetic population, this study assesses the echocardiographic changes in Saudi patients with type 2 DM (T2DM) compared with healthy controls. : In this retrospective case-control study, 80 patients with diabetes (45 males, age: 58.78 ± 10.2 years) were compared with 80 controls (45 males, age: 58.6 ± 10 years) who underwent an echocardiographic study in the King Saud University Medical City, Riyadh, Saudi Arabia. : There were no significant differences between the patients with diabetes and controls in terms of aortic root diameter, left atrium diameter, posterior wall, interventricular wall thickness, left ventricular diameters and ejection fraction. However, diastolic dysfunction was statistically significantly higher in the diabetic group than in the control group (
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