Thioredoxin Superfamily and Its Effects on Cardiac Physiology and Pathology

Abstract

A precise control of oxidation/reduction of protein thiols is essential for intact cardiac physiology. Irreversible oxidative modifications have been proposed to play a role in the pathogenesis of cardiovascular diseases. An imbalance of redox homeostasis with diminution of antioxidant capacities predisposes the heart to oxidant injury. There is growing interest in endoplasmic reticulum (ER) stress in the cardiovascular field, since perturbation of redox homeostasis in the ER is sufficient to cause ER stress. Because a number of human diseases are related to altered redox homeostasis and defects in protein folding, many research efforts have been devoted in recent years to understanding the structure and enzymatic properties of the thioredoxin superfamily. The thioredoxin superfamily has been well documented as thiol oxidoreductases to exert a role in various cell signaling pathways. The redox properties of the thioredoxin motif account for the different functions of several members of the thioredoxin superfamily. While thioredoxin and glutaredoxin primarily act as antioxidants by reducing protein disulfides and mixed disulfide, another member of the superfamily, protein disulfide isomerase (PDI), can act as an oxidant by forming intrachain disulfide bonds that contribute to proper protein folding. Increasing evidence suggests a pivotal role of PDI in the survival pathway that promotes cardiomyocyte survival and leads to more favorable cardiac remodeling. Thus, the thiol redox state is important for cellular redox signaling and survival pathway in the heart. This review summarizes the key features of major members of the thioredoxin superfamily directly involved in cardiac physiology and pathology.

Protein disulfide isomerase-mediated apoptosis and proliferation of vascular smooth muscle cells induced by mechanical stress and advanced glycosylation end products result in diabetic mouse vein graft atherosclerosis

“…However, regardless of short- or long-term stimulation of SS, AGEs or both, makes the intracellular phosphorylation of MAPKs change, and the total amount of MAPK protein does not change, implying that MAPKs are not the key player in regulating the process. However, data indicate that PDI is directly involved in the regulation of endoplasmic reticulum stress 15, 19 and oxidative stress, 20 resulting in the development of cancer, neurological degenerative changes, immune and viral infections, and infertility. 14, 19, 21, 22, 23 In this study, we for the first time connected PDI with the simultaneous increases in VSMC proliferation and apoptosis in vitro and in vivo and confirmed different PDI expression across individual VSMCs (Figure 8).…”

“…PDI is one of the members of the thioredoxin superfamily oxidoreductases, which includes about 20 subtypes, 13 in this system. 13, 14, 15 PDI gene knockout is lethal to cells and embryos. 16 PDI has three main functions: molecular chaperones, oxidoreductase and isomerase 13, 17, 18 and can promote the disulfide formation (oxidase), breakage (reductase) or rearrangement (isomerase) of oxidized proteins, which are directly involved in the regulation of endoplasmic reticulum stress, 15, 19 oxidative stress, 20 resulting in the occurrence and development of many human major diseases, such as cancer, neurological degenerative changes, immune and viral infections and infertility.…”

“…13, 14, 15 PDI gene knockout is lethal to cells and embryos. 16 PDI has three main functions: molecular chaperones, oxidoreductase and isomerase 13, 17, 18 and can promote the disulfide formation (oxidase), breakage (reductase) or rearrangement (isomerase) of oxidized proteins, which are directly involved in the regulation of endoplasmic reticulum stress, 15, 19 oxidative stress, 20 resulting in the occurrence and development of many human major diseases, such as cancer, neurological degenerative changes, immune and viral infections and infertility. 14, 19, 21, 22, 23 PDI inhibition prevents an increase in the reduced form of PDI in human neuroblastoma SH-SY5Y cells treated by 1-methyl-4-phenylpyridinium (MPP + ), suppresses excessive protein folding, endoplasmic reticulum stress and induces clearance of aggregated α -synuclein in Parkinson’s disease by increased autophagy.…”

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“…The PDI family is a part of the thioredoxin (TRX) superfamily which also includes TRXs, peroxiredoxins, and glutaredoxins. Most of the enzymes catalyzing the formation of S-S bonds belong to the TRX superfamily ( 9 ). According to the HUGO gene nomenclature committee (HGNC) database, the human PDI gene family is comprised of 21 members ( http://www.genenames.org/cgi-bin/genefamilies/set/692 ), which vary in length, domain arrangement and substrate specificity but share a common structural feature - the TRX-like domain ( Table 1 , Fig.…”

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“…The downstream component of Prx is the Trx system, which is comprised of NADPH, Trx and thioredoxin reductase (TrxR), and is involved in the regulation of DNA synthesis, gene transcription, cell growth and apoptosis ( 49 – 51 ). Trx is a small dithiol oxidoreductase that serves as a major carrier of redox potential in cells ( 52 ) and a cofactor for essential enzymes, and is involved in protein repair via methionine sulphoxide reductase ( 53 ) and the reduction of protein disulphides ( 54 ). This redox control of the Trx system is considered to regulate the expression of multiple stress defensive enzymes and protect cells against oxidative stress ( 54 ).…”