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Decreased autophagy induced by ?1-adrenoceptor autoantibodies contributes to cardiomyocyte apoptosis.

ABSTRACT: It has been recognized that myocardial apoptosis is one major factor in the development of heart dysfunction and autophagy has been shown to influence the apoptosis. In previous studies, we reported that anti-?1-adrenergic receptor autoantibodies (?1-AABs) decreased myocardial autophagy, but the role of decreased autophagy in cardiomyocyte apoptosis remains unclear. In the present study, we used a ?1-AAB-immunized rat model to investigate the role of decreased autophagy in cardiomyocyte apoptosis. We reported that the level of autophagic flux increased early and then decreased in an actively ?1-AAB-immunized rat model. Rapamycin, an mTOR inhibitor, restored myocardial apoptosis in the presence of ?1-AABs. Further, we found that the early increase of autophagy was an adaptive stress response that is possibly unrelated to ?1-AR, and the activation of the ?1-AR and PKA contributed to late decreased autophagy. Then, after upregulating or inhibiting autophagy with rapamycin, Atg5 overexpression adenovirus or 3-methyladenine in cultured primary neonatal rat cardiomyocytes, we found that autophagy decline promoted myocardial apoptosis effectively through the mitochondrial apoptotic pathway. In conclusion, the reduction of apoptosis through the proper regulation of autophagy may be important for treating patients with ?1-AAB-positive heart dysfunction.

SUBMITTER: Wang L

PROVIDER: S-EPMC5852148 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Decreased autophagy induced by β1-adrenoceptor autoantibodies contributes to cardiomyocyte apoptosis.

Wang Li L Li Yang Y Ning Na N Wang Jin J Yan Zi Z Zhang Suli S Jiao Xiangying X Wang Xiaohui X Liu Huirong H

Cell death & disease 20180314 3

It has been recognized that myocardial apoptosis is one major factor in the development of heart dysfunction and autophagy has been shown to influence the apoptosis. In previous studies, we reported that anti-β1-adrenergic receptor autoantibodies (β1-AABs) decreased myocardial autophagy, but the role of decreased autophagy in cardiomyocyte apoptosis remains unclear. In the present study, we used a β1-AAB-immunized rat model to investigate the role of decreased au ...[more]

PMID: 29540670

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Project description:Background Autoantibodies against the second extracellular loop of the β1-adrenoceptor (β1- AA ) act similarly to agonist of β1-adrenergic receptor, which plays an important role in the pathophysiological characteristics of ventricular remodeling. Recently, considerable lines of evidence have suggested that CTRP9 (C1q tumor necrosis factor-related protein 9) is a potent cardioprotective cardiokine and protects the heart from ventricular remodeling. The aim of this study was to determine the role of CTRP 9 in ventricular remodeling induced by β1- AA . Methods and Results Blood samples were collected from 131 patients with coronary heart disease and 131 healthy subjects. The serum levels of β1- AA and CTRP 9 were detected using ELISA . The results revealed that CTRP 9 levels in β1- AA -positive patients were lower than those in β1- AA -negative patients, and serum CTRP 9 concentrations were inversely correlated with β1- AA . β1- AA monoclonal antibodies (β1- AA mAbs) were administered in mice with and without rAAV 9- cTnT -Full Ctrp9- FLAG virus for 8 weeks. Reverse transcription-polymerase chain reaction/Western analysis showed that cardiomyocyte CTRP 9 expression was significantly reduced in β1- AA mAb-treated mice. Moreover, compared with the β1- AA mAb alone group, cardiac-specific CTRP 9 overexpression improved cardiac function, attenuated adverse remodeling, and ameliorated cardiomyocyte apoptosis and fibrosis. Mechanistic studies demonstrated that CTRP 9 overexpression decreased the levels of G-protein-coupled receptor kinase 2 and promoted the activation of AMP-dependent kinase pathway. However, cardiac-specific overexpression of CTRP 9 had no effect on the levels of cAMP and protein kinase A activity elevated by β1-AAmAb. Conclusions This study provides the first evidence that the long-term existence of β1- AA mAb suppresses cardiac CTRP 9 expression and exaggerates cardiac remodeling, suggesting that CTRP 9 may be a novel therapeutic target against pathologic remodeling in β1- AA -positive patients with coronary heart disease.

Project description:ObjectivesTo explore the effects of miR-16-5p and PTPN4 on the apoptosis and autophagy of AC16 cardiomyocytes after hypoxia/reoxygenation treatment.MethodsAC16 cells were divided into the control group (NC), hypoxia/reoxygenation group (H/R), knockdown miR-16-5p negative control group (NC inhibitor), knockdown miR-16-5p group (miR-16-5p inhibitor), overexpression miR-16-5p negative control group (NC mimics), overexpression miR-16-5p group (miR-16-5p mimics), silent PTPN4 negative control group (sh-NC), silent PTPN4 group (sh-PTPN4), and silent PTPN4 + knockdown miR-16-5p group (sh-PTPN4 + miR-16-5p inhibitor). Real-time fluorescent quantitative PCR (RT-qPCR) and western blotting (WB) were used to measure the expression level of miR-16-3p, miR-16-5p, protein tyrosine phosphatase nonreceptor type 4 (PTPN4), and autophagy-related proteins (beclin-1, LC3 II/I, and P26) in AC16 cells. The apoptosis level of AC16 cells in each group was measured by flow cytometry and TUNEL. The dual-luciferase reporter gene experiment was also used to verify the targeting relationship between miR-16-5p and PTPN4.ResultsAfter H/R treatment, the levels of myocardial injury markers including LDH and CK-MB in AC16 cells were increased significantly (P < 0.05), and the levels of cell apoptosis and autophagy also increased significantly (P < 0.05). The level of miR-16-3p in AC16 cells did not change significantly after H/R treatment, whereas the level of miR-16-5p was increased significantly (P < 0.05). After miR-16-5p was knocked down, the levels of LDH and CK-MB in AC16 cells treated with H/R were significantly reduced (P < 0.05), and the rates of cell apoptosis and autophagy were also significantly reduced (P < 0.05). miR-16-5p negatively regulated the expression level of PTPN4 protein in AC16 cells (P < 0.05), and the dual-luciferase reporter gene experiment confirmed that PTPN4 was the downstream target of miR-16-5p. Silencing of PTPN4 significantly increased the damage of AC16 cells induced by H/R treatment (P < 0.05), but simultaneously inhibiting the expression of PTPN4 and miR-16-5p reversed the protective effect of miR-16-5p knockdown on AC16 cells (P < 0.05).ConclusionsThe expression of miR-16-5p is upregulated in AC16 cells after H/R treatment and the knockdown which can protect AC16 cells from H/R-induced cell damage that may be due to its regulation on the expression of PTPN4.

Project description:BackgroundDrug memories become labile and reconsolidated after retrieval by presentation of environmental cues (conditioned stimulus) or drugs (unconditioned stimulus). Whether conditioned stimulus and unconditioned stimulus retrieval trigger different memory reconsolidation processes is not clear.MethodsProtein synthesis inhibitor or β-adrenergic receptor (β-AR) antagonist was systemically administrated or intra-central amygdala infused immediately after cocaine reexposure in cocaine-conditioned place preference or self-administration mice models. β-ARs were selectively knocked out in the central amygdala to further confirm the role of β-adrenergic receptor in cocaine reexposure-induced memory reconsolidation of cocaine-conditioned place preference.ResultsCocaine reexposure triggered de novo protein synthesis dependent memory reconsolidation of cocaine-conditioned place preference. Cocaine-priming-induced reinstatement was also impaired with post cocaine retrieval manipulation, in contrast to the relapse behavior with post context retrieval manipulation. Cocaine retrieval, but not context retrieval, induced central amygdala activation. Protein synthesis inhibitor or β1-adrenergic receptor antagonist infused in the central amygdala after cocaine retrieval, but not context retrieval, inhibited memory reconsolidation and reinstatement. β1-adrenergic receptor knockout in the central amygdala suppressed cocaine retrieval-triggered memory reconsolidation and reinstatement of cocaine conditioned place preference. β1-adrenergic receptor antagonism after cocaine retrieval also impaired reconsolidation and reinstatement of cocaine self-administration.ConclusionsCocaine reward memory triggered by unconditioned stimulus retrieval is distinct from conditioned stimulus retrieval. Unconditioned stimulus retrieval induced reconsolidation of cocaine reward memory depends on β1-adrenergic signaling in the central amygdala. Post unconditioned stimulus retrieval manipulation can prevent drug memory reconsolidation and relapse to cocaine, thus providing a potential strategy for the prevention of substance addiction.Significance statementIt is well known that drug memories become labile and reconsolidated upon retrieval by the presentation of conditioned stimulus (CS) or unconditioned stimulus (US). Whether CS and US retrieval trigger different memory reconsolidation processes is unknown. In this study, we found that US retrieval, but not CS retrieval, triggered memory reconsolidation of cocaine-conditioned place preference dependent on β1-AR and de novo protein synthesis in the central amygdala. Furthermore, cocaine priming-induced reinstatement was impaired with post US retrieval manipulation in contrast to the relapse behavior with post CS retrieval manipulation. In cocaine self-administration, β1-AR antagonism after US retrieval also impaired reconsolidation and reinstatement. Our study indicates that reconsolidation of cocaine reward memory triggered by US retrieval is distinct from CS retrieval. US retrieval induced reconsolidation of cocaine reward memory depends on β1-adrenergic signaling in the central amygdala.

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Decreased autophagy induced by ?1-adrenoceptor autoantibodies contributes to cardiomyocyte apoptosis.

Publications

Decreased autophagy induced by β<sub>1</sub>-adrenoceptor autoantibodies contributes to cardiomyocyte apoptosis.

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