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Ju J, Cheng C, Cui L, Hong B, Zhan Q, Wang Q, Cui X, Su D, Huang Y, Kang C. EPIC-1042 alleviates cerebral ischemic/reperfusion injury through TAX1BP1-induced mitophagy. Free Radic Biol Med 2025; 232:367-381. [PMID: 40107570 DOI: 10.1016/j.freeradbiomed.2025.03.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Revised: 03/14/2025] [Accepted: 03/15/2025] [Indexed: 03/22/2025]
Abstract
Post ischemia-reperfusion (I/R) injury, an upregulation in Polymerase I and transcript release factor (PTRF) expression is observed. PTRF is implicated in the regulation of various cellular processes within neuronal cells, thereby exacerbating the deleterious effects of I/R injury. EPIC-1042 is a small molecule pharmacological agent that exhibits specificity in binding to PTRF. Therefore, this study aimed to explore whether EPIC-1042 could be used as a treatment for I/R injury. To achieve this goal, we observed brain injury in mice following EPIC-1042 pre-administration, and then transitioned to therapeutic administration. After observing the pre-protective and therapeutic effects of the drug, proteomic analysis revealed that the expression of TAX1BP1 continued to decline in a time-dependent manner, while EPIC-1042 was able to inhibit this decline. However, the function of TAX1BP1 in ischemic stroke is not yet fully understood. Subsequent experiments confirmed that the addition of EPIC-1042 resulted in an enhancement of mitophagy. Silencing the expression of TAX1BP1 abrogated the drug's effects, indicating that EPIC-1042 exerts a protective function by promoting mitophagy via TAX1BP1 mediation. We further investigated the synergistic effects of EPIC-1042 and edaravone by administering the two drugs in combination, observing an enhanced therapeutic efficacy compared to the administration of each drug alone. Subsequently, we optimized the administration protocol for the two drugs by utilizing liposome encapsulation for both drugs. This approach enabled us to achieve significant therapeutic outcomes while reducing both the dosage and frequency of administration, thereby demonstrating the potential for clinical translation of EPIC-1042.
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Affiliation(s)
- Jiasheng Ju
- General Hospital of Tianjin Medical University, Lab of Neuro-oncology, Tianjin Neurological Institute, Tianjin, 300052, China
| | - Chunchao Cheng
- General Hospital of Tianjin Medical University, Lab of Neuro-oncology, Tianjin Neurological Institute, Tianjin, 300052, China
| | - Longtao Cui
- General Hospital of Tianjin Medical University, Lab of Neuro-oncology, Tianjin Neurological Institute, Tianjin, 300052, China
| | - Biao Hong
- General Hospital of Tianjin Medical University, Lab of Neuro-oncology, Tianjin Neurological Institute, Tianjin, 300052, China
| | - Qi Zhan
- General Hospital of Tianjin Medical University, Lab of Neuro-oncology, Tianjin Neurological Institute, Tianjin, 300052, China
| | - Qixue Wang
- General Hospital of Tianjin Medical University, Lab of Neuro-oncology, Tianjin Neurological Institute, Tianjin, 300052, China
| | - Xiaoteng Cui
- General Hospital of Tianjin Medical University, Lab of Neuro-oncology, Tianjin Neurological Institute, Tianjin, 300052, China
| | - Dongyuan Su
- General Hospital of Tianjin Medical University, Lab of Neuro-oncology, Tianjin Neurological Institute, Tianjin, 300052, China
| | - Yanping Huang
- General Hospital of Tianjin Medical University, Lab of Neuro-oncology, Tianjin Neurological Institute, Tianjin, 300052, China
| | - Chunsheng Kang
- General Hospital of Tianjin Medical University, Lab of Neuro-oncology, Tianjin Neurological Institute, Tianjin, 300052, China.
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Li YY, Meng FL, Zhou SY, Du JM, Li WJ, Liu QY, Wu L, Zhao MM, Jin Y, Zhang QY, Li Y, Su GH. CDX1 improves nicotine induced cardiac fibroblasts activation and cardiomyocyte hypertrophy by alleviating autophagic flux impairment through modulation of LAPTM4B. Sci Rep 2025; 15:9985. [PMID: 40121311 PMCID: PMC11929911 DOI: 10.1038/s41598-025-94160-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2024] [Accepted: 03/12/2025] [Indexed: 03/25/2025] Open
Abstract
Nicotine-induced impairment of autophagic flux promotes the onset of myocardial remodelling, thereby exacerbating heart failure. In this study, we investigated the role and molecular mechanisms of the transcription factor CDX1 in cardiac fibroblasts (CFs) activation and cardiomyocyte hypertrophy induced by nicotine. We found that CDX1 expression was increased in response to nicotine. However, a decrease in CDX1 further exacerbated the nicotine-induced blockade of autophagic flux, thereby aggravating CFs activation and cardiomyocyte hypertrophy. This effect was attributed to the suppression of the autophagic regulator LAPTM4B transcription by CDX1 and the subsequent activation of the mTOR pathway. In contrast, CDX1 overexpression promoted LAPTM4B expression, resulting in the opposite effect. In conclusion, our study demonstrated that CDX1/LAPTM4B axis could alleviate nicotine-induced autophagy flux impairment by inhibiting mTORC1 pathway activation, thereby alleviating CFs activation and cardiomyocyte hypertrophy, and exerting cardioprotective functions.
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Affiliation(s)
- Yue-Yan Li
- Department of Cardiology, Jinan Central Hospital, Shandong University, Jinan, China
- Research Center for Translational Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Fan-Liang Meng
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Si-Yuan Zhou
- Department of Cardiology, Jinan Central Hospital, Shandong University, Jinan, China
| | - Jia-Min Du
- Department of Cardiology, Jinan Central Hospital, Shandong University, Jinan, China
| | - Wen-Jing Li
- Research Center for Translational Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Qi-Yun Liu
- Department of Cardiology, Shandong Second Medical University, Weifang, China
| | - Lei Wu
- Research Center for Translational Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Meng-Meng Zhao
- Research Center for Translational Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Yi Jin
- Research Center for Translational Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Qun-Ye Zhang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Department of Cardiology, Qilu Hospital, Shandong University, Jinan, 250012, China
| | - Ying Li
- Department of Cardiology, Jinan Central Hospital, Shandong University, Jinan, China.
- Research Center for Translational Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, China.
| | - Guo-Hai Su
- Department of Cardiology, Jinan Central Hospital, Shandong University, Jinan, China.
- Research Center for Translational Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, China.
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Luo XY, Huang LH, Kang KP. Association between high-sensitivity troponin T levels below the ninety-ninth percentile and diabetic kidney disease: A cross-sectional study. World J Diabetes 2025; 16:99108. [PMID: 40093281 PMCID: PMC11885984 DOI: 10.4239/wjd.v16.i3.99108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Revised: 12/13/2024] [Accepted: 01/06/2025] [Indexed: 01/21/2025] Open
Abstract
BACKGROUND Identification of myocardial injury has traditionally relied on high-sensitivity troponin T (hs-TnT) levels exceeding the 99th percentile threshold. However, patients with detectable hs-TnT levels below this threshold represent a heterogeneous group with an inadequately characterized risk profile. AIM To investigate the association between hs-TnT levels below the 99th percentile and the presence of diabetic kidney disease (DKD) in patients with diabetes mellitus. METHODS This study analyzed data from the National Health and Nutrition Examination Survey obtained between 1999 and 2004, focusing on adults with type 2 diabetes mellitus. Serum hs-TnT concentrations were evaluated. DKD was defined as impaired glomerular filtration rate (< 60 mL/minute/1.73 m²), proteinuria (urinary albumin-to-creatinine ratio of ≥ 30 mg/g), or both conditions in patients with diabetes mellitus. Weighted multivariable logistic regression analysis and restricted cubic spline analyses were employed to examine the independent association between hs-TnT and DKD, with the likelihood ratio test being used to evaluate nonlinearity. RESULTS The study included 2505 patients with a mean age of 55.02 (standard error: 0.72) years, of whom 44.87% were females. Among the participants, 909 (32.34%) were diagnosed with DKD. Multivariable logistic regression analysis indicated that, compared to the lowest tertile of hs-TnT (< 5.93 ng/L), tertile 2 (5.94-9.79 ng/L) had an odds ratio of 1.25 (95% confidence interval: 0.77-2.02, P = 0.350), while tertile 3 (9.80-21.88 ng/L) had an odds ratio of 2.07 (95% confidence interval: 1.13-3.80, P = 0.022), with a significant trend (P for trend = 0.022). Smoothed curve fitting demonstrated a linear association between hs-TnT levels and DKD in the overall population (P = 0.061 for nonlinearity) and in male (P = 0.136 for nonlinearity) and female (P = 0.067 for nonlinearity) subgroups. Further stratification and sensitivity analyses yielded consistent conclusions. CONCLUSION Our study findings suggest that in individuals with type 2 diabetes, detectable hs-TnT levels below the 99th percentile are associated with DKD.
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Affiliation(s)
- Xiao-Yan Luo
- Department of Interventional Radiology, The Second Affiliated Hospital of Gannan Medical University, Ganzhou 341600, Jiangxi Province, China
| | - Li-Hua Huang
- Department of Clinical Laboratory, The Second Affiliated Hospital of Gannan Medical University, Ganzhou 341600, Jiangxi Province, China
| | - Kun-Peng Kang
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
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Xu M, Zhao J, Zhu L, Ge C, Sun Y, Wang R, Li Y, Dai X, Kuang Q, Hu L, Luo J, Kuang G, Ren Y, Wang B, Tan J, Shi S. Targeting PYK2 with heterobifunctional T6BP helps mitigate MASLD and MASH-HCC progression. J Hepatol 2025; 82:277-300. [PMID: 39260704 DOI: 10.1016/j.jhep.2024.08.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 08/01/2024] [Accepted: 08/12/2024] [Indexed: 09/13/2024]
Abstract
BACKGROUND & AIMS The mechanisms underlying the regulation of hepatocyte non-receptor tyrosine kinases in metabolic dysfunction-associated steatohepatitis (MASH) remain largely unclear. METHODS Hepatocyte-specific overexpression or deletion and anti-protein tyrosine kinase 2 beta (PYK2) or anti-TRAF6-binding protein (T6BP) crosslinking were utilized to study fatty liver protection by T6BP. A P-PTC (peptide-proteolysis targeting chimera) degrades PYK2 to block MASH progression. RESULTS We found that T6BP is a novel and critical suppressor of PYK2 that reduces hepatic lipid accumulation, pro-inflammatory factor release, and pro-fibrosis production. Mechanistic evidence suggests that T6BP directly targets PYK2 and prevents its N-terminal FERM domain-triggered dimerization, disrupting downstream PYK2-JNK signaling hyperactivation. Additionally, T6BP favorably recruits CBL, a particular E3 ubiquitin ligase targeting PYK2, to form a complex and degrade PYK2. T6BP (F1), a core fragment of T6BP, directly blocks N-terminal FERM domain-associated dimerization of PYK2, followed by T6BP-recruiting CBL-mediated PYK2 degradation in a typical T6BP-dependent manner when the tiny fragment is specifically expressed using thyroxine binding globulin (TBG) vectors. This inhibits the progression of MASH, MASH-related hepatocellular carcinoma, and metabolic syndrome in dietary rodent models. We devised, and validated in animal models, the first-ever P-PTC based on the core segment of T6BP, as a ligand for the targeted recruitment of CBL, that could be used to target metabolic disorders like MASH. CONCLUSIONS Our study uncovered a previously unknown mechanism, with T6BP identified as a key suppressor of steatosis. This, alongside the discovery of crucial T6BP-based fragments that interrupt PYK2 dimerization hold much promise for the treatment of MASH. IMPACT AND IMPLICATIONS Excessive high-energy diet ingestion is critical in driving steatohepatitis via regulation of hepatocyte non-receptor tyrosine kinases. The mechanisms underlying the regulation of hepatocyte PYK2 in metabolic dysfunction-associated steatohepatitis remain largely unclear. Here, we found that T6BP as a critical fatty liver eliminator could be used for the development of promising therapeutic options. Additionally, vital T6BP-based pharmacon fragments that impede PYK2 dimerization have been found, offering new and effective treatments for advanced fatty liver symptoms and complications.
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Affiliation(s)
- Minxuan Xu
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education, Chongqing 400067, PR China; College of Modern Health Industry, Chongqing University of Education, Chongqing 400067, PR China; Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400030, PR China.
| | - Junjie Zhao
- Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400030, PR China
| | - Liancai Zhu
- Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400030, PR China
| | - Chenxu Ge
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education, Chongqing 400067, PR China; College of Modern Health Industry, Chongqing University of Education, Chongqing 400067, PR China; Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400030, PR China
| | - Yan Sun
- Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400030, PR China
| | - Ranran Wang
- College of Modern Health Industry, Chongqing University of Education, Chongqing 400067, PR China; School of Biological and Chemical Engineering, Chongqing University of Education, Chongqing 400067, PR China; Collaborative Innovation Center for Child Nutrition and Health Development, Chongqing University of Education, Chongqing 400067, PR China
| | - Yuanyuan Li
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education, Chongqing 400067, PR China; College of Modern Health Industry, Chongqing University of Education, Chongqing 400067, PR China
| | - Xianling Dai
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education, Chongqing 400067, PR China; Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400030, PR China
| | - Qin Kuang
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education, Chongqing 400067, PR China; Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400030, PR China
| | - Linfeng Hu
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education, Chongqing 400067, PR China; College of Modern Health Industry, Chongqing University of Education, Chongqing 400067, PR China; Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400030, PR China
| | - Jing Luo
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education, Chongqing 400067, PR China; College of Modern Health Industry, Chongqing University of Education, Chongqing 400067, PR China
| | - Gang Kuang
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education, Chongqing 400067, PR China; College of Modern Health Industry, Chongqing University of Education, Chongqing 400067, PR China
| | - Yanrong Ren
- College of Modern Health Industry, Chongqing University of Education, Chongqing 400067, PR China; School of Biological and Chemical Engineering, Chongqing University of Education, Chongqing 400067, PR China.
| | - Bochu Wang
- Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400030, PR China.
| | - Jun Tan
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education, Chongqing 400067, PR China; College of Modern Health Industry, Chongqing University of Education, Chongqing 400067, PR China.
| | - Shengbin Shi
- Department of Gastrointestinal Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University & Shandong Academy of Medical Science, Jinan 250117, PR China.
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Shen C, Yang S, Wu N, Jian W, Du T, Chu H, Du W. Overexpression of MD1 ameliorates pathological myocardial remodeling in diabetic cardiomyopathy by TLR4/STAT3 signaling pathway. Mol Cell Endocrinol 2024; 592:112315. [PMID: 38878954 DOI: 10.1016/j.mce.2024.112315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 06/11/2024] [Accepted: 06/12/2024] [Indexed: 06/21/2024]
Abstract
Diabetic cardiomyopathy (DCM) is characterized by oxidative damage and inflammatory responses. Myeloid differentiation protein 1 (MD1) exhibits antioxidant and anti-inflammatory properties. However, the specific role of MD1 in DCM has yet to be elucidated. This study aims to investigate the role of MD1 in DCM and to elucidate the underlying mechanisms. We utilized a gain-of-function approach to explore the involvement of MD1 in DCM. Diabetes was induced in MD1-transgenic (MD1-TG) mice and their wild-type (WT) counterparts via streptozotocin (STZ) injection. Additionally, a diabetes cell model was established using H9c2 cells exposed to high glucose levels. We conducted comprehensive evaluations, including pathological analyses, echocardiography, electrocardiography, and molecular assessments, to elucidate the underlying mechanisms of MD1 in DCM. Notably, MD1 expression was reduced in the hearts of STZ-induced diabetic mice. Overexpression of MD1 significantly improved cardiac function and markedly inhibited ventricular pathological hypertrophy and fibrosis in these mice. Furthermore, MD1 overexpression resulted in a substantial decrease in myocardial reactive oxygen species (ROS) accumulation, mitigating myocardial oxidative stress and reducing the levels of inflammation-related markers such as IL-1β, IL-6, and TNF-α. Mechanistically, MD1 overexpression inhibited the activation of the TLR4/STAT3 signaling pathway, as demonstrated in both in vivo and in vitro experiments. The overexpression of MD1 significantly impeded pathological cardiac remodeling and improved cardiac function in STZ-induced diabetic mice. This effect was primarily attributed to a reduction in ROS accumulation and mitigation of myocardial oxidative stress and inflammation, facilitated by the inhibition of the TLR4/STAT3 signaling pathway.
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Affiliation(s)
- Caijie Shen
- Department of Cardiology, The First Affiliated Hospital of Ningbo University, Ningbo, China
| | - Shuwen Yang
- Department of Cardiology, The First Affiliated Hospital of Ningbo University, Ningbo, China; Health Science Center, Ningbo University, Ningbo, China
| | - Nan Wu
- Department of Cardiology, The First Affiliated Hospital of Ningbo University, Ningbo, China
| | - Wang Jian
- Department of Cardiology, The First Affiliated Hospital of Ningbo University, Ningbo, China
| | - Tingsha Du
- Health Science Center, Ningbo University, Ningbo, China
| | - Huimin Chu
- Department of Cardiology, The First Affiliated Hospital of Ningbo University, Ningbo, China.
| | - Weiping Du
- Department of Cardiology, The First Affiliated Hospital of Ningbo University, Ningbo, China.
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Wang Y, Feng W, Li S, Liu C, Jia L, Wang P, Li L, Du H, Yu W. Oxycodone attenuates lipopolysaccharide-induced myocardial injury by inhibiting inflammation, oxidation and pyroptosis via Nrf2/HO-1 signalling pathway. Clin Exp Pharmacol Physiol 2024; 51:e13910. [PMID: 39073215 DOI: 10.1111/1440-1681.13910] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Revised: 05/27/2024] [Accepted: 06/20/2024] [Indexed: 07/30/2024]
Abstract
Myocardial injury and cardiovascular dysfunction are the most common complications of sepsis, and effective therapeutic candidate is still lacking. This study aims to investigate the protective effect of oxycodone in myocardial injury of lipopolysaccharide-induced sepsis and its related signalling pathways. Wild-type and nuclear factor erythroid 2-related factor 2 (Nrf2)-knockout mice, as well as H9c2 cardiomyocytes cultures treated with lipopolysaccharide (LPS) were used as models of septic myocardial injury. H9c2 cardiomyocytes culture showed that oxycodone protected cells from pyroptosis induced by LPS. Mice model confirmed that oxycodone pretreatment significantly attenuated myocardial pathological damage and improved cardiac function demonstrated by increased ejection fraction (EF) and fractional shortening (FS), as well as decreased cardiac troponin I (cTnI) and creatine kinase isoenzymes MB (CK-MB). Oxycodone also reduced the levels of inflammatory factors and oxidative stress damage induced by LPS, which involves pyroptosis-related proteins including: Nod-like receptor protein 3 (NLRP3), Caspase 1, Apoptosis-associated speck-like protein contain a CARD (ASC), and Gasdermin D (GSDMD). These changes were mediated by Nrf2 and heme oxygenase-1 (HO-1) because Nrf2-knockout mice or Nrf2 knockdown in H9c2 cells significantly reversed the beneficial effect of oxycodone on oxidative stress, inflammatory responses and NLRP3-mediated pyroptosis. Our findings yielded that oxycodone therapy reduces LPS-induced myocardial injury by suppressing NLRP3-mediated pyroptosis via the Nrf2/HO-1 signalling pathway in vivo and in vitro.
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Affiliation(s)
- Yanting Wang
- The First Central Clinical College, Tianjin Medical University, Tianjin, China
| | - Wei Feng
- Department of Anesthesiology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Shaona Li
- Department of Anesthesiology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Cuicui Liu
- Department of Anesthesiology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Lili Jia
- Department of Anesthesiology, Tianjin First Central Hospital, Tianjin, China
| | - Pei Wang
- Department of Anesthesiology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Linlin Li
- Department of Anesthesiology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Hongyin Du
- Tianjin Municipal Health Commission, Tianjin, China
| | - Wenli Yu
- Department of Anesthesiology, The Affiliated Hospital of Qingdao University, Qingdao, China
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Li J, Xie Y, Zheng S, He H, Wang Z, Li X, Jiao S, Liu D, Yang F, Zhao H, Li P, Sun Y. Targeting autophagy in diabetic cardiomyopathy: From molecular mechanisms to pharmacotherapy. Biomed Pharmacother 2024; 175:116790. [PMID: 38776677 DOI: 10.1016/j.biopha.2024.116790] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Revised: 05/13/2024] [Accepted: 05/17/2024] [Indexed: 05/25/2024] Open
Abstract
Diabetic cardiomyopathy (DCM) is a cardiac microvascular complication caused by metabolic disorders. It is characterized by myocardial remodeling and dysfunction. The pathogenesis of DCM is associated with abnormal cellular metabolism and organelle accumulation. Autophagy is thought to play a key role in the diabetic heart, and a growing body of research suggests that modulating autophagy may be a potential therapeutic strategy for DCM. Here, we have summarized the major signaling pathways involved in the regulation of autophagy in DCM, including Adenosine 5'-monophosphate-activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR), Forkhead box subfamily O proteins (FOXOs), Sirtuins (SIRTs), and PTEN-inducible kinase 1 (PINK1)/Parkin. Given the significant role of autophagy in DCM, we further identified natural products and chemical drugs as regulators of autophagy in the treatment of DCM. This review may help to better understand the autophagy mechanism of drugs for DCM and promote their clinical application.
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Affiliation(s)
- Jie Li
- China-Japan Friendship Hospital (Institute of Clinical Medical Sciences), Beijing, China
| | - Yingying Xie
- Department of Cardiology, China-Japan Friendship Hospital (Institute of Clinical Medical Sciences), Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Shuwen Zheng
- Beijing University of Chinese Medicine School of Traditional Chinese Medicine, Beijing, China
| | - Haoming He
- Department of Cardiology, China-Japan Friendship Hospital (Institute of Clinical Medical Sciences), Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Zhe Wang
- Department of Cardiology, China-Japan Friendship Hospital (Institute of Clinical Medical Sciences), Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Xuexi Li
- Department of Cardiology, China-Japan Friendship Hospital (Institute of Clinical Medical Sciences), Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Siqi Jiao
- Peking University China-Japan Friendship School of Clinical Medicine, Beijing, China
| | - Dong Liu
- Peking University China-Japan Friendship School of Clinical Medicine, Beijing, China
| | - Furong Yang
- Beijing University of Chinese Medicine School of Traditional Chinese Medicine, Beijing, China
| | - Hailing Zhao
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China.
| | - Ping Li
- Beijing Key Laboratory for Immune-Mediated Inflammatory Diseases, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China.
| | - Yihong Sun
- Department of Cardiology, China-Japan Friendship Hospital (Institute of Clinical Medical Sciences), Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China; Peking University China-Japan Friendship School of Clinical Medicine, Beijing, China.
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8
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Zuo GF, Wang LG, Huang L, Ren YF, Ge Z, Hu ZY, Zhang JJ, Chen SL. TAX1BP1 downregulation by STAT3 in cardiac fibroblasts contributes to diabetes-induced heart failure with preserved ejection fraction. Biochim Biophys Acta Mol Basis Dis 2024; 1870:166979. [PMID: 38065272 DOI: 10.1016/j.bbadis.2023.166979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 11/22/2023] [Accepted: 11/27/2023] [Indexed: 12/30/2023]
Abstract
Heart failure (HF) with preserved ejection fraction (HFpEF) is now the most common form of HF and has been reported to be closely related to diabetes. Accumulating evidence suggests that HFpEF patients exhibit cardiac fibrosis. This study investigates whether direct targeted inhibition of the activation of cardiac fibroblasts (CFs), the main effector cells in cardiac fibrosis, improves diabetes-induced HFpEF and elucidates the underlying mechanisms. Twenty-week-old db/db mice exhibited HFpEF, as confirmed by echocardiography and hemodynamic measurements. Proteomics was performed on CFs isolated from the hearts of 20-week-old C57BL/6 and db/db mice. Bioinformatic prediction was used to identify target proteins. Experimental validation was performed in both high glucose (HG)-treated neonatal mouse CFs (NMCFs) and diabetic hearts. TAX1 binding protein 1 (TAX1BP1) was identified as the most significantly differentially expressed protein between 20-week-old C57BL/6 and db/db mice. TAX1BP1 mRNA and protein were markedly downregulated in CFs from diabetic hearts and HG-cultured NMCFs. Overexpression of TAX1BP1 profoundly inhibited HG/diabetes-induced NF-κB nuclear translocation and collagen synthesis in CFs, improved cardiac fibrosis, hypertrophy, inflammation and HFpEF in diabetic mice. Mechanistically, signal transducer and activator of transcription 3 (STAT3), which is phosphorylated and translocated from the cytoplasm into the nucleus under hyperglycemic conditions, bound to TAX1BP1 promoter and blocked TAX1BP1 transcriptional activity, consequently promoting NF-κB nuclear translocation and collagen synthesis in CFs, aggravating cardiac fibrosis, hypertrophy and inflammation, leading to HFpEF in db/db mice. Taken together, our findings demonstrate that targeting regulation of STAT3-TAX1BP1-NF-κB signaling in CFs may be a promising therapeutic approach for diabetes-induced HFpEF.
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Affiliation(s)
- Guang-Feng Zuo
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Li-Guo Wang
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Lu Huang
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Yi-Fei Ren
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China; Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China
| | - Zhen Ge
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Zuo-Ying Hu
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
| | - Jun-Jie Zhang
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
| | - Shao-Liang Chen
- Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
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Hu Y, Zhang S, Lou H, Mikaye MS, Xu R, Meng Z, Du M, Tang P, Chen Z, Chen Y, Liu X, Du Z, Zhang Y. Aloe-Emodin Derivative, an Anthraquinone Compound, Attenuates Pyroptosis by Targeting NLRP3 Inflammasome in Diabetic Cardiomyopathy. Pharmaceuticals (Basel) 2023; 16:1275. [PMID: 37765083 PMCID: PMC10536457 DOI: 10.3390/ph16091275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 08/27/2023] [Accepted: 09/06/2023] [Indexed: 09/29/2023] Open
Abstract
Diabetic cardiomyopathy (DCM) is widely recognized as a major contributing factor to the development of heart failure in patients with diabetes. Previous studies have demonstrated the potential benefits of traditional herbal medicine for alleviating the symptoms of cardiomyopathy. We have chemically designed and synthesized a novel compound called aloe-emodin derivative (AED), which belongs to the aloe-emodin (AE) family of compounds. AED was formed by covalent binding of monomethyl succinate to the anthraquinone mother nucleus of AE using chemical synthesis techniques. The purpose of this study was to investigate the effects and mechanisms of AED in treating DCM. We induced type 2 diabetes in Sprague-Dawley (SD) rats by administering a high-fat diet and streptozotocin (STZ) injections. The rats were randomly divided into six groups: control, DCM, AED low concentration (50 mg/kg/day), AED high concentration (100 mg/kg/day), AE (100 mg/kg/day), and positive control (glyburide, 2 mg/kg/day) groups. There were eight rats in each group. The rats that attained fasting blood glucose of ˃16.7 mmol/L were considered successful models. We observed significant improvements in cardiac function in the DCM rats with both AED and AE following four weeks of intragastric treatment. However, AED had a more pronounced therapeutic effect on DCM compared to AE. AED exhibited an inhibitory effect on the inflammatory response in the hearts of DCM rats and high-glucose-treated H9C2 cells by suppressing the pyroptosis pathway mediated by the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain 3 (NLRP3) inflammasome. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of differentially expressed genes showed a significant enrichment in the NOD-like receptor signaling pathway compared to the high-glucose group. Furthermore, overexpression of NLRP3 effectively reversed the anti-pyroptosis effects of AED in high-glucose-treated H9C2 cells. This study is the first to demonstrate that AED possesses the ability to inhibit myocardial pyroptosis in DCM. Targeting the pyroptosis pathway mediated by the NLRP3 inflammasome could provide a promising therapeutic strategy to enhance our understanding and treatment of DCM.
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Affiliation(s)
- Yingying Hu
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150086, China
| | - Shuqian Zhang
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150086, China
| | - Han Lou
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150086, China
| | - Monayo Seth Mikaye
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150086, China
| | - Run Xu
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150086, China
| | - Ziyu Meng
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150086, China
| | - Menghan Du
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150086, China
| | - Pingping Tang
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150086, China
| | - Zhouxiu Chen
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150086, China
| | - Yongchao Chen
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150086, China
| | - Xin Liu
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150086, China
- Research Unit of Noninfectious Chronic Diseases in Frigid Zone, Chinese Academy of Medical Sciences, 2019RU070, Harbin 150081, China
| | - Zhimin Du
- Institute of Clinical Pharmacology, The Second Affliated Hospital of Harbin Medical University (University Key Laboratory of Drug Research, Heilongjiang Province), Harbin 150086, China
- Department of Clinical Pharmacology College of Pharmacy, Harbin Medical University, Harbin 150081, China
- State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau 999078, China
| | - Yong Zhang
- Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150086, China
- Research Unit of Noninfectious Chronic Diseases in Frigid Zone, Chinese Academy of Medical Sciences, 2019RU070, Harbin 150081, China
- Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Harbin 150086, China
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10
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Liu Q, Deng C, Xing X, Hu Y, Wang Z, Liang Y. Silencing RIPK1/mTORC1 signalling attenuated the inflammation and oxidative stress in diabetic cardiomyopathy. Exp Cell Res 2023; 422:113417. [PMID: 36379276 DOI: 10.1016/j.yexcr.2022.113417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 10/20/2022] [Accepted: 11/09/2022] [Indexed: 11/13/2022]
Abstract
BACKGROUND Diabetes cardiomyopathy (DCM) is one of the major risk factors for the heart failure of the diabetic patients. RIPK1 maybe participate in the regulation of the oxidative stress and inflammation during DCM. METHODS H&E and Masson staining were utilized to assess the inflammation and fibrosis in myocardial tissues. CCK-8 and TUNEL staining were utilized to analyze cell viability and apoptosis, respectively. SOD activity and MDA content were detected utilizing the kits. The formation of autophagosomes was measured by immunofluorescence assay. RESULTS RIPK1 and RPTOR (a component of mTORC1) expression and oxidative stress level were upregulated, but autophagy was decreased in the myocardial tissues of DCM rat characterized by the high body weight and blood glucose, abnormal cardiac function, myocardial inflammation and fibrosis. High glucose (HG) treatment resulted in cell viability and autophagy level decreasing, inflammatory cytokines expression increasing and oxidative stress increasing in cardiac fibroblasts (CFs). Meanwhile, RIPK1 and RPTOR expression also was increased in HG-treated cells. HG-induced CFs apoptosis, inflammation, oxidative stress and the inhibition of HG to cell viability and autophagy was partly reversed by the inhibitor of RIPK1 and mTORC1. CONCLUSION Overall, RIPK1/mTORC1 signalling suppression improved HG-induced apoptosis, inflammation and oxidative stress through activation autophagy. These data provided a reliable evidence that RIPK1 may be a potential target for DCM therapeutic.
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Affiliation(s)
- Qin Liu
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, PR China
| | - Changqing Deng
- Department of Gastroenterology, The Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, Nanchang, 330006, Jiangxi Province, PR China
| | - Xianliang Xing
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, PR China
| | - Yanhui Hu
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, PR China
| | - Zhong Wang
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, PR China.
| | - Yingping Liang
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, PR China.
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11
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Shim JY, Chung JO, Jung D, Kang PS, Park SY, Kendi AT, Lowe VJ, Lee S. Parkin-mediated mitophagy is negatively regulated by FOXO3A, which inhibits Plk3-mediated mitochondrial ROS generation in STZ diabetic stress-treated pancreatic β cells. PLoS One 2023; 18:e0281496. [PMID: 37134105 PMCID: PMC10155949 DOI: 10.1371/journal.pone.0281496] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 01/24/2023] [Indexed: 05/04/2023] Open
Abstract
Diabetes mellitus (DM) is one of the most researched metabolic diseases worldwide. It leads to extensive complications such as cardiovascular disease, nephropathy, retinopathy, and peripheral and central nervous system through an inability to produce or respond to insulin. Although oxidative stress-mediated mitophagy has been reported to play an important role in the pathogenesis of DM, specific studies are still lacking as well as remain highly controversial. Here, we found that Parkin-mediated mitophagy in pancreatic β cells under streptozotocin (STZ)-diabetic stress was induced by Polo-like kinase 3 (Plk3) and inhibited by the transcription factor Forkhead Box O3A (FOXO3A). STZ stress induces mitochondrial recruitment of Parkin through Plk3-mediated mitochondrial reactive oxygen species (ROS) generation, which causes pancreatic cell damage. Conversely, FOXO3A acts as negative feedback to prevent diabetic stress by inhibiting Plk3. Meanwhile, antioxidants including N-acetylcysteine (NAC) and natural COA water scientifically block these mitochondrial ROS and mitochondrial recruitment of Parkin by inhibiting Plk3. Through a 3D organoid ex vivo model, we confirmed that not only ROS inhibitors but also mitophagy inhibitory factors such as 3-MA or Parkin deletion can compensate for pancreatic cell growth and insulin secretion under STZ diabetic stress. These findings suggest that the Plk3-mtROS-PINK1-Parkin axis is a novel mitophagy process that inhibits pancreatic β-cell growth and insulin secretion and FOXO3A and antioxidants may provide new alternatives for effective diabetes treatment strategies in the future.
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Affiliation(s)
- Ji Yeon Shim
- College of Nursing, Dankook University, Cheonan, Chungcheongnam, Republic of Korea
| | - Jin Ook Chung
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea
| | - Dawa Jung
- U&Hang Clinic, Asan, Chungcheongnam, Republic of Korea
| | - Pil Soo Kang
- U&Hang Clinic, Asan, Chungcheongnam, Republic of Korea
| | - Seon-Young Park
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea
| | - Ayse Tuba Kendi
- Division of Radiology, Mayo Clinic, Rochester, Minnesota, United States of America
| | - Val J Lowe
- Division of Radiology, Mayo Clinic, Rochester, Minnesota, United States of America
| | - SeungBaek Lee
- Division of Radiology, Mayo Clinic, Rochester, Minnesota, United States of America
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, United States of America
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12
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Chen J, Zhu G, Xiao W, Huang X, Wang K, Zong Y. Ginsenoside Rg1 Ameliorates Pancreatic Injuries via the AMPK/mTOR Pathway in vivo and in vitro. Diabetes Metab Syndr Obes 2023; 16:779-794. [PMID: 36945297 PMCID: PMC10024876 DOI: 10.2147/dmso.s401642] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 02/21/2023] [Indexed: 03/16/2023] Open
Abstract
BACKGROUND The main propanaxatriol-type saponin found in ginseng (Panax ginseng C. A. Mey), ginsenoside Rg1 (G-Rg1), has bioactivities that include anti-inflammatory, antioxidant, and anti-diabetic properties. This study aimed to investigate the effects of G-Rg1 on streptozotocin (STZ)-induced Type 1 Diabetes mellitus (T1DM) mice and the insulin-secreting cell line in RIN-m5F cells with high-glucose (HG) treatment. METHODS The STZ-induced DM mice model was treated with G-Rg1 alone or combined with 3-Methyladenine (3-MA, an autophagy inhibitor)/rapamycin (RAPA, an autophagy activator) for 8 weeks, and levels of glucose and lipid metabolism, histopathological changes, as well as autophagy and apoptosis of relevant markers were estimated. In vitro, the HG-induced RIN-m5F cells were treated with G-Rg1, 3-MA, and Compound C (CC), an AMPK inhibitor, or their combinations to estimate the influences on cell apoptosis, autophagy, and AMPK/mTOR pathway-associated target gene levels. RESULTS G-Rg1 treatment attenuated glucose and lipid metabolism disorder and pancreatic fibrosis in diabetic mice. In addition, subdued autophagy and p-AMPK protein expression, and enhanced p-mTOR protein expression and apoptosis levels in TIDM mice and HG-induced RIN-m5F cells were ameliorated by G-Rg1 treatment. Furthermore, these anti-apoptosis effects of G-Rg1 were partially abolished by 3-MA and CC. CONCLUSION Our findings revealed that G-Rg1 exhibits strong anti-apoptosis ability in pancreatic tissues of type 1 diabetic mice and HG-induced RIN-m5F cells, and the mechanisms involved in activating AMPK and inhibiting mTOR-mediated autophagy, indicating that G-Rg1 may have the therapeutic and preventive potential for treating pancreatic injury in diabetic patients.
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Affiliation(s)
- Jin Chen
- Department of Hematology, Yiwu Central Hospital, Yiwu, People’s Republic of China
| | - Guoping Zhu
- Department of Radiology, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, People’s Republic of China
| | - Wenbo Xiao
- Department of Radiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China
| | - Xiaosong Huang
- Department of Pharmacy, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, People’s Republic of China
| | - Kewu Wang
- Department of Radiology, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, People’s Republic of China
- Correspondence: Kewu Wang; Yi Zong, Department of Radiology, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, No. N1, Shangcheng Avenue, Yiwu, Zhejiang, People’s Republic of China, Email ;
| | - Yi Zong
- Department of Radiology, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, People’s Republic of China
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13
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Guan L, Yu Z, Che Z, Zhang H, Yu Y, Yang D, Qian D, Chen R, Yu M. Experimental diabetes exacerbates autophagic flux impairment during myocardial I/R injury through calpain-mediated cleavage of Atg5/LAMP2. J Cell Mol Med 2022; 27:232-245. [PMID: 36562207 PMCID: PMC9843523 DOI: 10.1111/jcmm.17642] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 11/15/2022] [Accepted: 11/21/2022] [Indexed: 12/24/2022] Open
Abstract
To explore the role of autophagic flux in the increased susceptibility of the experimental diabetic heart to ischaemia-reperfusion (I/R) injury, we established STZ-induced diabetic mice and performed I/R. In vitro, neonatal mouse cardiomyocytes were subjected to high glucose and hypoxia/reoxygenation challenge to mimic diabetic I/R injury. We found that experimental diabetes aggravated I/R-induced injury than compared with nondiabetic mice. Autophagic flux was impaired in I/R hearts, and the impairment was exacerbated in diabetic mice subjected to I/R with defective autophagosome formation and clearance. Calpains, calcium-dependent thiol proteases, were upregulated and highly activated after I/R of diabetes, while calpain inhibition attenuated cardiac function and cell death and partially restored autophagic flux. The expression levels of Atg5 and LAMP2, two crucial autophagy-related proteins, were significantly degraded in diabetic I/R hearts, alterations that were associated with calpain activation and could be reversed by calpain inhibition. Co-overexpression of Atg5 and LAMP2 reduced myocardial injury and normalized autophagic flux. In conclusion, experimental diabetes exacerbates autophagic flux impairment of cardiomyocytes under I/R stress, resulting in worse I/R-induced injury. Calpain activation and cleavage of Atg5 and LAMP2 at least partially account for the deterioration of autophagic flux impairment.
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Affiliation(s)
- Lichun Guan
- Department of Cardiovascular Surgery, Shanghai General HospitalShanghai Jiao Tong University, School of MedicineShanghaiChina
| | - Ziqin Yu
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan HospitalFudan UniversityShanghaiChina
| | - Zhimei Che
- Department of Anesthesiology, Shanghai Chest HospitalShanghai Jiao Tong University, School of MedicineShanghaiChina
| | - Hang Zhang
- Department of Cardiovascular Surgery, Nanjing First HospitalNanjing Medical UniversityNanjingChina
| | - Yong Yu
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan HospitalFudan UniversityShanghaiChina
| | - Dicheng Yang
- Department of Cardiovascular Surgery, Shanghai General HospitalShanghai Jiao Tong University, School of MedicineShanghaiChina
| | - Dewei Qian
- Department of Cardiovascular Surgery, Shanghai General HospitalShanghai Jiao Tong University, School of MedicineShanghaiChina
| | - Ruizhen Chen
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan HospitalFudan UniversityShanghaiChina
| | - Min Yu
- Department of Cardiovascular Surgery, Shanghai General HospitalShanghai Jiao Tong University, School of MedicineShanghaiChina
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14
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Gasdermin D mediates endoplasmic reticulum stress via FAM134B to regulate cardiomyocyte autophagy and apoptosis in doxorubicin-induced cardiotoxicity. Cell Death Dis 2022; 13:901. [PMID: 36289195 PMCID: PMC9606128 DOI: 10.1038/s41419-022-05333-3] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Revised: 10/05/2022] [Accepted: 10/10/2022] [Indexed: 01/23/2023]
Abstract
Cardiomyocyte pyroptosis and apoptosis play a vital role in the pathophysiology of several cardiovascular diseases. Our recent study revealed that gasdermin D (GSDMD) can promote myocardial I/R injury via the caspase-11/GSDMD pathway. We also found that GSDMD deletion attenuated myocardial I/R and MI injury by reducing cardiomyocyte apoptosis and pyroptosis. However, how GSDMD mediates cardiomyocyte apoptosis and protects myocardial function remains unclear. Here, we found that doxorubicin (DOX) treatment resulted in increased apoptosis and pyroptosis in cardiomyocytes and that caspase-11/GSDMD could mediate DOX-induced cardiotoxicity (DIC) injury. Interestingly, GSDMD overexpression promoted cardiomyocyte apoptosis, which was attenuated by GSDMD knockdown. Notably, GSDMD overexpression exacerbated DIC injury, impaired cardiac function in vitro and in vivo, and enhanced DOX-induced cardiomyocyte autophagy. Mechanistically, GSDMD regulated the activity of FAM134B, an endoplasmic reticulum autophagy receptor, by pore formation on the endoplasmic reticulum membrane via its N-terminus, thus activating endoplasmic reticulum stress. In turn, FAM134B interacted with autophagic protein LC3, thus inducing cardiac autophagy, promoting cardiomyocyte apoptosis, and aggravating DIC. These results suggest that GSDMD promotes autophagy and induces cardiomyocyte apoptosis by modulating the reaction of FAM134B and LC3, thereby promoting DIC injury. Targeted regulation of GSDMD may be a new target for the prevention and treatment of DIC.
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15
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Li H, Wei Y, Xi Y, Jiao L, Wen X, Wu R, Chang G, Sun F, Hao J. DR1-CSE/H 2S pathway upregulates autophagy and inhibits H9C2 cells damage induced by high glucose. Acta Cardiol 2022:1-13. [PMID: 36197015 DOI: 10.1080/00015385.2022.2119663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022]
Abstract
In the cardiovascular system, long-term high glucose (HG) can lead to cardiomyocyte damage. Hydrogen sulfide (H2S) reduces cell autophagy in cardiomyocytes. Dopamine 1 receptors (DR1), a specific binding receptor for dopamine, which has a significant regulatory effect on cardiomyocytes. However, it is unclear whether DR1 inhibits HG-induced cardiomyocyte damage by regulating endogenous H2S production and the level of cell autophagy. The present data indicated that the expression of DR1 and cystathionine-γ-lyase (CSE, a key enzyme for endogenous H2S production) and H2S content were significantly reduced in HG-induced cardiomyocytes, which was reversed by SKF38393 (an agonist of DR1). NaHS (an exogenous H2S donor) only increased H2S content and the expression of CSE with no effect on DR1 expression. HG reduced cell viability, the expression of Bcl-2 and Beclin1, the production of autophagosomes and LC3 II/I ratio and increased the cell apoptotic ratio, the expression of cleaved caspase-3, cleaved caspase-9, cytochrome c, P62, and p-mTOR/t-mTOR ratio. SKF38393 and NaHS reversed the effects of HG. PPG (an inhibitor of CSE) and 3MA (an inhibitor of autophagy) abolished the beneficial effect of SKF38393. In addition, AICAR (an agonist of AMPK) and Rapamycin (an inhibitor of mTOR) increased the production of autophagosomes but decreased the p-mTOR/t-mTOR ratio, which was similar to the effects of SKF38393 and 3MA. Our findings suggest that DR1 reduces the HG-induced cardiomyocyte damage via up-regulating the CSE/H2S pathway, which increases cell autophagy by inhibiting the activation of mTOR.
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Affiliation(s)
- Hongzhu Li
- School of Medicine, Xiamen University, Xiamen, China.,Department of Pathophysiology, Harbin Medical University, Harbin, China
| | - Yaxin Wei
- Department of Pathophysiology, Harbin Medical University, Harbin, China.,Department of Pathology, Northeast Yunnan Regional Central Hospital, Zhaotong, China
| | - Yuxin Xi
- Department of Pathophysiology, Harbin Medical University, Harbin, China
| | - Lijie Jiao
- School of Medicine, Xiamen University, Xiamen, China
| | - Xin Wen
- Department of Pathophysiology, Harbin Medical University, Harbin, China
| | - Ren Wu
- Department of Pathophysiology, Harbin Medical University, Harbin, China
| | - Guiquan Chang
- Department of Pathophysiology, Harbin Medical University, Harbin, China
| | - Fengqi Sun
- Department of Pathophysiology, Harbin Medical University, Harbin, China
| | - Jinghui Hao
- Department of Pathophysiology, Harbin Medical University, Harbin, China
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16
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Wu QQ, Yao Q, Hu TT, Wan Y, Xie QW, Zhao JH, Yuan Y, Tang QZ. Tax1 banding protein 1 exacerbates heart failure in mice by activating ITCH-P73-BNIP3-mediated cardiomyocyte apoptosis. Acta Pharmacol Sin 2022; 43:2562-2572. [PMID: 35948751 PMCID: PMC9525615 DOI: 10.1038/s41401-022-00950-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 06/26/2022] [Indexed: 11/09/2022]
Abstract
Tax1 banding protein 1 (Tax1bp1) was originally identified as an NF-κB regulatory protein that participated in inflammatory, antiviral and innate immune processes. Tax1bp1 also functions as an autophagy receptor that plays a role in autophagy. Our previous study shows that Tax1bp1 protects against cardiomyopathy in STZ-induced diabetic mice. In this study we investigated the role of Tax1bp1 in heart failure. Pressure overload-induced heart failure model was established in mice by aortic banding (AB) surgery, and angiotensin II (Ang II)-induced heart failure model was established by infusion of Ang II through osmotic minipump for 4 weeks. We showed that the expression levels of Tax1bp1 in the heart were markedly increased 2 and 4 weeks after AB surgery. Knockdown of Tax1bp1 in mouse hearts significantly ameliorated both AB- and Ang II infusion-induced heart failure parameters. On the contrary, AB-induced heart failure was aggravated in cardiac-specific Tax1bp1 transgenic mice. Similar results were observed in neonatal rat cardiomyocytes (NRCMs) under Ang II insult. We demonstrated that the pro-heart failure effect of Tax1bp1 resulted from its interaction with the E3 ligase ITCH to promote the transcription factor P73 ubiquitination and degradation, causing enhanced BCL2 interacting protein 3 (BNIP3)-mediated cardiomyocyte apoptosis. Knockdown ITCH or BNIP3 in NRCMs significantly reduced Ang II-induced apoptosis in vitro. Similarly, BNIP3 knockdown attenuated heart failure in cardiac-specific Tax1bp1 transgenic mice. In the left ventricles of heart failure patients, Tax1bp1 expression level was significantly increased; Tax1bp1 gene expression was negatively correlated with left ventricular ejection fraction in heart failure patients. Collectively, the Tax1bp1 increase in heart failure enhances ITCH-P73-BNIP3-mediated cardiomyocyte apoptosis and induced cardiac injury. Tax1bp1 may serve as a potent therapeutic target for the treatment of heart failure.• Cardiac Tax1bp1 transgene mice were more vulnerable to cardiac dysfunction under stress.• Cardiac Tax1bp1 transgene mice were more vulnerable to cardiac dysfunction under stress.• Knockout of Tax1bp1 in mouse hearts ameliorated heart failure induced by pressure overload.• Tax1bp1 interacts with the E3 ligase Itch to promote P73 ubiquitination and degradation, causing enhanced BNIP3-mediated apoptosis.• Tax1bp1 may become a target of new therapeutic methods for treating heart failure.
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Affiliation(s)
- Qing-Qing Wu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, China
| | - Qi Yao
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, China
| | - Tong-Tong Hu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, China
| | - Ying Wan
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, China
| | - Qing-Wen Xie
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, China
| | - Jin-Hua Zhao
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, China
| | - Yuan Yuan
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China
- Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, China
| | - Qi-Zhu Tang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
- Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, China.
- Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, China.
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17
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Liang W, Gustafsson ÅB. Recent Insights into the Role of Autophagy in the Heart. CURRENT OPINION IN PHYSIOLOGY 2022. [DOI: 10.1016/j.cophys.2022.100593] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
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18
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Yuan S, Cai Z, Luan X, Wang H, Zhong Y, Deng L, Feng J. Gut microbiota: A new therapeutic target for diabetic cardiomyopathy. Front Pharmacol 2022; 13:963672. [PMID: 36091756 PMCID: PMC9461091 DOI: 10.3389/fphar.2022.963672] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 08/04/2022] [Indexed: 11/17/2022] Open
Abstract
Diabetic cardiomyopathy seriously affects quality of life and even threatens life safety of patients. The pathogenesis of diabetic cardiomyopathy is complex and multifactorial, and it is widely accepted that its mechanisms include oxidative stress, inflammation, insulin resistance, apoptosis, and autophagy. Some studies have shown that gut microbiota plays an important role in cardiovascular diseases. Gut microbiota and its metabolites can affect the development of diabetic cardiomyopathy by regulating oxidative stress, inflammation, insulin resistance, apoptosis, and autophagy. Here, the mechanisms of gut microbiota and its metabolites resulting in diabetic cardiomyopathy are reviewed. Gut microbiota may be a new therapeutic target for diabetic cardiomyopathy.
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Affiliation(s)
- Suxin Yuan
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Zhengyao Cai
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Xingzhao Luan
- Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Haibo Wang
- Department of Cardiology, Gulin People’s Hospital, Luzhou, Sichuan, China
| | - Yi Zhong
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Li Deng
- Department of Rheumatology, The Affiliated, Hospital of Southwest Medical University, Luzhou, Sichaun, China
| | - Jian Feng
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
- *Correspondence: Jian Feng,
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19
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El-Azab MF, Wakiel AE, Nafea YK, Youssef ME. Role of cannabinoids and the endocannabinoid system in modulation of diabetic cardiomyopathy. World J Diabetes 2022; 13:387-407. [PMID: 35664549 PMCID: PMC9134026 DOI: 10.4239/wjd.v13.i5.387] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/18/2021] [Accepted: 04/28/2022] [Indexed: 02/06/2023] Open
Abstract
Diabetic complications, chiefly seen in long-term situations, are persistently deleterious to a large extent, requiring multi-factorial risk reduction strategies beyond glycemic control. Diabetic cardiomyopathy is one of the most common deleterious diabetic complications, being the leading cause of mortality among diabetic patients. The mechanisms of diabetic cardiomyopathy are multi-factorial, involving increased oxidative stress, accumulation of advanced glycation end products (AGEs), activation of various pro-inflammatory and cell death signaling pathways, and changes in the composition of extracellular matrix with enhanced cardiac fibrosis. The novel lipid signaling system, the endocannabinoid system, has been implicated in the pathogenesis of diabetes and its complications through its two main receptors: Cannabinoid receptor type 1 and cannabinoid receptor type 2, alongside other components. However, the role of the endocannabinoid system in diabetic cardiomyopathy has not been fully investigated. This review aims to elucidate the possible mechanisms through which cannabinoids and the endocannabinoid system could interact with the pathogenesis and the development of diabetic cardiomyopathy. These mechanisms include oxidative/ nitrative stress, inflammation, accumulation of AGEs, cardiac remodeling, and autophagy. A better understanding of the role of cannabinoids and the endocannabinoid system in diabetic cardiomyopathy may provide novel strategies to manipulate such a serious diabetic complication.
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Affiliation(s)
- Mona F El-Azab
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
| | - Ahmed E Wakiel
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
| | - Yossef K Nafea
- Program of Biochemistry, McMaster University, Hamilton L8S 4L8, Ontario, Canada
| | - Mahmoud E Youssef
- Department of Pharmacology and Biochemistry, Delta University for Science and Technology, Mansoura 35511, New Cairo, Egypt
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20
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Lipotoxicity-induced mtDNA release promotes diabetic cardiomyopathy by activating the cGAS-STING pathway in obesity-related diabetes. Cell Biol Toxicol 2022; 39:277-299. [PMID: 35235096 PMCID: PMC10042943 DOI: 10.1007/s10565-021-09692-z] [Citation(s) in RCA: 90] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 12/22/2021] [Indexed: 11/02/2022]
Abstract
Diabetic cardiomyopathy (DCM) is characterized by lipid accumulation, mitochondrial dysfunction, and aseptic inflammatory activation. Mitochondria-derived cytosolic DNA has been reported to induce inflammation by activating cyclic GMP-AMP synthase (cGAS)/the stimulator of interferon genes (STING) pathway in the adipose, liver, and kidney tissues. However, the role of cytosolic mtDNA in the progression of DCM is unclear. In this study, with an obesity-related DCM mouse model established by feeding db/db mice with a high-fat diet (HFD), we observed increased mtDNA in the cytosol and activated cGAS-STING signaling pathway during DCM, as well as the downstream targets, IRF3, NF-κB, IL-18, and IL-1β. In a further study with a palmitic acid (PA)-induced lipotoxic cell model established in H9C2 cells, we revealed that the cytosolic mtDNA was the result of PA-induced overproduction of mitochondrial ROS, which also led to the activation of the cGAS/STING system and its downstream targets. Notably, treatment of extracted mtDNA alone was sufficient to activate the cGAS-STING signaling pathway in cultured H9C2 cells. Besides, both knockdown of STING in PA-induced H9C2 cells and inhibition of STING by C-176 injection in the DCM mouse model could remarkably block the inflammation and apoptosis of cardiomyocytes. In conclusion, our study elucidated the critical role of cytosolic mtDNA-induced cGAS-STING activation in the pathogenesis of obesity-related DCM and provided preclinical validation for using a STING inhibitor as a new potential therapeutic strategy for the treatment of DCM.
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21
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Miao H, Li X, Zhou C, Liang Y, Li D, Ji Q. NR4A2 alleviates cardiomyocyte loss and myocardial injury in rats by transcriptionally suppressing CCR5 and inducing M2 polarization of macrophages. Microvasc Res 2022; 140:104279. [PMID: 34774582 DOI: 10.1016/j.mvr.2021.104279] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 10/22/2021] [Accepted: 11/08/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND CC chemokine receptor 5 (CCR5) has been demonstrated to be correlated to activation of pro-inflammatory immune cells and tissue injury. This study focused on the role of CCR5 in myocardial injury in rats with diabetic cardiomyopathy (DCM) and the mechanism of action. METHODS A rat model of DCM was induced by streptozotocin (STZ). CCR5 was knocked down in rats to determine its role in myocardial injury and immune cell infiltration. The upstream regulators of CCR5 were bioinformatically predicted and the binding between nuclear receptor subfamily 4 group A member 2 (NR4A2) and CCR5 was validated. The portion of M1 and M2 macrophages in tissues was determined by flow cytometry or double-labeling immunofluorescence. Rat bone marrow mononuclear cells (BMMCs) were treated with granulocyte/macrophage colony stimulating factor (GM-CSF/M-CSF) and co-cultured with H9C2 cells for in vitro experiments. RESULTS STZ-treated rats had impaired cardiac function and increased levels of creatine kinase-MB, cardiac troponin I and lactate dehydrogenase. CCR5 inhibition significantly alleviated myocardial injury in rats and reduced the portion of M1 macrophages in rat cardiac tissues. NR4A2, which could suppress CCR5 transcription, was poorly expressed in rats with DCM. NR4A2 overexpression played a similar myocardium-protective role in rats. In vitro, overexpression of NR4A2 induced M2 polarization of macrophages, which protected the co-cultured H9C2 cells from high glucose-induced damage, but the protective role was blocked after CCR5 overexpression. CONCLUSION This study demonstrated that NR4A2 suppresses CCR5 expression and promotes M2 polarization of macrophages to alleviate cardiomyocyte loss and myocardial injury.
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MESH Headings
- Animals
- Male
- Cell Line
- Coculture Techniques
- Diabetic Cardiomyopathies/genetics
- Diabetic Cardiomyopathies/immunology
- Diabetic Cardiomyopathies/metabolism
- Diabetic Cardiomyopathies/pathology
- Disease Models, Animal
- Down-Regulation
- Macrophages/immunology
- Macrophages/metabolism
- Macrophages/pathology
- Myocytes, Cardiac/immunology
- Myocytes, Cardiac/metabolism
- Myocytes, Cardiac/pathology
- Nuclear Receptor Subfamily 4, Group A, Member 2/genetics
- Nuclear Receptor Subfamily 4, Group A, Member 2/metabolism
- Phenotype
- Rats, Sprague-Dawley
- Receptors, CCR5/genetics
- Receptors, CCR5/metabolism
- Signal Transduction
- Transcription, Genetic
- Rats
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Affiliation(s)
- Huangtai Miao
- Center for Cononary Artery Disease, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, PR China
| | - Xiaoying Li
- Department of Health Care for Cadres, Beijing Jishuitan Hospital, Beijing 100035, PR China
| | - Can Zhou
- Center for Cononary Artery Disease, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, PR China
| | - Ying Liang
- Emergency & Critical Care Center, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, PR China
| | - Deshun Li
- Department of Cardiology, Huanghua Traditional Chinese Medicine Hospital of Hebei Province, Huanghua 061100, Hebei, PR China
| | - Qingwei Ji
- Department of Cardiology, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning 530021, Guangxi Zhuang Autonomous Region, PR China.
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22
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Guo Z, Tuo H, Tang N, Liu FY, Ma SQ, An P, Yang D, Wang MY, Fan D, Yang Z, Tang QZ. Neuraminidase 1 deficiency attenuates cardiac dysfunction, oxidative stress, fibrosis, inflammatory via AMPK-SIRT3 pathway in diabetic cardiomyopathy mice. Int J Biol Sci 2022; 18:826-840. [PMID: 35002528 PMCID: PMC8741837 DOI: 10.7150/ijbs.65938] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 11/24/2021] [Indexed: 11/30/2022] Open
Abstract
Diabetic cardiomyopathy (DCM) is associated with oxidative stress and augmented inflammation in the heart. Neuraminidases (NEU) 1 has initially been described as a lysosomal protein which plays a role in the catabolism of glycosylated proteins. We investigated the role of NEU1 in the myocardium in diabetic heart. Streptozotocin (STZ) was injected intraperitoneally to induce diabetes in mice. Neonatal rat ventricular myocytes (NRVMs) were used to verify the effect of shNEU1 in vitro. NEU1 is up-regulated in cardiomyocytes under diabetic conditions. NEU1 inhibition alleviated oxidative stress, inflammation and apoptosis, and improved cardiac function in STZ-induced diabetic mice. Furthermore, NEU1 inhibition also attenuated the high glucose-induced increased reactive oxygen species generation, inflammation and, cell death in vitro. ShNEU1 activated Sirtuin 3 (SIRT3) signaling pathway, and SIRT3 deficiency blocked shNEU1-mediated cardioprotective effects in vitro. More importantly, we found AMPKα was responsible for the elevation of SIRT3 expression via AMPKα-deficiency studies in vitro and in vivo. Knockdown of LKB1 reversed the effect elicited by shNEU1 in vitro. In conclusion, NEU1 inhibition activates AMPKα via LKB1, and subsequently activates sirt3, thereby regulating fibrosis, inflammation, apoptosis and oxidative stress in diabetic myocardial tissue.
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Affiliation(s)
- Zhen Guo
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, RP China.,Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, RP China
| | - Hu Tuo
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, RP China.,Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, RP China
| | - Nan Tang
- The Affiliated Suqian Hospital of Xuzhou Medical University, Suqian 223800, RP China.,People's Hospital affiliated to Nanjing Drama Tower Hospital Group, Suqian 223800, RP China
| | - Fang-Yuan Liu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, RP China.,Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, RP China
| | - Shu-Qing Ma
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, RP China.,Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, RP China
| | - Peng An
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, RP China.,Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, RP China
| | - Dan Yang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, RP China.,Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, RP China
| | - Min-Yu Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, RP China.,Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, RP China
| | - Di Fan
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, RP China.,Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, RP China
| | - Zheng Yang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, RP China.,Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, RP China
| | - Qi-Zhu Tang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, RP China.,Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, RP China
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23
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Cao XJ, Wu R, Qian HY, Chen X, Zhu HY, Xu GY, Sun YZ, Zhang PA. Metformin attenuates diabetic neuropathic pain via AMPK/NF-κB signaling pathway in dorsal root ganglion of diabetic rats. Brain Res 2021; 1772:147663. [PMID: 34555415 DOI: 10.1016/j.brainres.2021.147663] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 08/26/2021] [Accepted: 09/15/2021] [Indexed: 10/20/2022]
Abstract
Neuropathic pain is a common complication of diabetes mellitus with poorly relieved by conventional analgesics. Metformin, a first-line drug for type 2 diabetes, reduces blood glucose by activating adenosine monophosphate protein kinase (AMPK) signalling system. However, the effect of Metformin on diabetic neuropathic pain is still unknown. In the present study, we showed that Metformin was capable of attenuating diabetes induced mechanical allodynia, and the analgesia effect could be blocked by Compound C (an AMPK inhibitor). Importantly, Metformin enhanced the phosphorylation level of AMPK in L4-6 DRGs of diabetic rats but not affect the expression of total AMPK. Intrathecal injection of AICAR (an AMPK agonist) could activate AMPK and alleviate the mechanical allodynia of diabetic rats. Additionally, phosphorylated AMPK and NF-κB was co-localized in small and medium neurons of L4-6 DRGs. Interestingly, the regulation of NF-κB in diabetic rats was obviously reduced when AMPK was activated by AICAR. Notably, Metformin could decrease NF-κB expression in L4-6 DRGs of diabetic rats, but the decrease was blocked by Compound C. In conclusion, Metformin alleviates diabetic mechanical allodynia via activation of AMPK signaling pathway in L4-6 DRGs of diabetic rats, which might be mediated by the downregulation of NF-κB, and this providing certain basis for Metformin to become a potential drug in the clinical treatment of diabetic neuropathic pain.
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Affiliation(s)
- Xiao-Jun Cao
- Department of Endocrine, The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou 215123, PR China
| | - Rui Wu
- Center for Translational Medicine, The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou 215123, PR China; Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou 215123, PR China
| | - He-Ya Qian
- Center for Translational Medicine, The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou 215123, PR China
| | - Xiang Chen
- Center for Translational Medicine, The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou 215123, PR China
| | - Hong-Yan Zhu
- Center for Translational Medicine, The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou 215123, PR China
| | - Guang-Yin Xu
- Center for Translational Medicine, The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou 215123, PR China; Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou 215123, PR China
| | - Ye-Zi Sun
- Department of Endocrine, The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou 215123, PR China.
| | - Ping-An Zhang
- Center for Translational Medicine, The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou 215123, PR China; Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou 215123, PR China.
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24
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Zheng H, Zhu H, Liu X, Huang X, Huang A, Huang Y. Mitophagy in Diabetic Cardiomyopathy: Roles and Mechanisms. Front Cell Dev Biol 2021; 9:750382. [PMID: 34646830 PMCID: PMC8503602 DOI: 10.3389/fcell.2021.750382] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 09/06/2021] [Indexed: 12/20/2022] Open
Abstract
Cardiovascular disease is the leading complication of diabetes mellitus (DM), and diabetic cardiomyopathy (DCM) is a major cause of mortality in diabetic patients. Multiple pathophysiologic mechanisms, including myocardial insulin resistance, oxidative stress and inflammation, are involved in the development of DCM. Recent studies have shown that mitochondrial dysfunction makes a substantial contribution to the development of DCM. Mitophagy is a type of autophagy that takes place in dysfunctional mitochondria, and it plays a key role in mitochondrial quality control. Although the precise molecular mechanisms of mitophagy in DCM have yet to be fully clarified, recent findings imply that mitophagy improves cardiac function in the diabetic heart. However, excessive mitophagy may exacerbate myocardial damage in patients with DCM. In this review, we aim to provide a comprehensive overview of mitochondrial quality control and the dual roles of mitophagy in DCM. We also propose that a balance between mitochondrial biogenesis and mitophagy is essential for the maintenance of cellular metabolism in the diabetic heart.
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Affiliation(s)
- Haoxiao Zheng
- Department of Cardiology, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde), Foshan, China
| | - Hailan Zhu
- Department of Cardiology, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde), Foshan, China
| | - Xinyue Liu
- Department of Cardiology, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde), Foshan, China
| | - Xiaohui Huang
- Department of Cardiology, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde), Foshan, China
| | - Anqing Huang
- Department of Cardiology, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde), Foshan, China
| | - Yuli Huang
- Department of Cardiology, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde), Foshan, China
- Guangdong Provincial Key Laboratory of Shock and Microcirculation Research, Guangzhou, China
- The George Institute for Global Health, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
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25
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Fibronectin type III domain-containing 5 in cardiovascular and metabolic diseases: a promising biomarker and therapeutic target. Acta Pharmacol Sin 2021; 42:1390-1400. [PMID: 33214697 PMCID: PMC8379181 DOI: 10.1038/s41401-020-00557-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 10/13/2020] [Indexed: 12/11/2022]
Abstract
Cardiovascular and metabolic diseases are the leading causes of death and disability worldwide and impose a tremendous socioeconomic burden on individuals as well as the healthcare system. Fibronectin type III domain-containing 5 (FNDC5) is a widely distributed transmembrane glycoprotein that can be proteolytically cleaved and secreted as irisin to regulate glycolipid metabolism and cardiovascular homeostasis. In this review, we present the current knowledge on the predictive and therapeutic role of FNDC5 in a variety of cardiovascular and metabolic diseases, such as hypertension, atherosclerosis, ischemic heart disease, arrhythmia, metabolic cardiomyopathy, cardiac remodeling, heart failure, diabetes mellitus, and obesity.
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26
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Dewanjee S, Vallamkondu J, Kalra RS, John A, Reddy PH, Kandimalla R. Autophagy in the diabetic heart: A potential pharmacotherapeutic target in diabetic cardiomyopathy. Ageing Res Rev 2021; 68:101338. [PMID: 33838320 DOI: 10.1016/j.arr.2021.101338] [Citation(s) in RCA: 115] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 02/24/2021] [Accepted: 03/29/2021] [Indexed: 12/20/2022]
Abstract
Association of diabetes with an elevated risk of cardiac failure has been clinically evident. Diabetes potentiates diastolic and systolic cardiac failure following the myocardial infarction that produces the cardiac muscle-specific microvascular complication, clinically termed as diabetic cardiomyopathy. Elevated susceptibility of diabetic cardiomyopathy is primarily caused by the generation of free radicals in the hyperglycemic milieu, compromising the myocardial contractility and normal cardiac functions with increasing redox insult, impaired mitochondria, damaged organelles, apoptosis, and cardiomyocytes fibrosis. Autophagy is essentially involved in the recycling/clearing the damaged organelles, cytoplasmic contents, and aggregates, which are frequently produced in cardiomyocytes. Although autophagy plays a vital role in maintaining the cellular homeostasis in diligent cardiac tissues, this process is frequently impaired in the diabetic heart. Given its clinical significance, accumulating evidence largely showed the functional aspects of autophagy in diabetic cardiomyopathy, elucidating its intricate protective and pathogenic outcomes. However, etiology and molecular readouts of these contrary autophagy activities in diabetic cardiomyopathy are not yet comprehensively assessed and translated. In this review, we attempted to assess the role of autophagy and its adaptations in the diabetic heart. To delineate the molecular consequences of these events, we provided detailed insights into the autophagy regulation pieces of machinery including the mTOR/AMPK, TFEB/ZNSCAN3, FOXOs, SIRTs, PINK1/Parkin, Nrf2, miRNAs, and others in the diabetic cardiomyopathy. Given the clinical significance of autophagy in the diabetic heart, we further discussed the potential pharmacotherapeutic strategies towards targeting autophagy. Taken together, the present report meticulously assessed autophagy, its adaptations, and molecular regulations in diabetic cardiomyopathy and reviewed the current autophagy-targeting strategies.
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Affiliation(s)
- Saikat Dewanjee
- Advanced Pharmacognosy Research Laboratory, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, 700032, India.
| | | | - Rajkumar Singh Kalra
- AIST-INDIA DAILAB, National Institute of Advanced Industrial Science & Technology (AIST), Higashi 1-1-1, Tsukuba, 305 8565, Japan.
| | - Albin John
- Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA
| | - P Hemachandra Reddy
- Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA; Neuroscience & Pharmacology, Texas Tech University Health Sciences Center, Lubbock, TX, USA; Neurology, Departments of School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA; Public Health Department of Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, Lubbock, TX, USA; Department of Speech, Language and Hearing Sciences, School Health Professions, Texas Tech University Health Sciences Center, Lubbock, TX, USA.
| | - Ramesh Kandimalla
- Department of Biochemistry, Kakatiya Medical College, Warangal, 506007, Telangana, India; Applied Biology, CSIR-Indian Institute of Technology, Uppal Road, Tarnaka, Hyderabad, 50000, Telangana, India.
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27
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Zhang X, Hu C, Yuan XP, Yuan YP, Song P, Kong CY, Teng T, Hu M, Xu SC, Ma ZG, Tang QZ. Osteocrin, a novel myokine, prevents diabetic cardiomyopathy via restoring proteasomal activity. Cell Death Dis 2021; 12:624. [PMID: 34135313 PMCID: PMC8209005 DOI: 10.1038/s41419-021-03922-2] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 06/08/2021] [Accepted: 06/09/2021] [Indexed: 02/06/2023]
Abstract
Proteasomal activity is compromised in diabetic hearts that contributes to proteotoxic stresses and cardiac dysfunction. Osteocrin (OSTN) acts as a novel exercise-responsive myokine and is implicated in various cardiac diseases. Herein, we aim to investigate the role and underlying molecular basis of OSTN in diabetic cardiomyopathy (DCM). Mice received a single intravenous injection of the cardiotrophic adeno-associated virus serotype 9 to overexpress OSTN in the heart and then were exposed to intraperitoneal injections of streptozotocin (STZ, 50 mg/kg) for consecutive 5 days to generate diabetic models. Neonatal rat cardiomyocytes were isolated and stimulated with high glucose to verify the role of OSTN in vitro. OSTN expression was reduced by protein kinase B/forkhead box O1 dephosphorylation in diabetic hearts, while its overexpression significantly attenuated cardiac injury and dysfunction in mice with STZ treatment. Besides, OSTN incubation prevented, whereas OSTN silence aggravated cardiomyocyte apoptosis and injury upon hyperglycemic stimulation in vitro. Mechanistically, OSTN treatment restored protein kinase G (PKG)-dependent proteasomal function, and PKG or proteasome inhibition abrogated the protective effects of OSTN in vivo and in vitro. Furthermore, OSTN replenishment was sufficient to prevent the progression of pre-established DCM and had synergistic cardioprotection with sildenafil. OSTN protects against DCM via restoring PKG-dependent proteasomal activity and it is a promising therapeutic target to treat DCM.
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Affiliation(s)
- Xin Zhang
- Department of Cardiology, Renmin Hospital of Wuhan University, 430060, Wuhan, China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, 430060, Wuhan, China
| | - Can Hu
- Department of Cardiology, Renmin Hospital of Wuhan University, 430060, Wuhan, China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, 430060, Wuhan, China
| | - Xiao-Pin Yuan
- Department of Cardiology, Renmin Hospital of Wuhan University, 430060, Wuhan, China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, 430060, Wuhan, China
| | - Yu-Pei Yuan
- Department of Cardiology, Renmin Hospital of Wuhan University, 430060, Wuhan, China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, 430060, Wuhan, China
| | - Peng Song
- Department of Cardiology, Renmin Hospital of Wuhan University, 430060, Wuhan, China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, 430060, Wuhan, China
| | - Chun-Yan Kong
- Department of Cardiology, Renmin Hospital of Wuhan University, 430060, Wuhan, China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, 430060, Wuhan, China
| | - Teng Teng
- Department of Cardiology, Renmin Hospital of Wuhan University, 430060, Wuhan, China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, 430060, Wuhan, China
| | - Min Hu
- Department of Cardiology, Renmin Hospital of Wuhan University, 430060, Wuhan, China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, 430060, Wuhan, China
| | - Si-Chi Xu
- Department of Cardiology, Renmin Hospital of Wuhan University, 430060, Wuhan, China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, 430060, Wuhan, China
| | - Zhen-Guo Ma
- Department of Cardiology, Renmin Hospital of Wuhan University, 430060, Wuhan, China.
- Hubei Key Laboratory of Metabolic and Chronic Diseases, 430060, Wuhan, China.
| | - Qi-Zhu Tang
- Department of Cardiology, Renmin Hospital of Wuhan University, 430060, Wuhan, China.
- Hubei Key Laboratory of Metabolic and Chronic Diseases, 430060, Wuhan, China.
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Zhou Q, Guo H, Yu C, Huang XR, Liang L, Zhang P, Yu J, Zhang J, Chan TF, Ma RCW, Lan HY. Identification of Smad3-related transcriptomes in type-2 diabetic nephropathy by whole transcriptome RNA sequencing. J Cell Mol Med 2020; 25:2052-2068. [PMID: 33369170 PMCID: PMC7882931 DOI: 10.1111/jcmm.16133] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 11/01/2020] [Accepted: 11/04/2020] [Indexed: 12/21/2022] Open
Abstract
Smad3 deficiency prevents the development of type 2 diabetic nephropathy; however, the underlying molecular mechanisms remain unknown. In this study, we aimed to identify Smad3‐related genes involved in the pathogenesis of diabetic kidney disease. High‐throughput RNA sequencing was performed to profile the whole transcriptome in the diabetic kidney of Smad3 WT‐db/db, Smad3 KO‐db/db, Smad3+/− db/db and their littermate control db/m mice at 20 weeks. The gene ontology, pathways and alternative splicing of differentially expressed protein‐coding genes and long non‐coding RNAs related to Smad3 in diabetic kidney were analysed. Compared to Smad3 WT‐db/db mice, Smad3 KO‐db/db mice exhibited an alteration of genes associated with RNA splicing and metabolism, whereas heterozygosity deletion of Smad3 (Smad3+/− db/db mice) significantly altered genes related to cell division and cell cycle. Notably, three protein‐coding genes (Upk1b, Psca and Gdf15) and two lncRNAs (NONMMUG023520.2 and NONMMUG032975.2) were identified to be Smad3‐dependent and to be associated with the development of diabetic nephropathy. By using whole transcriptome RNA sequencing, we identified novel Smad3 transcripts related to the development of diabetic nephropathy. Thus, targeting these transcripts may represent a novel and effective therapy for diabetic nephropathy.
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Affiliation(s)
- Qin Zhou
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,National Health Commission Key Laboratory of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Honghong Guo
- State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Chaolun Yu
- Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiao-Ru Huang
- Guangdong-Hong Kong Joint Laboratory for Immunological and Genetic Kidney Disease, Guangdong Academy of Medical Sciences, Guangdong Provincial People's Hospital, Guangzhou, China.,Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Liying Liang
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Puhua Zhang
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,National Health Commission Key Laboratory of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jianwen Yu
- Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,National Health Commission Key Laboratory of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jizhou Zhang
- School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Ting-Fung Chan
- School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Ronald C W Ma
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Hui-Yao Lan
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.,Guangdong-Hong Kong Joint Laboratory on Immunological and Genetic Kidney Diseases, The Chinese University of Hong Kong, Hong Kong, China
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29
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Li N, Wang W, Zhou H, Wu Q, Duan M, Liu C, Wu H, Deng W, Shen D, Tang Q. Ferritinophagy-mediated ferroptosis is involved in sepsis-induced cardiac injury. Free Radic Biol Med 2020; 160:303-318. [PMID: 32846217 DOI: 10.1016/j.freeradbiomed.2020.08.009] [Citation(s) in RCA: 424] [Impact Index Per Article: 84.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 08/11/2020] [Accepted: 08/15/2020] [Indexed: 02/06/2023]
Abstract
Ferroptosis is a reactive oxygen species (ROS)- and iron-dependent form of regulated cell death (RCD), playing critical roles in organ injury and targeting therapy of cancers. Previous studies have demonstrated that ferroptosis participates in the development of cardiomyopathy including cardiac hypertrophy, diabetic cardiomyopathy and doxorubicin-induced cardiotoxicity. However, the role of ferroptosis in sepsis-induced cardiac injury remains unclear. This study aimed to explore the role and underlying mechanism of ferroptosis on lipopolysaccharide (LPS)-induced cardiac injury. Mice were injected with LPS (10 mg/kg) for 12 h to generate experimental sepsis. Ferrostatin-1 (Fer-1) and Dexrazoxane (DXZ) were used to suppress ferroptosis of mice with sepsis-induced cardiac injury. LPS increased the levels of ferroptotic markers involving prostaglandin endoperoxide synthase 2 (PTGS2), malonaldehyde (MDA) and lipid ROS, apart from resulting in obvious mitochondria damage, which were alleviated by Fer-1 and DXZ. In vitro experiments showed that Fer-1 inhibited LPS-induced lipid peroxidation and injury of H9c2 myofibroblasts while erastin and sorafenib aggravated LPS-induced ferroptosis. Additionally, Fer-1 and DXZ improved survival rate and cardiac function of mice with sepsis. Mechanistically, LPS increased the expression of nuclear receptor coactivator 4 (NCOA4) and the level of intracellular Fe2+ but decreased the level of ferritin. NCOA4 could directly interact with ferritin and degrade it in a ferritinophagy-dependent manner, which subsequently released a great amount of iron. Cytoplasmic Fe2+ further activated the expression of siderofexin (SFXN1) on mitochondrial membrane, which in turn transported cytoplasmic Fe2+ into mitochondria, giving rise to the production of mitochondrial ROS and ferroptosis. Based on these findings, we concluded that ferritinophagy-mediated ferroptosis is one of the critical mechanisms contributing to sepsis-induced cardiac injury. Targeting ferroptosis in cardiomyocytes may be a therapeutic strategy for preventing sepsis in the future.
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Affiliation(s)
- Ning Li
- Department of Cardiology, Renmin Hospital of Wuhan University, Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, PR China; Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, PR China
| | - Wei Wang
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, PR China
| | - Heng Zhou
- Department of Cardiology, Renmin Hospital of Wuhan University, Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, PR China
| | - Qingqing Wu
- Department of Cardiology, Renmin Hospital of Wuhan University, Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, PR China
| | - Mingxia Duan
- Department of Cardiology, Renmin Hospital of Wuhan University, Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, PR China
| | - Chen Liu
- Department of Cardiology, Renmin Hospital of Wuhan University, Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, PR China
| | - Haiming Wu
- Department of Cardiology, Renmin Hospital of Wuhan University, Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, PR China
| | - Wei Deng
- Department of Cardiology, Renmin Hospital of Wuhan University, Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, PR China
| | - Difei Shen
- Department of Cardiology, Renmin Hospital of Wuhan University, Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, PR China.
| | - Qizhu Tang
- Department of Cardiology, Renmin Hospital of Wuhan University, Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, PR China.
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Sajadimajd S, Bahrami G, Mohammadi B, Nouri Z, Farzaei MH, Chen JT. Protective effect of the isolated oligosaccharide from Rosa canina in STZ-treated cells through modulation of the autophagy pathway. J Food Biochem 2020; 44:e13404. [PMID: 32761921 DOI: 10.1111/jfbc.13404] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Revised: 07/01/2020] [Accepted: 07/03/2020] [Indexed: 12/26/2022]
Abstract
Isolation of active components of therapeutic plants and discovering molecular mechanisms play a pivotal role in therapy of diabetes. This study aimed to determine the antidiabetic mechanism of an oligosaccharide isolated from Rosa canina (RCO) by measuring the expression of some miRNAs and their targets involved in autophagy. RCO was extracted and characterized by using HPLC and spectroscopic methods. Rin-5F cells were treated with STZ and RCO alone and in combination. The viability of the cells and the expression of miR-21, miR-22, Akt, ATG5, Beclin1, LC3A, and LC3B were analyzed using MTT assay, and qRT-PCR, respectively. Oligosaccharide fraction could improve the viability of RCO-treated cells as compared to STZ-treated cells. Further, the expression of autophagy markers was increased in RCO-treated diabetic cells compared to STZ-treated cells. The results indicated that the antidiabetic effects of the oligosaccharide components of R. canina seem to be mediated by modulation of autophagy pathway. PRACTICAL APPLICATIONS: Given effectiveness of an oligosaccharide fraction isolated from Rosa canina in management of diabetes in STZ-induced diabetic rats, we have intention to scrutinize its molecular mechanism as modulation of autophagy pathway in STZ-treated Rin-5F cells. It is expected that the results paved the way to speculate novel antidiabetic strategies.
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Affiliation(s)
| | - Gholamreza Bahrami
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Bahareh Mohammadi
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Zeinab Nouri
- Student's Research Committee, Faculty of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mohammad Hosein Farzaei
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Jen-Tsung Chen
- Department of Life Sciences, National University of Kaohsiung, Kaohsiung, Taiwan
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Abstract
Autophagy is a dynamic process, regulated by a variety of factors, and may play different roles in different thyroid diseases or in different stages of the same thyroid disease. Autophagy can mediate inflammatory response and immunity, which is closely related to the pathogenesis of thyroid autoimmune diseases. Therefore, it is still necessary to further understand the relationship between autophagy and autoimmune thyroid disease and hypothyroidism. With more and more studies on the relationship between autophagy and thyroid cancer, the relationship between the two is becoming more and more complicated. From the perspective of current studies, it is still worth pondering whether inhibition or activation of autophagy can be a valuable targeted therapy for thyroid cancer, and further research and efforts are still needed.
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32
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Li Y, Liu R, Wu J, Li X. Self-eating: friend or foe? The emerging role of autophagy in fibrotic diseases. Am J Cancer Res 2020; 10:7993-8017. [PMID: 32724454 PMCID: PMC7381749 DOI: 10.7150/thno.47826] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 06/16/2020] [Indexed: 01/18/2023] Open
Abstract
Fibrosis occurs in most human organs including the liver, lung, heart and kidney, and is crucial for the progression of most chronic diseases. As an indispensable catabolic process for intracellular quality control and homeostasis, autophagy occurs in most mammalian cells and is implicated in many biological processes including fibrogenesis. Although advances have been made in understanding autophagy process, the potential role of autophagy in fibrotic diseases remains controversial and has recently attracted a great deal of attention. In the current review, we summarize the commonalities of autophagy affecting different types of fibrosis in different organs, including the liver, lung, heart, and kidney as well as in cystic fibrosis, systematically outline the contradictory results and highlight the distinct role of autophagy during the various stages of fibrosis. In summary, the exact role autophagy plays in fibrogenesis depends on specific cell types and different stimuli, and identifying and evaluating the pathogenic contribution of autophagy in fibrogenesis will promote the discovery of novel therapeutic strategies for the clinical management of these fibrotic diseases.
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High-mobility group AT-hook 1 promotes cardiac dysfunction in diabetic cardiomyopathy via autophagy inhibition. Cell Death Dis 2020; 11:160. [PMID: 32123163 PMCID: PMC7052237 DOI: 10.1038/s41419-020-2316-4] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2019] [Revised: 01/09/2020] [Accepted: 01/09/2020] [Indexed: 12/12/2022]
Abstract
High-mobility group AT-hook1 (HMGA1, formerly HMG-I/Y), an architectural transcription factor, participates in a number of biological processes. However, its effect on cardiac remodeling (refer to cardiac inflammation, apoptosis and dysfunction) in diabetic cardiomyopathy remains largely indistinct. In this study, we found that HMGA1 was upregulated in diabetic mouse hearts and high-glucose-stimulated cardiomyocytes. Overexpression of HMGA1 accelerated high-glucose-induced cardiomyocyte inflammation and apoptosis, while HMGA1 knockdown relieved inflammation and apoptosis in cardiomyocytes in response to high glucose. Overexpression of HMGA1 in mice heart by adeno-associated virus 9 (AAV9) delivery system deteriorated the inflammatory response, increased apoptosis and accelerated cardiac dysfunction in streptozotocin-induced diabetic mouse model. Knockdown of HMGA1 by AAV9-shHMGA1 in vivo ameliorated cardiac remodeling in diabetic mice. Mechanistically, we found that HMGA1 inhibited the formation rather than the degradation of autophagy by regulating P27/CDK2/mTOR signaling. CDK2 knockdown or P27 overexpression blurred HMGA1 overexpression-induced deteriorating effects in vitro. P27 overexpression in mice heart counteracted HMGA1 overexpression-induced increased cardiac remodeling in diabetic mice. The luciferase reporter experiment confirmed that the regulatory effect of HMGA1 on P27 was mediated by miR-222. In addition, a miR-222 antagomir counteracted HMGA1 overexpression-induced deteriorating effects in vitro. Taken together, our data indicate that HMGA1 aggravates diabetic cardiomyopathy by directly regulating miR-222 promoter activity, which inhibits P27/mTOR-induced autophagy.
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Yao H, Lu F, Shao Y. The E2F family as potential biomarkers and therapeutic targets in colon cancer. PeerJ 2020; 8:e8562. [PMID: 32117628 PMCID: PMC7035869 DOI: 10.7717/peerj.8562] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Accepted: 01/13/2020] [Indexed: 12/22/2022] Open
Abstract
Background The E2F family is a group of genes encoding a series of transcription factors in higher eukaryotes and participating in the regulation of cell cycle and DNA synthesis in mammals. This study was designed to investigate the role of E2F family in colon cancer. Methods In this study, the transcriptional levels of E2F1-8 in patients with colon cancer from GEPIA was examined. Meanwhile, the immunohistochemical data of the eight genes were also obtained in the The Human Protein Atlas website. Additionally, we re-identified the mRNA expression levels of these genes via real time PCR. Furthermore, the association between the levels of E2F family and stage plot as wells overall survival of patients with colon cancer were analyzed. Results We found that the mRNA and protein levels of E2F1, E2F2, E3F3, E2F5, E2F7 and E2F8 were significantly higher in colon cancer tissues than in normal colon tissues while the expression levels of E2F4 and E2F6 displayed no significant difference between colon cancer tissues and normal tissues. Additionally, E2F3, E2F4, E2F7 and E2F8 were significantly associated with the stages of colon cancer. The Kaplan-Meier Plotter showed that the high levels of E2F3 conferred a worse overall survival and disease free survival of patients with colon cancer. Also, high levels of E2F4 resulted in a worse overall survival. Conclusion Our study implied that E2F3, E2F4, E2F7 and E2F8 are potential targets of precision therapy for patients with colon cancer while E2F1, E2F2, E3F3, E2F5, E2F7 and E2F8 are potential biomarkers for the diagnosis of colon cancer.
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Affiliation(s)
- Haibo Yao
- Department of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College, Key Laboratory of Gastroenterology of Zhejiang Province), Hangzhou, China
| | - Fang Lu
- Department of Neurology, Second People's Hospital of Yuhang District, Hangzhou, China
| | - Yanfei Shao
- Department of Pharmacy, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, China
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35
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Tao T, Xu H. Autophagy and Obesity and Diabetes. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1207:445-461. [PMID: 32671767 DOI: 10.1007/978-981-15-4272-5_32] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
The prevalence of obesity is increasing rapidly and is closely associated with a variety of metabolic diseases. Recent studies have suggested that autophagy is likely to play an important role in the development of obesity and may be related to insulin sensitivity. Autophagy may be involved in the browning of white adipose tissue and may also affect the metabolic balance of lipids. Autophagy can degrade cytoplasmic lipids by lipophagy in hepatocytes. Furthermore, Autophagy in hepatocytes helps prevent NAFLD. The study of autophagy in glucose metabolism is still in a very preliminary stage. Changes in autophagy activity play an important role in the development of insulin resistance in diabetes and many metabolic diseases. Therefore, it is still worth further exploration on the deeper mechanism of oxidative stress induction of insulin resistance to autophagy and whether there will be corresponding complications to the body.
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Affiliation(s)
- Tao Tao
- Department of Endocrinology and Metabolism, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 160 Pujian Road, Shanghai, 200127, China.
| | - Huanbai Xu
- Department of Endocrinology and Metabolism, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200080, China
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36
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Zheng X, Peng M, Li Y, Wang X, Lu W, Wang X, Shan Y, Li R, Gao L, Qiu C. Cathelicidin-related antimicrobial peptide protects against cardiac fibrosis in diabetic mice heart by regulating endothelial-mesenchymal transition. Int J Biol Sci 2019; 15:2393-2407. [PMID: 31595157 PMCID: PMC6775320 DOI: 10.7150/ijbs.35736] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2019] [Accepted: 07/25/2019] [Indexed: 12/19/2022] Open
Abstract
Cathelicidin-related antimicrobial peptide (CRAMP), antimicrobial peptide, was reported to protect against myocardial ischemia/reperfusion injury. In the pathology of diabetic cardiomyopathy, endothelial-to-mesenchymal transition (EndMT) results from hyperglycemia-induced endothelial injury, leading to cardiac fibrosis. This study aims to evaluate the effect of CRAMP on EndMT and cardiac fibrosis on diabetic mice heart. Mice were subjected to streptozotocin to induce diabetes. CRAMP was administered by intraperitoneal injection (1 or 8 mg/kg/d) for 4 weeks from 12 weeks till 16 weeks after final streptozotocin injection. Cardiac dysfunction was observed in diabetic mice. Only 8 mg/kg/d CRAMP treatment proved cardiac function. Increased EndMT and fibrosis level were also observed in diabetic mice heart. 8mg/kg CRAMP inhibited EndMT and fibrosis level in diabetic mice. Mouse heart endothelial cells (MHECs) were treated with CRAMP and exposed to high glucose. Hyperglycemia-induced EndMT in MHECs was also attenuated by CRAMP treatment. Activation of TGFβ/Smad signalling was increased in diabetic mice heart tissue and hyperglycemia stimulated MHECs, which was prevented following CRAMP treatment. Activation of AMPKa1/mTOR showed similar changes. AMPKa1 siRNA abrogated the effects of CRAMP in MHECs. TGFβ/Smad inhibitor LY2109761 and AMPKa agonist AIRCA mimic the effect of CRAMP. In summary, CRAMP can inhibit EndMT, cardiac fibrosis and protect against diabetic cardiomyopathy by regulating AMPKa1/TGFβ signalling.
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Affiliation(s)
- Xiaolin Zheng
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Meng Peng
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yan Li
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xule Wang
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Wenjie Lu
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xi Wang
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yingguang Shan
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ran Li
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Lu Gao
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Chunguang Qiu
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Wang Y, Lu YH, Tang C, Xue M, Li XY, Chang YP, Cheng Y, Li T, Yu XC, Sun B, Li CJ, Chen LM. Calcium Dobesilate Restores Autophagy by Inhibiting the VEGF/PI3K/AKT/mTOR Signaling Pathway. Front Pharmacol 2019; 10:886. [PMID: 31447680 PMCID: PMC6696883 DOI: 10.3389/fphar.2019.00886] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Accepted: 07/15/2019] [Indexed: 01/10/2023] Open
Abstract
Objective: Calcium dobesilate (CaD), an effective drug for the treatment of diabetic microvascular complications, especially diabetic retinopathy, is widely used in the clinic. Interestingly, several studies have indicated that CaD is therapeutic for diabetic kidney disease (DKD). Recently, evidence has indicated that altered vascular endothelial growth factor (VEGF) expression and decreased autophagy are the main pathological mechanisms of proteinuria. Thus, this study was conducted to explore the effect of CaD on restoring autophagy in DKD and the possible signaling pathway between VEGF and autophagy. Methods: Obese mice with spontaneous diabetes (KK-Ay) and high-fat diet- and streptozotocin-induced diabetic mice (HFD/STZ) were used in this study. Biochemical staining, western blotting, and immunohistochemistry were conducted to determine the angioprotective effect of CaD and the underlying mechanism between autophagy and VEGF/VEGFR. Results: Our results showed that CaD was capable of reducing albuminuria and restoring renal histological changes in KK-Ay and HFD/STZ-induced diabetic mice. CaD restored autophagy by decreasing the protein expression of LC3 II, Atg5, and beclin 1 and increasing the expression of P62. Moreover, CaD reduced the activation of the autophagy-related PI3K/AKT/mTOR pathway possibly via decreasing VEGF and downregulating VEGF receptor 2. Conclusion: Overall, CaD, as a novel potential therapeutic drug for DKD, plays a key role in protecting renal function and restoring autophagy by blocking VEGF/VEGFR2 and inhibiting the PI3K/AKT/mTOR signaling pathway.
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Affiliation(s)
- Yue Wang
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital, Tianjin Institute of Endocrinology, Tianjin, China
| | - Yun-Hong Lu
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital, Tianjin Institute of Endocrinology, Tianjin, China
| | - Chao Tang
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital, Tianjin Institute of Endocrinology, Tianjin, China
| | - Mei Xue
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital, Tianjin Institute of Endocrinology, Tianjin, China
| | - Xiao-Yu Li
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital, Tianjin Institute of Endocrinology, Tianjin, China
| | - Yun-Peng Chang
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital, Tianjin Institute of Endocrinology, Tianjin, China
| | - Ying Cheng
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital, Tianjin Institute of Endocrinology, Tianjin, China
| | - Ting Li
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital, Tianjin Institute of Endocrinology, Tianjin, China
| | - Xiao-Chen Yu
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital, Tianjin Institute of Endocrinology, Tianjin, China
| | - Bei Sun
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital, Tianjin Institute of Endocrinology, Tianjin, China
| | - Chun-Jun Li
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital, Tianjin Institute of Endocrinology, Tianjin, China
| | - Li-Ming Chen
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital, Tianjin Institute of Endocrinology, Tianjin, China
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Wang Z, Wang Z, Gao L, Xiao L, Yao R, Du B, Li Y, Wu L, Liang C, Huang Z, Li P, Zhang Y. miR-222 inhibits cardiac fibrosis in diabetic mice heart via regulating Wnt/β-catenin-mediated endothelium to mesenchymal transition. J Cell Physiol 2019; 235:2149-2160. [PMID: 31389030 DOI: 10.1002/jcp.29119] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Accepted: 03/05/2019] [Indexed: 12/13/2022]
Abstract
miR-222 participates in many cardiovascular diseases, but its effect on cardiac remodeling induced by diabetes is unclear. This study evaluated the functional role of miR-222 in cardiac fibrosis in diabetic mice. Streptozotocin (STZ) was used to establish a type 1 diabetic mouse model. After 10 weeks of STZ injection, mice were intravenously injected with Ad-miR-222 to induce the overexpression of miR-222. miR-222 overexpression reduced cardiac fibrosis and improved cardiac function in diabetic mice. Mechanistically, miR-222 inhibited the endothelium to mesenchymal transition (EndMT) in diabetic mouse hearts. Mouse heart fibroblasts and endothelial cells were isolated and cultured with high glucose (HG). An miR-222 mimic did not affect HG-induced fibroblast activation and function but did suppress the HG-induced EndMT process. The antagonism of miR-222 by antagomir inhibited HG-induced EndMT. miR-222 regulated the promoter region of β-catenin, thus negatively regulating the Wnt/β-catenin pathway, which was confirmed by β-catenin siRNA. Taken together, our results indicated that miR-222 inhibited cardiac fibrosis in diabetic mice via negatively regulating Wnt/β-catenin-mediated EndMT.
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Affiliation(s)
- Zheng Wang
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhongmin Wang
- Cardiology Department, Fuwai Central China Cardiovascular Hospital, Zhengzhou, China
| | - Lu Gao
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Lili Xiao
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Rui Yao
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Binbin Du
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yapeng Li
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Leiming Wu
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Cui Liang
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhen Huang
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Pengcheng Li
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yanzhou Zhang
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Shen Z, Chen Q, Jin T, Wang M, Ying H, Lu J, Wang M, Zhang W, Qiu F, Jin C, Zhao Y, Fu G. Theaflavin 3,3'-digallate reverses the downregulation of connexin 43 and autophagy induced by high glucose via AMPK activation in cardiomyocytes. J Cell Physiol 2019; 234:17999-18016. [PMID: 30847932 DOI: 10.1002/jcp.28432] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2018] [Revised: 02/03/2019] [Accepted: 02/14/2019] [Indexed: 12/16/2022]
Abstract
Theaflavin 3,3'-digallate (TF3), is reported to protect cardiomyocytes from lipotoxicity and reperfusion injury. However, the role of TF3 in the protection of high-glucose injury is still poorly understood. This study investigated the protective effects of TF3 on gap junctions and autophagy in neonatal cardiomyocytes (NRCMs). NRCMs preincubated with high glucose were coincubated with TF3. The expression of connexins and autophagy-related proteins was determined. The functioning of gap-junctional intercellular communication (GJIC) was measured by a dye transfer assay. Adenosine monophosphate-activated protein kinase (AMPK) activity was determined by western blot. Moreover, AMPK was activated with aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) or inhibited by AMPKα small interfering RNA (siRNA) to explore the role of AMPK in the modulation of connexin 43 (Cx43) and autophagy. Meanwhile, autophagy was activated or blocked to observe the change in Cx43 expression. It was found that the protein expression of Cx43 and autophagy-related proteins was increased in a TF3 dose- and time-dependent manner under high glucose. TF3 also recovered the reduced GJIC function induced by high glucose concentrations. TF3 activated phosphorylated AMPK in a time-dependent way. AMPKα siRNA abrogated the protection of TF3, while AICAR showed similar results compared to the TF3 treatment. Meanwhile, autophagy activation caused decreased Cx43, while cotreatment with baf A1 enhanced Cx43 expression further compared with the TF3 treatment alone under high glucose. We concluded that TF3 partly reversed the inhibition of Cx43 expression and autophagy induced by high glucose in NRCMs, partly by restoring AMPK activity. Inhibition of autophagy might be protective by preserving Cx43 expression in NRCMs stimulated by high glucose.
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Affiliation(s)
- Zhida Shen
- Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Qi Chen
- Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Tingting Jin
- Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Meihui Wang
- Department of Cardiology Basic Research, Biomedical Research Center, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Hangying Ying
- Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Jiangting Lu
- Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Ming Wang
- Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Wenbin Zhang
- Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Fuyu Qiu
- Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Chongying Jin
- Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Yanbo Zhao
- Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Guosheng Fu
- Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
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Li N, Zhou H, Wu H, Wu Q, Duan M, Deng W, Tang Q. STING-IRF3 contributes to lipopolysaccharide-induced cardiac dysfunction, inflammation, apoptosis and pyroptosis by activating NLRP3. Redox Biol 2019; 24:101215. [PMID: 31121492 PMCID: PMC6529775 DOI: 10.1016/j.redox.2019.101215] [Citation(s) in RCA: 405] [Impact Index Per Article: 67.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 04/27/2019] [Accepted: 05/06/2019] [Indexed: 12/18/2022] Open
Abstract
Mountainous evidence suggests that inflammation, cardiomyocyte apoptosis and pyroptosis are involved in the development of sepsis and sepsis-induced cardiomyopathy (SIC). Stimulator of interferon genes (STING) is an indispensable molecule that could regulate inflammation and immune response in multiple diseases. However, the role of STING in cardiovascular disease, especially SIC remains unclear. This study was designed to investigate the potential molecular mechanisms of STING in lipopolysaccharide (LPS)-induced cardiac injury using STING global knockout mice. In wild type mice and cardiomyocytes, LPS stimulation triggered the perinuclear translocation of STING, which further bound to Type-I interferons (IFN) regulatory factor 3 (IRF3) and phosphorylated IRF3. Phosphorylated (P-) IRF3 subsequently translocated into nucleus and increased the expression of NOD-like receptor protein 3 (NLRP3). Knockout of STING in mice significantly improved survival rate and cardiac function, apart from suppressing myocardial and serum inflammatory cytokines, apoptosis, as well as cardiomyocyte pyroptosis. In vitro experiments revealed that NLRP3 overexpression by adenovirus could offset protective effects of STING knockdown in LPS-induced cardiomyocytes. Additionally, LPS stimulation also promoted the production of intracellular reactive oxygen (ROS), which further induced the NLRP3 translocation to the cytoplasm from the nucleus. Dissociative TXNIP could directly interact with cytoplasmic NLRP3 and form inflammasome, eventually triggering cardiomyocyte injury. Collectively, our findings disclose that STING deficiency could alleviate LPS-induced SIC in mice. Hence, targeting STING in cardiomyocytes may be a promising therapeutic strategy for preventing SIC.
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Affiliation(s)
- Ning Li
- Department of Cardiology, Renmin Hospital of Wuhan University, Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, PR China
| | - Heng Zhou
- Department of Cardiology, Renmin Hospital of Wuhan University, Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, PR China.
| | - Haiming Wu
- Department of Cardiology, Renmin Hospital of Wuhan University, Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, PR China
| | - Qingqing Wu
- Department of Cardiology, Renmin Hospital of Wuhan University, Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, PR China
| | - Mingxia Duan
- Department of Cardiology, Renmin Hospital of Wuhan University, Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, PR China
| | - Wei Deng
- Department of Cardiology, Renmin Hospital of Wuhan University, Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, PR China
| | - Qizhu Tang
- Department of Cardiology, Renmin Hospital of Wuhan University, Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, PR China.
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41
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MiR-451 antagonist protects against cardiac fibrosis in streptozotocin-induced diabetic mouse heart. Life Sci 2019; 224:12-22. [DOI: 10.1016/j.lfs.2019.02.059] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2018] [Revised: 02/25/2019] [Accepted: 02/27/2019] [Indexed: 01/30/2023]
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42
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Yin L, Fang Y, Song T, Lv D, Wang Z, Zhu L, Zhao Z, Yin X. FBXL10 regulates cardiac dysfunction in diabetic cardiomyopathy via the PKC β2 pathway. J Cell Mol Med 2019; 23:2558-2567. [PMID: 30701683 PMCID: PMC6433654 DOI: 10.1111/jcmm.14146] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Revised: 12/16/2018] [Accepted: 12/18/2018] [Indexed: 12/14/2022] Open
Abstract
Diabetic cardiomyopathy (DCM) is a condition associated with significant structural changes including cardiac tissue necrosis, localized fibrosis, and cardiomyocyte hypertrophy. This study sought to assess whether and how FBXL10 can attenuate DCM using a rat streptozotocin (STZ)‐induced DCM model system. In the current study, we found that FBXL10 expression was significantly decreased in diabetic rat hearts. FBXL10 protected cells from high glucose (HG)‐induced inflammation, oxidative stress, and apoptosis in vitro. In addition, FBXL10 significantly activated PKC β2 signaling pathway in H9c2 cells and rat model. The cardiomyocyte‐specific overexpression of FBXL10 at 12 weeks after the initial STZ administration attenuated oxidative stress and inflammation, thereby reducing cardiomyocyte death and preserving cardiac function in these animals. Moreover, FBXL10 protected against DCM via activation of the PKC β2 pathway. In conclusion, FBXL has the therapeutic potential for the treatment of DCM.
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Affiliation(s)
- Leilei Yin
- Department of Cardiology, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yingying Fang
- Department of Digestive, Heilongjiang Institute of traditional Chinese Medicine, Harbin, China
| | - Tao Song
- Department of Cardiology, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Dan Lv
- Department of Cardiology, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zheng Wang
- Department of Cardiology, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Li Zhu
- Department of Cardiology, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zihui Zhao
- Department of Cardiology, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xinhua Yin
- Department of Cardiology, the First Affiliated Hospital of Harbin Medical University, Harbin, China
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Sharma V, Verma S, Seranova E, Sarkar S, Kumar D. Selective Autophagy and Xenophagy in Infection and Disease. Front Cell Dev Biol 2018; 6:147. [PMID: 30483501 PMCID: PMC6243101 DOI: 10.3389/fcell.2018.00147] [Citation(s) in RCA: 184] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Accepted: 10/10/2018] [Indexed: 12/29/2022] Open
Abstract
Autophagy, a cellular homeostatic process, which ensures cellular survival under various stress conditions, has catapulted to the forefront of innate defense mechanisms during intracellular infections. The ability of autophagy to tag and target intracellular pathogens toward lysosomal degradation is central to this key defense function. However, studies involving the role and regulation of autophagy during intracellular infections largely tend to ignore the housekeeping function of autophagy. A growing number of evidences now suggest that the housekeeping function of autophagy, rather than the direct pathogen degradation function, may play a decisive role to determine the outcome of infection and immunological balance. We discuss herein the studies that establish the homeostatic and anti-inflammatory function of autophagy, as well as role of bacterial effectors in modulating and coopting these functions. Given that the core autophagy machinery remains largely the same across diverse cargos, how selectivity plays out during intracellular infection remains intriguing. We explore here, the contrasting role of autophagy adaptors being both selective as well as pleotropic in functions and discuss whether E3 ligases could bring in the specificity to cargo selectivity.
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Affiliation(s)
- Vartika Sharma
- Cellular Immunology Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India
| | - Surbhi Verma
- Cellular Immunology Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India
| | - Elena Seranova
- Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Sovan Sarkar
- Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Dhiraj Kumar
- Cellular Immunology Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India
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Zheng L, Shen X, Ye J, Xie Y, Yan S. Metformin alleviates hyperglycemia-induced apoptosis and differentiation suppression in osteoblasts through inhibiting the TLR4 signaling pathway. Life Sci 2018; 216:29-38. [PMID: 30414431 DOI: 10.1016/j.lfs.2018.11.008] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Revised: 10/27/2018] [Accepted: 11/05/2018] [Indexed: 02/07/2023]
Abstract
AIMS Metformin was found to protect against hyperglycemia-induced injury in osteoblasts, but the cellular mechanisms involved remain unclear. Therefore, the aim of this study was to determine the effect of metformin on hyperglycemia-induced apoptosis and differentiation suppression in osteoblasts and to explore its relationships with the TLR4 signaling pathway. MAIN METHODS A mouse osteoblast cell line, MC3T3-E1, and a diabetic rat model were used to survey the protective effects of metformin on hyperglycemia-induced injury. TLR4 expression was altered using small interfering (si)RNA and lentivirus-mediated TLR4 overexpression. LPS was used as a specific TLR4 activator, and CLI-095 was used as a TLR4 inhibitor. KEY FINDINGS Metformin improved osteoblast differentiation, reduced apoptosis in hyperglycemic osteoblasts, and inhibited TLR4, MyD88 and NF-κB expression in a dose-dependent manner. Down-regulating the expression or inhibiting the activity of TLR4 enhanced these protective effects of metformin on osteoblast differentiation, cell viability and cell apoptosis in hyperglycemic conditions, whereas up-regulating the expression or activating the activity of TLR4 had the opposite effects. Activating NF-κB suppressed the protective effects of metformin, while inhibiting NF-κB activity had the opposite effects. Metformin increased ALP and OCN secretion, enhanced BMP-2 expression, improved bone mineral density (BMD), and decreased TLR4, MyD88 and NF-κB levels in the femur tissues of diabetic rats. SIGNIFICANCE Taken together our experimentation support the hypothesis that metformin may alleviate hyperglycemia-induced apoptosis and differentiation suppression in osteoblasts by inhibiting the TLR4/MyD88/NF-κB signaling pathway.
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Affiliation(s)
- Lifeng Zheng
- Department of Orthopedics, the First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, Fujian, China
| | - Ximei Shen
- Department of Endocrinology, the First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, Fujian, China; Diabetes Research Institute of Fujian Province, Fuzhou 350005, Fujian, China
| | - Junjian Ye
- Department of Orthopedics, the First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, Fujian, China
| | - Yun Xie
- Department of Orthopedics, the First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, Fujian, China
| | - Sunjie Yan
- Department of Endocrinology, the First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, Fujian, China; Diabetes Research Institute of Fujian Province, Fuzhou 350005, Fujian, China.
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Wu A, Hu P, Lin J, Xia W, Zhang R. Activating Cannabinoid Receptor 2 Protects Against Diabetic Cardiomyopathy Through Autophagy Induction. Front Pharmacol 2018; 9:1292. [PMID: 30459625 PMCID: PMC6232417 DOI: 10.3389/fphar.2018.01292] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Accepted: 10/22/2018] [Indexed: 12/11/2022] Open
Abstract
Cannabinoid receptor 2 (CB2) has been reported to produce a cardio-protective effect in cardiovascular diseases such as myocardial infarction. Here in this study, we investigated the role of CB2 in diabetic cardiomyopathy (DCM) and its underlying mechanisms. HU308 was used for the selective activation of CB2. Bafilomycin A1 was used for the blockade of autophagy and compound C was used to inhibit AMPK signaling. An streptozotocin (STZ)-induced mice model and high glucose (HG)-challenged cardiomyocytes were applied for study. Cardiac function was detected by echocardiography and Western blot for the detection of autophagy-related and its signaling-related proteins. Transmission electron microscopy was used for the analysis of autophagosome number. Cell viability was detected by Cell Counting Kit-8 (CCK-8) and lactate dehydrogenase (LDH) release assays. We found that activating CB2 by HU308 improved cardiac function in DCM as well as cell viability in cardiomyocytes under HG challenge, while the administration of bafilomycin A1 attenuated the protective effects. HU308 enhanced the level of autophagy in the heart tissues from DCM mice as well as cardiomyocytes under HG challenge. HU308 triggered the AMPK-mTOR-p70S6K signaling pathway, while the administration of compound C attenuated the cardio-protective effect of HU308 in cardiomyocytes under HG challenge. In conclusion, we initially demonstrated that activating CB2 produced a cardio-protective effect in DCM as well as cardiomyocytes under HG challenge through inducing the AMPK-mTOR-p70S6K signaling-mediated autophagy.
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Affiliation(s)
- Aiping Wu
- Department of Rehabilitation Medicine, Zhejiang Hospital, Hangzhou, China
| | - Pengfei Hu
- Department of Cardiology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Jian Lin
- Department of Rehabilitation Medicine, Zhejiang Hospital, Hangzhou, China
| | - Wan Xia
- Department of Rehabilitation Medicine, Zhejiang Hospital, Hangzhou, China
| | - Rui Zhang
- Department of Rehabilitation Medicine, Zhejiang Hospital, Hangzhou, China
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Zhang Y, Whaley-Connell AT, Sowers JR, Ren J. Autophagy as an emerging target in cardiorenal metabolic disease: From pathophysiology to management. Pharmacol Ther 2018; 191:1-22. [PMID: 29909238 PMCID: PMC6195437 DOI: 10.1016/j.pharmthera.2018.06.004] [Citation(s) in RCA: 95] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Accepted: 06/05/2018] [Indexed: 12/16/2022]
Abstract
Although advances in medical technology and health care have improved the early diagnosis and management for cardiorenal metabolic disorders, the prevalence of obesity, insulin resistance, diabetes, hypertension, dyslipidemia, and kidney disease remains high. Findings from numerous population-based studies, clinical trials, and experimental evidence have consolidated a number of theories for the pathogenesis of cardiorenal metabolic anomalies including resistance to the metabolic action of insulin, abnormal glucose and lipid metabolism, oxidative and nitrosative stress, endoplasmic reticulum (ER) stress, apoptosis, mitochondrial damage, and inflammation. Accumulating evidence has recently suggested a pivotal role for proteotoxicity, the unfavorable effects of poor protein quality control, in the pathophysiology of metabolic dysregulation and related cardiovascular complications. The ubiquitin-proteasome system (UPS) and autophagy-lysosomal pathways, two major although distinct cellular clearance machineries, govern protein quality control by degradation and clearance of long-lived or damaged proteins and organelles. Ample evidence has depicted an important role for protein quality control, particularly autophagy, in the maintenance of metabolic homeostasis. To this end, autophagy offers promising targets for novel strategies to prevent and treat cardiorenal metabolic diseases. Targeting autophagy using pharmacological or natural agents exhibits exciting new strategies for the growing problem of cardiorenal metabolic disorders.
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Affiliation(s)
- Yingmei Zhang
- Shanghai Institute of Cardiovascular Diseases, Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA.
| | - Adam T Whaley-Connell
- Research Service, Harry S Truman Memorial Veterans' Hospital, University of Missouri-Columbia School of Medicine, Columbia, MO, USA; Diabetes and Cardiovascular Center, Department of Medicine, University of Missouri-Columbia School of Medicine, Columbia, MO, USA
| | - James R Sowers
- Research Service, Harry S Truman Memorial Veterans' Hospital, University of Missouri-Columbia School of Medicine, Columbia, MO, USA; Diabetes and Cardiovascular Center, Department of Medicine, University of Missouri-Columbia School of Medicine, Columbia, MO, USA
| | - Jun Ren
- Shanghai Institute of Cardiovascular Diseases, Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA.
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Gao L, Liu Y, Guo S, Xiao L, Wu L, Wang Z, Liang C, Yao R, Zhang Y. LAZ3 protects cardiac remodeling in diabetic cardiomyopathy via regulating miR-21/PPARa signaling. Biochim Biophys Acta Mol Basis Dis 2018; 1864:3322-3338. [PMID: 30031228 DOI: 10.1016/j.bbadis.2018.07.019] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Revised: 07/06/2018] [Accepted: 07/16/2018] [Indexed: 12/11/2022]
Abstract
Diabetes contributes to cardiovascular complications and the pathogenesis of cardiac remodeling that can lead to heart failure. We aimed to evaluate the functional role of LAZ3 in diabetic cardiomyopathy (DCM). Streptozotocin (STZ) was used to induce a diabetic mouse model. Three months after induction, the mice were subjected to retro-orbital venous plexus injection of adeno-associated virus 9 (AAV9) that overexpressed LAZ3. Six weeks after the infection, mouse hearts were removed to assess the degree of cardiac remodeling. LAZ3 was down-regulated in the diabetic mouse hearts and high glucose stimulated cardiomyocytes. Knock-down of LAZ3 in cardiomyocytes with LAZ3 siRNA reduced cell viability, increased the inflammatory response and induced oxidative stress and cell apoptosis. Overexpression of LAZ3 by infection with adeno-associated virus (AAV9)-LAZ3 protected against an inflammatory response, oxidative stress and cell apoptosis in both a high glucose stimulated in vitro study and diabetic mouse hearts. We found that LAZ3 increased the activation of PPARa, which increased PGC-1a activation and subsequently augmented NRF2 expression and nuclear translocation. This outcome was confirmed by NRF2 siRNA and a PPARa activator, since NRF2 siRNA abrogated the protective effects of LAZ3 overexpression, while the PPARa activator reversed the deteriorating phenotype of LAZ3 knock-down in both the in vitro and vivo study. Furthermore, LAZ3 decreased miR-21 expression, which resulted in PPARa activation, NRF2 expression and nuclear translocation. In conclusion, LAZ3 protects against cardiac remodeling in DCM by decreasing miR-21, thus regulating PPARa/NRF2 signaling.
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Affiliation(s)
- Lu Gao
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yuan Liu
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Sen Guo
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Lili Xiao
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Leiming Wu
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zheng Wang
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Cui Liang
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Rui Yao
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yanzhou Zhang
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
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