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SIRT1 modulates MAPK pathways in ischemic–reperfused cardiomyocytes

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Abstract

SIRT1, an ubiquitous NAD(+)-dependent deacetylase that plays a role in biological processes such as longevity and stress response, is significantly activated in response to reactive oxygen species (ROS) production. Resveratrol (Resv), an important activator of SIRT1, has been shown to exert major health benefits in diseases associated with oxidative stress. In ischemia–reperfusion (IR) injury, a major role has been attributed to the mitogen-activated protein kinase (MAPK) pathway, which is upregulated in response to a variety of stress stimuli, including oxidative stress. In neonatal rat ventricular cardiomyocytes subjected to simulated IR, the effect of Resv-induced SIRT1 activation and the relationships with the MAPK pathway were investigated. Resv-induced SIRT1 overexpression protected cardiomyocytes from oxidative injury, mitochondrial dysfunction, and cell death induced by IR. For the first time, we demonstrate that SIRT1 overexpression positively affects the MAPK pathway—via Akt/ASK1 signaling—by reducing p38 and JNK phosphorylation and increasing ERK phosphorylation. These results reveal a new protective mechanism elicited by Resv-induced SIRT1 activation in IR tissues and suggest novel potential therapeutic targets to manage IR-induced cardiac dysfunction.

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Abbreviations

ASK1:

Apoptosis signal-regulating kinase 1

Bcl-xl:

B cell lymphoma-extra large

Bcl-2:

B cell lymphoma-2

BODIPY:

Boron-dipyrromethene

Calcein-AM:

Calcein acetoxymethyl ester

DEVD:

Asp Glu Val Asp

DMEM:

Dulbecco’s modified Eagle’s medium

DMSO:

Dimethyl sulfoxide

EDTA:

Ethylenediaminetetraacetic acid

EIA:

Enzyme immunoassay

ELISA:

Enzyme-linked immunosorbent assay

ERK:

Extracellular signal-regulated kinase

FACS:

Fluorescence-activated cell sorting

FAM:

Fluorescein acetoxymethyl ester

FLICA:

Fluorochrome Inhibitor of caspases

FMK:

Fluoromethyl ketone

FOXO1:

Forkhead box O1

H2DCFDA:

2′, 7′-Dichlorofluorescein diacetate

JNK:

Jun N-terminal kinase

LDH:

Lactate dehydrogenase

MAPK:

Mitogen-activated protein kinase

MnSOD:

Manganese superoxide dismutase

mPTP:

Mitochondrial permeability transition pore

PAGE:

Polyacrylamide gel electrophoresis

PBS:

Buffered saline solution

PMSF:

Phenylmethanesulphonylfluoride

PVDF:

Polyvinylidene fluoride

ROS:

Reactive oxygen species

Resv:

Resveratrol

SD:

Standard deviation

SDS:

Sodium dodecyl sulphate

SIRT1:

Sirtuin (Silent information regulator 2) 1

TAC:

Total antioxidant capacity

TMRM:

Tetramethylrhodamine, methyl ester, perchlorate

Trx1:

Thioredoxin-1

UV:

Ultraviolet

Δψ:

Mitochondrial membrane potential

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Acknowledgments

This work was supported by Italian MIUR and by Ente Cassa di Risparmio di Firenze.

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  1. Department of Biochemical Sciences, University of Florence, Viale GB Morgagni 50, 50134, Florence, Italy

    Matteo Becatti, Niccolò Taddei, Cristina Cecchi, Niccolò Nassi, Paolo Antonio Nassi & Claudia Fiorillo

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  1. Matteo Becatti
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Correspondence to Claudia Fiorillo.

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Becatti, M., Taddei, N., Cecchi, C. et al. SIRT1 modulates MAPK pathways in ischemic–reperfused cardiomyocytes. Cell. Mol. Life Sci. 69, 2245–2260 (2012). https://doi.org/10.1007/s00018-012-0925-5

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