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Perturbed ER homeostasis by IGF-IIRα promotes cardiac damage under stresses

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Abstract

The heart is a very dynamic pumping organ working perpetually to maintain a constant blood supply to the whole body to transport oxygen and nutrients. Unfortunately, it is also subjected to various stresses based on physiological or pathological conditions, particularly more vulnerable to damages caused by oxidative stress. In this study, we investigate the molecular mechanism and contribution of IGF-IIRα in endoplasmic reticulum stress induction in the heart under doxorubicin-induced cardiotoxicity. Using in vitro H9c2 cells, in vivo transgenic rat cardiac tissues, siRNAs against CHOP, chemical ER chaperone PBA, and western blot experiments, we found that IGF-IIRα overexpression enhanced ER stress markers ATF4, ATF6, IRE1α, and PERK which were further aggravated by DOX treatment. This was accompanied by a significant perturbation in stress-associated MAPKs such as p38 and JNK. Interestingly, PARKIN, a stress responsive cellular protective mediator was significantly downregulated by IGF-IIRα concomitant with decreased expression of ER chaperone GRP78. Furthermore, ER stress-associated pro-apoptotic factor CHOP was increased considerably in a dose-dependent manner followed by elevated c-caspase-12 and c-caspase-3 activities. Conversely, treatment of H9c2 cells with chemical ER chaperone PBA or siRNA against CHOP abolished the IGF-IIRα-induced ER stress responses. Altogether, these findings suggested that IGF-IIRα contributes to ER stress induction and inhibits cellular stress coping proteins while increasing pro-apoptotic factors feeding into a cardio myocyte damage program that eventually paves the way to heart failure.

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All the data are contained in the manuscript file and will be made available from the corresponding author upon reasonable request.

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Funding

This study was supported by Grants from the China Medical University and Asia University, Taiwan. Grant numbers: [CMU107-ASIA-10]; [ASIA-106-CMUH-03].

Author information

Author notes

  1. Tsung-Jung Ho and Chih-Yang Huang have contributed equally to this work.

Authors and Affiliations

  1. Graduate Institute of Biomedical Science, China Medical University, Taichung, Taiwan

    Sudhir Pandey & Chih-Yang Huang

  2. Laboratory of Sports Nutrition, University of Taipei, Taipei, Taiwan

    Chia-Hua Kuo

  3. Department of Psychiatry, Buddhist Tzu Chi General Hospital, Hualien, Taiwan

    William Shao-Tsu Chen

  4. Department of Pathology, Changhua Christian Hospital, Changhua, Taiwan

    Yu-Lan Yeh

  5. Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli, Taiwan

    Yu-Lan Yeh

  6. Department of Biological Science and Technology, China Medical University, Taichung, Taiwan

    Wei-Wen Kuo

  7. Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

    Ray-Jade Chen

  8. Department of Nursing, Mei Ho University, Pingguang Road, Pingtung, Taiwan

    Cecilia Hsuan Day

  9. Division of Cardiology, China Medical University Hospital, Taichung, Taiwan

    Pei-Ying Pai

  10. Integration Center of Traditional Chinese and Modern Medicine, Hualien Tzu Chi Hospital, Hualien, 970, Taiwan

    Tsung-Jung Ho

  11. School of Post-Baccalaureate Chinese Medicine, College of Medicine, Tzu Chi University, Hualien, Taiwan

    Tsung-Jung Ho

  12. Department of Chinese Medicine, Hualien Tzu Chi Hospital, Hualien, Taiwan

    Tsung-Jung Ho & Chih-Yang Huang

  13. Department of Medical Research, China Medical University Hospital, China Medical University, No. 91, Hsueh-Shih Road, Taichung, 404, Taiwan

    Chih-Yang Huang

  14. Department of Biotechnology, Asia University, Taichung, Taiwan

    Chih-Yang Huang

  15. Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, 970, Taiwan

    Sudhir Pandey & Chih-Yang Huang

Authors
  1. Sudhir Pandey
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  2. Chia-Hua Kuo
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  3. William Shao-Tsu Chen
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  4. Yu-Lan Yeh
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  5. Wei-Wen Kuo
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  6. Ray-Jade Chen
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  7. Cecilia Hsuan Day
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  8. Pei-Ying Pai
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  9. Tsung-Jung Ho
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  10. Chih-Yang Huang
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Contributions

Conceptualization: SP; Data curation: YLY, WWK, and RJC; Formal analysis: CHK, YLY, and RJC; Funding acquisition: CYH; Investigation: SP; Methodology: SP; Project administration: TJH and CYH; Resources: TJH and CYH; Supervision: TJH and CYH; Validation: CYH; Writing—original draft: SP; Writing—review & editing: WSTC, CHD, and PYP.

Corresponding authors

Correspondence to Tsung-Jung Ho or Chih-Yang Huang.

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Pandey, S., Kuo, CH., Chen, W.ST. et al. Perturbed ER homeostasis by IGF-IIRα promotes cardiac damage under stresses. Mol Cell Biochem 477, 143–152 (2022). https://doi.org/10.1007/s11010-021-04261-8

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  • DOI: https://doi.org/10.1007/s11010-021-04261-8

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