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Unfolded protein response during cardiovascular disorders: a tilt towards pro-survival and cellular homeostasis

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Abstract

The endoplasmic reticulum (ER) is an organelle that orchestrates the production and proper assembly of an extensive types of secretory and membrane proteins. Endoplasmic reticulum stress is conventionally related to prolonged disruption in the protein folding machinery resulting in the accumulation of unfolded proteins in the ER. This disruption is often manifested due to oxidative stress, Ca2+ leakage, iron imbalance, disease conditions which in turn hampers the cellular homeostasis and induces cellular apoptosis. A mild ER stress is often reverted back to normal. However, cells retaliate to acute ER stress by activating the unfolded protein response (UPR) which comprises three signaling pathways, Activating transcription factor 6 (ATF6), inositol requiring enzyme 1 alpha (IRE1α), and protein kinase RNA-activated-like ER kinase (PERK). The UPR response participates in both protective and pro-apoptotic responses and not much is known about the mechanistic aspects of the switch from pro‐survival to pro‐apoptosis. When ER stress outpaces UPR response then cell apoptosis prevails which often leads to the development of various diseases including cardiomyopathies. Therefore, it is important to identify molecules that modulate the UPR that may serve as promising tools towards effective treatment of cardiovascular diseases. In this review, we elucidated the latest advances in construing the contribution imparted by the three arms of UPR to combat the adverse environment in the ER to restore cellular homeostasis during cardiomyopathies. We also summarized the various therapeutic agents that plays crucial role in tilting the UPR response towards pro-survival.

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Acknowledgements

We thank the members of the Sengupta lab for review of the manuscript.

Funding

The work was supported by Central University Grant Commission-Start Up Grant [No. F.4.5(192-FRP)/2015(BSR)] to AS, project Grant sponsored by Department of Science and Technology to AS (DST-SERB, CRG/2020.000348) project Grant sponsored by Department of Science and Technology to SC (DST-SERB, No.: EMR/2017/001382).

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Authors and Affiliations

  1. Department of Life Science and Biotechnology, Jadavpur University, 188, Raja S. C. Mallick Road, Kolkata, West Bengal, 700032, India

    Shreya Das, Arunima Mondal, Jayeeta Samanta & Arunima Sengupta

  2. Department of Life Sciences, Presidency University, Kolkata, India

    Santanu Chakraborty

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  1. Shreya Das
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  2. Arunima Mondal
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  3. Jayeeta Samanta
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  4. Santanu Chakraborty
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  5. Arunima Sengupta
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Contributions

SD, AM, JS all reviewed the literature. AS and SC designed the review paper and SD wrote the manuscript. All authors have read the manuscript.

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Correspondence to Arunima Sengupta.

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Das, S., Mondal, A., Samanta, J. et al. Unfolded protein response during cardiovascular disorders: a tilt towards pro-survival and cellular homeostasis. Mol Cell Biochem 476, 4061–4080 (2021). https://doi.org/10.1007/s11010-021-04223-0

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  • DOI: https://doi.org/10.1007/s11010-021-04223-0

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