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?1 adrenoceptor antibodies induce myocardial apoptosis via inhibiting PGC-1?-related pathway.

ABSTRACT: BACKGROUND:Peripartum cardiomyopathy (PPCM) is life-threatening heart disease. However, the causes and pathogenesis of PPCM remain unclear. Previous studies found that ?1 adrenoceptor antibodies (?1AA) had possible involvement in the development of PPCM. In the present study, we determined the potential relationship between PPCM and ?1AA, including the mechanism of ?1AA leading to PPCM. METHODS:We extracted the ?1AA from the postpartum Wistar rats that were injected by the antigen peptide segment of the ?1 adrenoceptor to produce PPCM. We tested the effects of ?1AA on H9C2 cell line by CCK-8, LDH, TUNEL, SA-ELISA, qRT-PCR, and western blot methods. Furthermore, PGC-1? was overexpressed to rescue the effect of ?1AA on H9C2 cells. RESULTS:We found that the extracted ?1AA induced apoptosis of cardiac myocytes of H9C2 cell line. Moreover, the expression of peroxisome proliferator-activated receptor ? coactivator-1? (PGC-1?), which is a master regulator of mitochondrial metabolism, and its downstream transcript vascular endothelial growth factor (VEGF) got decreased in H9C2 cells after ?1AA treatment. In addition, the effect of ?1AA could be inhibited by atenolol, the antagonist of ?1 adrenoceptors (?1AR) and imitated by isoprenaline, the agonist of ?1AR. Furthermore, overexpression of PGC-1? in the H9C2 cells rescued the apoptosis of cells and inhibitory expression of VEGF induced by ?1AA. CONCLUSIONS:Our results suggest that the symptoms of PPCM due to myocardial cell apoptosis induced by ?1AA inhibiting the PGC-1?-related pathway impairs mitochondrial energy metabolism. Therefore, our results uncover a previously unknown role of the ?1AA pathway in the etiology of PPCM and provide a novel potential target for the treatment of PPCM.

SUBMITTER: Shi L

PROVIDER: S-EPMC7275518 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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β1 adrenoceptor antibodies induce myocardial apoptosis via inhibiting PGC-1α-related pathway.

Shi Linying L Liu Jia J Zhang Yuan Y Chen Mulei M Liu Jiamei J

BMC cardiovascular disorders 20200605 1

<h4>Background</h4>Peripartum cardiomyopathy (PPCM) is life-threatening heart disease. However, the causes and pathogenesis of PPCM remain unclear. Previous studies found that β1 adrenoceptor antibodies (β1AA) had possible involvement in the development of PPCM. In the present study, we determined the potential relationship between PPCM and β1AA, including the mechanism of β1AA leading to PPCM.<h4>Methods</h4>We extracted the β1AA from the postpartum Wistar rats that were injected by the antigen ...[more]

PMID: 32503464

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Project description:BackgroundBone marrow mesenchymal stem cell (BMSC) transplantation represents a promising therapeutic strategy for ischemic heart disease. However, its effects are hampered by the poor viability of transplanted cells and the hostile microenvironment of the ischemic region. Insulin-like growth factor-1 (IGF-1) is an important paracrine growth factor of BMSC and plays an important role in the properties of BMSC. Here, we investigated whether overexpressing IGF-1 could enhance the BMSC viability, migration, anti-apoptosis, and protective effects of cardiomyocytes, and explore the underlying mechanisms' focus on the role of the AKT/secreted frizzled-related protein 2 (SFRP2)/β-catenin pathway.MethodsWe constructed BMSCs overexpressing insulin-like growth factor-1 (BMSCs-IGF-1) or empty vector (BMSCs-NC) using lentivirus, and evaluated cell survival, proliferation, and migration under normoxic and hypoxic conditions. Co-culture of rat cardiomyoblasts with BMSCs was performed to explore the paracrine effect of BMSCs-IGF-1 for rescuing cardiomyoblasts under hypoxia. Transplantation of BMSCs in acute myocardial infarction rats was used to explore the effect of BMSCs-IGF-1 therapy.ResultsBMSCs-IGF-1 exhibited a higher cell proliferation rate, migration capacity, and stemness, and were more resistant to apoptosis under hypoxia. Overexpression of IGF-1 upregulated the expression of total and nuclear β-catenin via the AKT-secreted frizzled-related protein 2 (SFRP2) pathway, which enhanced cell survival. Inhibition of AKT or SFRP2 knockdown by siRNA significantly antagonized the effect of IGF-1 and decreased the expression of β-catenin. The expression of β-catenin target genes, including cyclin D1 and c-Myc, were accordingly decreased. Moreover, BMSCs-IGF-1 could rescue cardiomyoblasts from hypoxia-induced apoptosis and preserve cell viability under hypoxia. Transplantation of BMSCs-IGF-1 into myocardial infarction rats greatly reduced infarct volume than BMSCs-NC, with significantly greater expression of SFRP2 and β-catenin.ConclusionsThese results suggest that in BMSCs overexpressing IGF-1, SFRP2 is an important mediator for the enhancement of stem cell viability via activating, rather than antagonizing, the Wnt/β-catenin pathway.

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?1 adrenoceptor antibodies induce myocardial apoptosis via inhibiting PGC-1?-related pathway.

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β1 adrenoceptor antibodies induce myocardial apoptosis via inhibiting PGC-1α-related pathway.

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