Mitoprotective effect of mesenchymal stem cells-derived conditioned medium in myocardial reperfusion injury of aged rats: role of SIRT-1/PGC-1α/NRF-2 network

Kazem Nejati-Koshki; Behnaz Mokhtari; Reza Badalzadeh; AmirAhmad Arabzadeh; Alireza Mohammadzadeh

doi:10.1007/s11033-023-08499-x

Mitoprotective effect of mesenchymal stem cells-derived conditioned medium in myocardial reperfusion injury of aged rats: role of SIRT-1/PGC-1α/NRF-2 network

Mol Biol Rep. 2023 Jul;50(7):5655-5665. doi: 10.1007/s11033-023-08499-x. Epub 2023 May 18.

Authors

Kazem Nejati-Koshki^#¹, Behnaz Mokhtari^#^{2

3

4

5}, Reza Badalzadeh^{2

3

4

5}, AmirAhmad Arabzadeh⁶, Alireza Mohammadzadeh⁷

Affiliations

¹ Pharmaceutical Sciences Research Center, Ardabil University of Medical Sciences, Ardabil, Iran.
² Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
³ Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
⁴ Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
⁵ Department of Physiology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
⁶ Department of Surgery, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran.
⁷ Department of Cardiothoracic Surgery, Imam Khomeini Hospital, Ardabil University of Medical Sciences, Ardabil, Iran. armohammadzadeh40@gmail.com.

^# Contributed equally.

PMID: 37199864
DOI: 10.1007/s11033-023-08499-x

Abstract

Background: The aged myocardium experiences various forms of stress that cause reduction of its tolerance to injury induced by ischemia/reperfusion (I/R). Developing effective cardioprotective modalities to prevent the amplification of I/R injury during aging is under focus of investigation. Mesenchymal stem cells (MSCs) have the ability to regenerate infarcted myocardium mostly by producing multiple secretory factors. This study aimed to explore the mechanisms of mitoprotection by MSCs-conditioned medium (CM) in myocardial I/R injury of aged rats.

Methods: Male Wistar rats (n = 72, 400-450 g, 22-24 months old) were randomized into groups with/without I/R and/or MSCs-CM treatment. To establish myocardial I/R injury, the method of LAD occlusion and re-opening was employed. MSCs-CM was administered intramyocardially (150 μl) at the onset of reperfusion in recipient group. After 24 h reperfusion, myocardial infarct size, LDH level, mitochondrial functional endpoints, expression of mitochondrial biogenesis-associated genes, and the levels of pro-inflammatory cytokines were evaluated. After 28 days reperfusion, echocardiographic assessment of cardiac function was performed.

Results: MSCs-CM treatment improved myocardial function and decreased infarct size and LDH level in aged I/R rats (P < .05 to P < .001). It also decreased mitochondrial ROS formation, enhanced mitochondrial membrane potential and ATP content, upregulated mitochondrial biogenesis-related genes including SIRT-1, PGC-1α, and NRF-2, and lessened TNF-α, IL-1β, and IL-6 levels (P < .05 to P < .01).

Conclusions: MSCs-CM treatment attenuated myocardial I/R injury in aged rats, in part by improving mitochondrial function and biogenesis and restraining inflammatory reaction. the upregulation of SIRT-1/PGC-1α/NRF-2 profiles is a possible target for the mitoprotective effects of MSCs-CM following I/R injury during aging.

Keywords: Aging; Cardioprotection; Conditioned medium; Mesenchymal stem cells; Mitoprotection; Myocardial reperfusion injury.

MeSH terms

Animals
Culture Media, Conditioned / metabolism
Culture Media, Conditioned / pharmacology
Male
Mesenchymal Stem Cells* / metabolism
Myocardial Infarction* / metabolism
Myocardial Infarction* / therapy
Myocardial Reperfusion Injury* / metabolism
Rats
Rats, Wistar
Reperfusion Injury* / metabolism

Substances

Culture Media, Conditioned