Chloroquine improves left ventricle diastolic function in streptozotocin-induced diabetic mice

Xiao, Yichuan; Zhang, Guiping; Hou, Ning; Wu, Xiaoqian; Chen, Wenliang; Luo, Jia; Zhang, Gen-Shui

doi:10.2147/dddt.s111253

Cited by 32 publications

(16 citation statements)

References 32 publications

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“…These pathological changes cause cardiac stiffness and consequent left ventricular diastole (Murtaza et al, 2019). The present study validated our earlier finding (Yuan et al, 2016) that diabetes leads to cardiac remodeling and diastolic dysfunction in both mice with T1DM and T2DM; this finding was supported by the increased gene expression of cardiac hypertrophic markers ( Nppa and Myh7 ), aggravation of cardiac fibrosis, and decreased E/A ratio in both types of diabetic mice. Furthermore, these changes indicate that mice with T1DM and T2DM had DCM, which significantly improved on carvacrol treatment.…”

Section: Discussionsupporting

confidence: 92%

Carvacrol Attenuates Diabetic Cardiomyopathy by Modulating the PI3K/AKT/GLUT4 Pathway in Diabetic Mice

et al. 2019

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Background: Diabetic cardiomyopathy (DCM), a common complication of diabetes mellitus, eventually leads to heart failure. Carvacrol is a food additive with diverse bioactivities. We aimed to study the protective effects and mechanisms of carvacrol in DCM. Methods: We used a streptozotocin-induced and db/db mouse model of types 1 and 2 diabetes mellitus (T1DM and T2DM), respectively. Both study groups received daily intraperitoneal injections of carvacrol for 6 weeks. Cardiac remodeling was evaluated by histological analysis. We determined gene expression of cardiac remodeling markers (Nppa and Myh7) by quantitative real-time PCR and cardiac function by echocardiography. Changes of PI3K/AKT signaling were determined with Western blotting. GLUT4 translocation was evaluated by Western blotting and immunofluorescence staining. Results: Compared with control mice, both T1DM and T2DM mice showed cardiac remodeling and left ventricular dysfunction. Carvacrol significantly reduced blood glucose levels and suppressed cardiac remodeling in mice with T1DM and T2DM. At the end of the treatment period, both T1DM and T2DM mice showed lesser cardiac hypertrophy, Nppa and Myh7 mRNA expressions, and cardiac fibrosis, compared to mice administered only the vehicle. Moreover, carvacrol significantly restored PI3K/AKT signaling, which was impaired in mice with T1DM and T2DM. Carvacrol increased levels of phosphorylated PI3K, PDK1, AKT, and AS160 and inhibited PTEN phosphorylation in mice with T1DM and T2DM. Carvacrol treatment promoted GLUT4 membrane translocation in mice with T1DM and T2DM. Metformin was used as the positive drug control in T2DM mice, and carvacrol showed comparable effects to that of metformin on cardiac remodeling and modulation of signaling pathways. Conclusion: Carvacrol protected against DCM in mice with T1DM and T2DM by restoring PI3K/AKT signaling-mediated GLUT4 membrane translocation and is a potential treatment of DCM.

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Section: Discussionsupporting

confidence: 92%

Carvacrol Attenuates Diabetic Cardiomyopathy by Modulating the PI3K/AKT/GLUT4 Pathway in Diabetic Mice

et al. 2019

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“…Echocardiography was done using Visualsonic Ultrasound System (Vevo770, Toronto, Canada) containing a 40 Mhz variable frequency probe. Standard imaging planes, M-mode, color-mode, Doppler, PW Doppler mode views were recorded when the mouse possessed a target heart rate between 450 and 550 beats per minute ( 44 ). Functional calculations were acquired according to the guidelines of the American Society of Echocardiography.…”

Section: Methodsmentioning

confidence: 99%

RETRACTED: The Role of Allograft Inflammatory Factor-1 in the Effects of Experimental Diabetes on B Cell Functions in the Heart

Sarkar

Shukla

Alqatawni

et al. 2018

Front. Cardiovasc. Med.

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Diabetes mellitus (DM) often causes chronic inflammation, hypertrophy, apoptosis and fibrosis in the heart and subsequently leads to myocardial remodeling, deteriorated cardiac function and heart failure. However, the etiology of the cardiac disease is unknown. Therefore, we assessed the gene expression in the left ventricle of diabetic and non-diabetic mice using Affymetrix microarray analysis. Allograft inflammatory factor-1 (AIF-1), one of the top downregulated B cell inflammatory genes, is associated with B cell functions in inflammatory responses. Real-time reverse transcriptase-polymerase chain reaction confirmed the Affymetrix data. The expression of CD19 and AIF-1 were downregulated in diabetic hearts as compared to control hearts. Using in vitro migration assay, we showed for the first time that AIF-1 is responsible for B cell migration as B cells migrated to GFP-AIF-1-transfected H9C2 cells compared to empty vector-transfected cells. Interestingly, overexpression of AIF-1 in diabetic mice prevented streptozotocin-induced cardiac dysfunction, inflammation and promoted B cell homing into the heart. Our results suggest that AIF-1 downregulation inhibited B cell homing into diabetic hearts, thus promoting inflammation that leads to the development of diabetic cardiomyopathy, and that overexpression of AIF-1 could be a novel treatment for this condition.

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“…In hypertrophic heart, autophagic processes are activated and studies on Beclin-1 suggested that autophagy enhanced tissue remodeling and disease progression [9,10]. In line with these results, treatment with autophagy inhibitor chloroquine ameliorated diastolic function and cardiac fibrosis in diabetic mice [11]. On the other hand, genetic deficiency of autophagy effector protein Atg5 led to increased hypertrophy and cardiac fibrosis [8,12].…”

Section: Introductionmentioning

confidence: 79%

“…Here, we demonstrated a novel mechanism, by which the TGF-β-Fosl-2 axis regulated profibrotic changes in cardiac fibroblasts by activating autophagocytosis. Previous studies have already shown the significance of autophagy in promoting fibrotic processes in multiple organs including skin [ 25 ], lung [ 26 ], liver [ 27 ], kidney [ 28 ] and heart [ 9 , 10 , 11 ]. It should be noted that in the heart, autophagocytosis might also be involved in antifibrotic and cardioprotective processes [ 8 , 12 , 13 ].…”

Section: Discussionmentioning

confidence: 99%

The AP-1 Transcription Factor Fosl-2 Regulates Autophagy in Cardiac Fibroblasts during Myocardial Fibrogenesis

Seidenberg

Stellato

Hukara

et al. 2021

IJMS

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Background: Pathological activation of cardiac fibroblasts is a key step in development and progression of cardiac fibrosis and heart failure. This process has been associated with enhanced autophagocytosis, but molecular mechanisms remain largely unknown. Methods and Results: Immunohistochemical analysis of endomyocardial biopsies showed increased activation of autophagy in fibrotic hearts of patients with inflammatory cardiomyopathy. In vitro experiments using mouse and human cardiac fibroblasts confirmed that blockade of autophagy with Bafilomycin A1 inhibited fibroblast-to-myofibroblast transition induced by transforming growth factor (TGF)-β. Next, we observed that cardiac fibroblasts obtained from mice overexpressing transcription factor Fos-related antigen 2 (Fosl-2tg) expressed elevated protein levels of autophagy markers: the lipid modified form of microtubule-associated protein 1A/1B-light chain 3B (LC3BII), Beclin-1 and autophagy related 5 (Atg5). In complementary experiments, silencing of Fosl-2 with antisense GapmeR oligonucleotides suppressed production of type I collagen, myofibroblast marker alpha smooth muscle actin and autophagy marker Beclin-1 in cardiac fibroblasts. On the other hand, silencing of either LC3B or Beclin-1 reduced Fosl-2 levels in TGF-β-activated, but not in unstimulated cells. Using a cardiac hypertrophy model induced by continuous infusion of angiotensin II with osmotic minipumps, we confirmed that mice lacking either Fosl-2 (Ccl19CreFosl2flox/flox) or Atg5 (Ccl19CreAtg5flox/flox) in stromal cells were protected from cardiac fibrosis. Conclusion: Our findings demonstrate that Fosl-2 regulates autophagocytosis and the TGF-β-Fosl-2-autophagy axis controls differentiation of cardiac fibroblasts. These data provide a new insight for the development of pharmaceutical targets in cardiac fibrosis.

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Chloroquine improves left ventricle diastolic function in streptozotocin-induced diabetic mice

Cited by 32 publications

References 32 publications

Carvacrol Attenuates Diabetic Cardiomyopathy by Modulating the PI3K/AKT/GLUT4 Pathway in Diabetic Mice

Carvacrol Attenuates Diabetic Cardiomyopathy by Modulating the PI3K/AKT/GLUT4 Pathway in Diabetic Mice

RETRACTED: The Role of Allograft Inflammatory Factor-1 in the Effects of Experimental Diabetes on B Cell Functions in the Heart

The AP-1 Transcription Factor Fosl-2 Regulates Autophagy in Cardiac Fibroblasts during Myocardial Fibrogenesis

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