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Low density lipoprotein receptor related protein 6 (LRP6) protects heart against oxidative stress by the crosstalk of HSF1 and GSK3?.

ABSTRACT: Low density lipoprotein receptor-related protein 6 (LRP6), a Wnt co-receptor, induces multiple functions in various organs. We recently reported cardiac specific LRP6 deficiency caused cardiac dysfunction in mice. Whether cardiomyocyte-expressed LRP6 protects hearts against ischemic stress is largely unknown. Here, we investigated the effects of cardiac LRP6 in response to ischemic reperfusion (I/R) injury. Tamoxifen inducible cardiac specific LRP6 overexpression mice were generated to build I/R model by occlusion of the left anterior descending (LAD) coronary artery for 40 min and subsequent release of specific time. Cardiac specific LRP6 overexpression significantly ameliorated myocardial I/R injury as characterized by the improved cardiac function, strain pattern and infarct area at 24 h after reperfusion. I/R induced-apoptosis and endoplasmic reticulum (ER) stress were greatly inhibited by LRP6 overexpression in cardiomyocytes. LRP6 overexpression enhanced the expression of heat shock transcription factor-1(HSF1) and heat shock proteins (HSPs), the level of p-glycogen synthase kinase 3?(GSK3?)(S9) and p-AMPK under I/R. HSF1 inhibitor deteriorated the apoptosis and decreased p-GSK3?(S9) level in LRP6 overexpressed -cardiomyocytes treated with H2O2. Si-HSF1 or overexpression of active GSK3? significantly attenuated the increased expression of HSF1 and p-AMPK, and the inhibition of apoptosis and ER stress induced by LRP6 overexpression in H2O2-treated cardiomyocytes. AMPK inhibitor suppressed the increase in p-GSK3? (S9) level but didn't alter HSF1 nucleus expression in LRP6 overexpressed-cardiomyocytes treated with H2O2. Active GSK3?, but not AMPK inhibitor, attenuated the inhibition of ubiquitination of HSF1 induced by LRP6-overexpressed-cardiomyocytes treated with H2O2. LRP6 overexpression increased interaction of HSF1 and GSK3? which may be involved in the reciprocal regulation under oxidative stress. In conclusion, cardiac LRP6 overexpression significantly inhibits cardiomyocyte apoptosis and ameliorates myocardial I/R injury by the crosstalk of HSF1 and GSK3? signaling.

SUBMITTER: Wang Y

PROVIDER: S-EPMC7486456 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Low density lipoprotein receptor related protein 6 (LRP6) protects heart against oxidative stress by the crosstalk of HSF1 and GSK3β.

Wang Ying Y Chen Zhidan Z Li Yang Y Ma Leilei L Zou Yan Y Wang Xiang X Yin Chao C Pan Le L Shen Yi Y Jia Jianguo J Yuan Jie J Zhang Guoping G Yang Chunjie C Ge Junbo J Zou Yunzeng Y Gong Hui H

Redox biology 20200825

Low density lipoprotein receptor-related protein 6 (LRP6), a Wnt co-receptor, induces multiple functions in various organs. We recently reported cardiac specific LRP6 deficiency caused cardiac dysfunction in mice. Whether cardiomyocyte-expressed LRP6 protects hearts against ischemic stress is largely unknown. Here, we investigated the effects of cardiac LRP6 in response to ischemic reperfusion (I/R) injury. Tamoxifen inducible cardiac specific LRP6 overexpression mice were generated to build I/R ...[more]

PMID: 32905882

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Project description:Introduction: Oxidative stress in monocyte-derived macrophages is a significant pathophysiological process in atherosclerosis. L-cystathionine (L-Cth) acts as a scavenger for oxygen free radicals. However, the impact of L-Cth on macrophage oxidative stress during atherogenesis has remained unclear. This study aimed to investigate whether L-Cth affects oxidative stress in THP-1-derived macrophages and its subsequent effects on DNA damage and cell apoptosis. Methods: We established a cellular model of oxLDL-stimulated macrophages. The content of superoxide anion, H2O2, NO, and H2S in the macrophage were in situ detected by the specific fluorescence probe, respectively. The activities of SOD, GSH-Px, and CAT were measured by colorimetrical assay. The protein expressions of SOD1, SOD2, and iNOS were detected using western blotting. The DNA damage and apoptosis in the macrophage was evaluated using an fluorescence kit. Results: The results demonstrated that oxLDL significantly increased the content of superoxide anion and H2O2, the expression of iNOS protein, and NO production in macrophages. Conversely, oxLDL decreased the activity of antioxidants GSH-Px, SOD, and CAT, and downregulated the protein expressions of SOD1 and SOD2 in macrophages. However, treatment with L-Cth reduced the levels of superoxide anion, H2O2, and NO, as well as the protein expression of iNOS induced by oxLDL. Moreover, L-Cth treatment significantly enhanced GSH-Px, SOD, and CAT activity, and upregulated the expressions of SOD1 and SOD2 proteins in macrophages treated with oxLDL. Furthermore, both L-Cth supplementation and activation of endogenous L-Cth production suppressed DNA damage and cell apoptosis in oxLDL-injured macrophages, whereas inhibition of endogenous L-Cth exacerbated the deleterious effects of oxLDL. Conclusion: These findings suggest that L-Cth exerts a pronounced inhibitory effect on the oxidative stress, subsequent DNA damage and cell apoptosis in oxLDL-stimulated THP-1 monocytes. This study deepens our understanding of the pathogenesis of macrophage-related cardiovascular pathology.

Dataset Information

Low density lipoprotein receptor related protein 6 (LRP6) protects heart against oxidative stress by the crosstalk of HSF1 and GSK3?.

Publications

Low density lipoprotein receptor related protein 6 (LRP6) protects heart against oxidative stress by the crosstalk of HSF1 and GSK3β.

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