Unravelling the effects of hormetic heat shock as a treatment for age-related macular degeneration

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School of Science | Doctoral thesis (article-based) | Defence date: 2023-05-26
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Date

2023

Department

Neurotieteen ja lääketieteellisen tekniikan laitos
Department of Neuroscience and Biomedical Engineering

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Mcode

Degree programme

Language

en

Pages

108 + app. 90

Series

Aalto University publication series DOCTORAL THESES, 47/2023

Abstract

Age-related macular degeneration (AMD) is associated with decreased efficacy of cells to combat sustained oxidative stress and maintain cellular homeostasis. To cope with cellular stressors, cells have evolved stress-response pathways such as a heat shock response (HSR), which facilitate refolding of misfolded proteins and autophagy process, which facilitates lysosomal degradation and recycles cytoplasmic protein aggregates. The current research aims to assess the possibilities of employing hormetic heat to uplift the reduced activity of the senescent cellular clearance mechanisms, such as protective chaperones and autophagy, in retinal pigment epithelium (RPE) cells. In Paper I of this thesis, the human ARPE-19 cells were treated with hormetic heat shock (HHS) and the profile of autophagy expression was studied. As demonstrated by the obtained results, HHS boosts the expression of essential autophagy-associated genes in ARPE-19 cells through HSF1 activation. As a result of HHS, autophagy is activated as evidenced by a transient increase in p62/SQSTM1 and LC3B-II levels. Thus, these results highlight a role for autophagic HSF1-regulated functions and demonstrate novel evidence that autophagy contributes to hormesis in the HSR by enhancing proteostasis. In Paper II, a transpupillary 1064 nm laser heating device was developed and applied to the mouse (C57BL/6J) fundus to assess HSR. The intensity and pattern of heat shock protein 70 (HSP70) expression and the concomitant damage probability were evaluated in the mouse RPE 24 hours after laser irradiation as a function of laser power. The work demonstrated that the range of heating intensity required to produce a HSR and prevent damage to the mouse RPE is narrow. HSP70 immunostaining at 64 and 70 mW indicated a 90 and 100% probability for reliably enhanced HSP expression, respectively, whereas the equivalent probability for damage is 20 and 33 %. The study in Paper II emphasized the necessity of a retinal temperature monitoring method for controlling fundus heating treatments of retinal diseases. In Paper III, a subthreshold laser treatment (SLT) modality where the retinal temperature is monitored with electroretinography (ERG)-based thermal dosimetry in anesthetized pigs was evaluated. The ED50 peak temperature for visible lesion formation in 60-second treatments with an 810-nm laser was 48°C, and the relative temperature determination error from temperature rise was less than 10%. At 44.2 °C, HSP expression and autophagy were activated, but neither oxidative stress nor apoptosis was observed. The presented technique improves controlled activation of intracellular chaperones and waste clearance in RPE cells, with a defined temperature margin for adverse events. These findings introduced a novel treatment modality that could be beneficial in treating retinal degenerative diseases, particularly AMD.

Description

Supervising professor

Koskelainen, Ari, Prof., Aalto University, Department of Neuroscience and Biomedical Engineering, Finland

Thesis advisor

André Helder, Dr., Karolinska Institutet, Sweden
Kaarniranta, Kai, Prof., University of Eastern Finland, Finland

Keywords

heat shock response, homeostasis, autophagy, retinal pigment epithelium, retinal temperature determination

Other note

Parts

  • [Publication 1]: Amirkavei Mooud, Plastino Flavia, Kvanta Anders, Kaarniranta Kai, André Helder, Koskelainen Ari.Hormetic Heat Shock Enhances Autophagy through HSF1 in Retinal Pigment Epithelium Cells. Cells, 11(11),1778, May 2022.
    Full text in Acris/Aaltodoc: http://urn.fi/URN:NBN:fi:aalto-202208104786
    DOI: 10.3390/cells11111778 View at publisher
  • [Publication 2]: Amirkavei Mooud, Pitkänen Marja, Kaikkonen Ossi, Kaarniranta Kai, André Helder, Koskelainen Ari. 2020. Induction of Heat Shock Protein 70 in Mouse RPE as an In Vivo Model of Transpupillary Thermal Stimulation. International Journal of Molecular Science, 21(6),2063, March 2020.
    Full text in Acris/Aaltodoc: http://urn.fi/URN:NBN:fi:aalto-202004032712
    DOI: 10.3390/ijms21062063 View at publisher
  • [Publication 3]: Amirkavei Mooud, Kaikkonen Ossi, Turunen Teemu, Meller Anna, Åhlgren Johanna, Kvanta Anders, André Helder, Koskelainen Ari. Novel Subthreshold Retinal Laser Treatment with ERG-based Thermal Dosimetry Activates Hormetic Heat Response in pig RPE In Vivo. 45 pages, Submitted. November 2022.
    DOI: 10.1101/2022.11.29.518343 View at publisher

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https://urn.fi/URN:ISBN:978-952-64-1217-7

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[diss] Perustieteiden korkeakoulu / SCI