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TRAIL and Cardiovascular Disease—A Risk Factor Or Risk Marker: a Systematic Review Journal of Clinical Medicine Review TRAIL and Cardiovascular Disease—A Risk Factor or Risk Marker: A Systematic Review Katarzyna Kakareko 1,* , Alicja Rydzewska-Rosołowska 1 , Edyta Zbroch 2 and Tomasz Hryszko 1 1 2nd Department of Nephrology and Hypertension with Dialysis Unit, Medical University of Białystok, 15-276 Białystok, Poland; [email protected] (A.R.-R.); [email protected] (T.H.) 2 Department of Internal Medicine and Hypertension, Medical University of Białystok, 15-276 Białystok, Poland; [email protected] * Correspondence: [email protected] Abstract: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a pro-apoptotic protein showing broad biological functions. Data from animal studies indicate that TRAIL may possibly contribute to the pathophysiology of cardiomyopathy, atherosclerosis, ischemic stroke and abdomi- nal aortic aneurysm. It has been also suggested that TRAIL might be useful in cardiovascular risk stratification. This systematic review aimed to evaluate whether TRAIL is a risk factor or risk marker in cardiovascular diseases (CVDs) focusing on major adverse cardiovascular events. Two databases (PubMed and Cochrane Library) were searched until December 2020 without a year limit in accor- dance to the PRISMA guidelines. A total of 63 eligible original studies were identified and included in our systematic review. Studies suggest an important role of TRAIL in disorders such as heart failure, myocardial infarction, atrial fibrillation, ischemic stroke, peripheral artery disease, and pul- monary and gestational hypertension. Most evidence associates reduced TRAIL levels and increased TRAIL-R2 concentration with all-cause mortality in patients with CVDs. It is, however, unclear Citation: Kakareko, K.; whether low TRAIL levels should be considered as a risk factor rather than a risk marker of CVDs. Rydzewska-Rosołowska, A.; Zbroch, Further studies are needed to better define the association of TRAIL with cardiovascular diseases. E.; Hryszko, T. TRAIL and Cardiovascular Disease—A Risk Keywords: TRAIL; cardiovascular diseases; cardiovascular risk; cerebrovascular disorders; apoptosis Factor or Risk Marker: A Systematic Review. J. Clin. Med. 2021, 10, 1252. https://doi.org/10.3390/jcm10061252 1. Introduction Academic Editor: Karol Kaminski The Greek term “apoptosis” meaning “falling leaves in autumn” was first used for the description of programmed cell death in 1972 by John Kerr [1]. Its origin dates back to Received: 28 January 2021 Hippocrates [2], and since then, substantial progress has been made in our understanding of Accepted: 15 March 2021 Published: 18 March 2021 this naturally occurring process. Apoptosis can be triggered by various factors (biological, chemical, physical) and it is tightly regulated by a family of proteases called caspases, Publisher’s Note: MDPI stays neutral which are activated during cellular response to a specific trigger. Apoptotic signaling can with regard to jurisdictional claims in be internal (intrinsic apoptosis) or external (extrinsic apoptosis). The intrinsic pathway can published maps and institutional affil- be induced by cellular stress or DNA damage. The extrinsic pathway is induced by signals iations. activating cell-surface death-receptors. Apart from an important role in physiological processes such as aging, apoptosis (especially when it is inadequate) contributes to the development of many disorders including malignancies [3], and neurological [4] and cardiovascular diseases (CVDs) [5]. In recent years, a large number of studies have tried to clarify how this complex process is actively driven by the cells. One of the proteins Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. involved in inducing apoptosis is TNF-related apoptosis-inducing ligand (TRAIL). TRAIL, This article is an open access article which is also known as Apo-2 ligand (Apo-2L) or TNF super family 10 (TNFSN10), is a distributed under the terms and 281-amino acid type II transmembrane protein [6]. The membrane-bound TRAIL can be conditions of the Creative Commons cleaved by cysteine proteases, and secreted into circulation, leading to the formation of Attribution (CC BY) license (https:// the soluble form of TRAIL. Activated monocytes and neutrophils are the most important creativecommons.org/licenses/by/ source of soluble TRAIL [7]. Interest in TRAIL rapidly increased when it turned out that 4.0/). TRAIL could selectively kill cancer cells whilst sparing normal cells [8]. This potential J. Clin. Med. 2021, 10, 1252. https://doi.org/10.3390/jcm10061252 https://www.mdpi.com/journal/jcm J. Clin. Med. 2021, 10, x FOR PEER REVIEW 2 of 18 J. Clin. Med. 2021, 10, 1252 2 of 17 cancer cells whilst sparing normal cells [8]. This potential anti-tumor effect led to identifying TRAILanti-tumor as a promising effect led anti to-cancer identifying agent TRAIL [9]. Those as a varied promising biological anti-cancer function agents result [9]. from Those differentvaried receptors biological being functions activated result by from TRAIL. different receptors being activated by TRAIL. FiveFive TR TRAILAIL receptors receptors have have been been identified: identified: TRAIL TRAIL-R1-R1 and and TRAIL TRAIL-R2-R2 (death (death receptors) receptors),, TRAILTRAIL-R3-R3 and and TRAIL TRAIL-R4-R4 (decoy (decoy receptors) receptors),, and and osteoprotegerin osteoprotegerin (OPG, (OPG, which which is a is soluble a soluble decoydecoy receptor). receptor). Their Their alternative alternative names names are detailed are detailed in Figure in Figure 1. Decoy1. Decoy receptors receptors act as act molasecular molecular traps trapsfor agonists for agonists,, binding binding TRAIL TRAIL and keeping and keeping it from it binding from binding with death with deathre- ceptors.receptors. TRAIL TRAIL-R1-R1 and andTRAIL TRAIL-R2-R2 have have intracellular intracellular death death domain domain motif motifss while while TRAIL TRAIL-- R3 R3and and TRAIL TRAIL-R4-R4 lack lackthe cytoplasmic the cytoplasmic domains domains necessary necessary to transduce to transduce apoptotic apoptotic signal (Fig- signal ure(Figure 1). Thus,1). Thus,TRAIL TRAIL may exert may exertpleiotropic pleiotropic effects effects,, inducing inducing apoptosis apoptosis when when binding binding to deathto deathreceptors receptors,, but with but TRAIL with TRAIL-induced-induced apoptosis apoptosis blocked blocked by the decoy by the receptors. decoy receptors. Solu- bleSoluble forms of forms those ofrecepto thosers receptors are also found are also in foundplasma. in TRAIL plasma. and TRAIL its receptor and its system receptor there- system foretherefore seem to seemmaintain to maintain a balance a balancebetween between apoptotic apoptotic and antiapoptotic and antiapoptotic actions. actions. TRAIL-R1 TRAIL-R2 TRAIL-R3 TRAIL-R4 OPG DR4 DR5 DcR1 DcR2 TNFRSF10A TNFRSF10B Cysteine-rich Domain Transmembrane Domain Death Domain FigureFigure 1. TRAIL 1. TRAIL receptors receptors and andtheir their alternative alternative names. names. TRAIL TRAIL-R1-R1 is also is known also known as DR4 as (death DR4(death re- ceptorreceptor 4) and 4) TNFRSF10A and TNFRSF10A (tumor (tumor necrosis necrosis factor factor receptor receptor superfamily superfamily member member 10A 10A);); TRAIL TRAIL-R2-R2 is is alsoalso known known as DR5 as DR5 (death (death receptor receptor 5) and 5) and TNFRSF10B TNFRSF10B (tumor (tumor necrosis necrosis factor factor receptor receptor superfamily superfamily membermember 10B); 10B); TRAIL TRAIL-R3-R3 is also is also known known as DcR1 as DcR1 (decoy (decoy receptor receptor 1), TRAIL 1), TRAIL-R4-R4 is also is also known known as DcR2 as DcR2 (decoy receptor 2); OPG—osteoprotegerin (soluble decoy receptor). (decoy receptor 2); OPG—osteoprotegerin (soluble decoy receptor). Recently,Recently, a lot a lot of ofattention attention has has been been focused focused on on the the components components of OPG/TRAIL axis as as proteins implicated in the development of CVDs.CVDs. The TRAIL receptors are expressedexpressed inin the thecardiovascular cardiovascular (CV) (CV) system system in in vascular vascular smooth smooth muscle muscle cells cells [10 [10]] and and cardiomyocytes cardiomyocytes [11 ]. [11].Data Data from from animal animal studies studies shows shows that that TRAIL TRAIL may may possibly possibly contribute contribute to to the the pathophysi- patho- physiologyology of cardiomyopathyof cardiomyopathy [12 ,[12,13],13], atherosclerosis atherosclerosis [14 ,15[14,15],], ischemic ischemic stroke stroke [16], [16], pulmonary pul- monaryhypertension hypertension [17] and[17] abdominaland abdominal aortic aortic aneurysm aneurysm [18]. [18]. It has It has also also been been suggested suggested that thatTRAIL TRAIL might might be be potentially potentially usefuluseful in CV risk stratification stratification [19 [19].]. TheThe association association between between TRAIL TRAIL and and CVD CVDss is not is not well well understood. understood. We We aimed aimed to answer to answer thethe question question of whether of whether TRAIL TRAIL is a is risk a risk factor factor or a or risk a risk marker marker in CVD in CVDs,s, particularly particularly taking taking intointo consideration consideration major major adverse adverse CV events CV events defined defined as a composite as a composite endpoint: endpoint: nonfatal nonfatal my- ocardialmyocardial infarction, infarction, nonfatal nonfatal stroke stroke and CV and death. CV death. We analyzed We analyzed clinical clinical
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