Implications of enigmatic transglutaminase 2 (TG2) in cardiac diseases and therapeutic developments

Involvement and possible role of transglutaminases 1 and 2 in mediating fibrotic signalling, collagen cross-linking and cell proliferation in neonatal rat ventricular fibroblasts

“…While the inhibition of TG2 and other isoforms may offer protection against cardiac fibrosis under certain conditions, their protective functions should also be considered when designing anti-fibrotic therapies involving TGs [ 21 , 51 ]. As pointed out by Griffin et al [ 22 ], Al-U’datt et al [ 21 ], and Szondy et al [ 51 ], the inhibition of TG2 to reduce the fibrotic response may compromise tissue repair and worsen certain pathologies, as in cardiac fibrosis associated with factor XIII-A deficiency. Likewise, TG2 appears to protect cardiomyocytes against heart ischemia/reperfusion injury and to attenuate ischemic-induced cell death by modulating specific transcriptional processes [ 77 , 78 ].…”

“…Additional pathway exploration studies are warranted to establish the mechanistic pathways of TG1 and TG2 actions in cardiac cells during normal and pathological remodelling of the ECM, which will help inform the selection of specific TG targets for therapeutic intervention. While several TG inhibitors have emerged as candidate drugs for cardiac diseases, they have not yet been tested in clinical trials specific to cardiac diseases [ 21 , 51 ]. The action of TGs in cardiac cells must be more fully elucidated to enable further innovations for safe, reliable and effective pharmacological interventions in this area.…”

“…Moreover, it is unclear what roles, if any, other isoforms may play in these cells. Some of the newly identified cellular signalling roles of TGs, including cell proliferation, apoptosis, and gene transcription [ 18 , 21 ], have seldom been investigated in cardiac cells. The present study aimed to evaluate the roles of TG1 and TG2 in mediating fibrotic signalling, collagen cross-linking, as well as fibroblast proliferation in healthy fibroblasts by silencing RNA (siRNA)-mediated knockdown.…”

“…TGs intra-and extracellular functions in cardiac physiology and disease have not yet been fully elucidated [18]. One of TG2 extracellular functions in normal ECM remodelling processes and cardiac fibrosis is collagen cross-linking due to its transamidase enzymatic activity [19][20][21]. Studies in animal models involving pressure overload, hypoxia or volume overload in different cardiac diseases (e.g., hypertrophic cardiomyopathy, myocardial ischemia, and heart failure) have showed that cardiac fibrosis is concomitant with increased TG2 expression and cross-linking of ECM proteins [17,19,[21][22][23][24].…”

Dynamic and static biomechanical traits of cardiac fibrosis

“…Secondly, the imbalance between MMPs and their tissue inhibitors (TIMP) have important effect on the progress of cardiac fibrosis ( Polyakova et al, 2011 ). Thirdly, growing evidence have indicated that transglutaminases (TGs) is involved in molecular responses underlying the pathogenesis of cardiac fibrosis including collagen cross-linking ( Al-U'datt et al, 2022 ). For non-enzymatical collagen cross-linker, proteoglycan fibromodulin has anti-fibrotic effects through regulating collagen fibrillogenesis in cardiac fibroblasts ( Andenæs et al, 2018 ).…”