Cardiac Cell Senescence and Redox Signaling

Abstract

Aging is characterized by a progressive loss of the ability of the organism to cope with stressors and to repair tissue damage. As a result, chronic diseases, including cardiovascular disease, increase their prevalence with aging, underlining the existence of common mechanisms that lead to frailty and age-related diseases. In this frame, the progressive decline of the homeostatic and reparative function of primitive cells has been hypothesized to play a major role in the evolution of cardiac pathology to heart failure. Although initially it was believed that reactive oxygen species (ROS) were produced in an unregulated manner as a byproduct of cellular metabolism, causing macromolecular damage and aging, accumulating evidence indicate the major role played by redox signaling in physiology. Aim of this review is to critically revise evidence linking ROS to cell senescence and aging and to provide evidence of the primary role played by redox signaling, with a particular emphasis on the multifunctional protein APE1/Ref in stem cell biology. Finally, we will discuss evidence supporting the role of redox signaling in cardiovascular cells.

Keywords: APE/Ref-1; aging; heart failure; metabolism; reactive oxygen species; redox signaling; stem cells.

Figure 1

Oxidative folding and endoplasmic reticulum (ER) stress. (A) Following protein synthesis, the activity of chaperones (such as BiP) and ER enzymes is coordinated to reach a correct protein folding. In this process, protein disulfide isomerase (PDI) oxidizes critical cysteine residues in nascent proteins to facilitate correct folding, resulting in PDI reduction. PDIs are subsequently oxidized [mainly by endoplasmic reticulum oxidoreductin 1 (ERO1)], thus generating H₂O₂, which is buffered by cytoplasmic glutathione. (B) In conditions associated with ER stress (e.g., increased protein synthesis or altered ER redox balance), unfolded proteins accumulate in the ER lumen. Part of these are sent to ER-associated degradation, part sequester BiP, thus activating the unfolded protein response (UPR).

Figure 2

Crosstalk between endoplasmic reticulum (ER) and mitochondria. In conditions of ER stress, PKR-like ER kinase (PERK) phosphorylates eIF2α which, in turn, reduces protein translation and promotes the expression of the transcription factor ATF4. This latter, subsequently promotes the transcription of Parkin, a protein that stimulates mitochondrial fission, mitochondrial autophagy, and the transfer of calcium from the ER to the mitochondria at the mitochondria-associated membranes (MAM). Furthermore, a kinase independent function of PERK promotes the tethering of the ER to mitochondria at the MAM and the oxidation of cardiolipin.

Figure 3

APE1 redox chaperone activity. Schematic representation of APE1 redox chaperone activity. Cysteine residues located within the DNA binding domain or regulatory domain of transcription factors are maintained in a reduced state by APE1, involved in a redox cycle with reducing molecules as TRX. The detailed redox mechanism by which APE1 controls the activity of transcription factors needs further investigation. [Image modified, with permission from the copyright holder, from Tell et al. (114) Cell Mol Life Sci].