Potential roles of visfatin/NAMPT on endothelial dysfunction in preeclampsia and pathways underlying cardiac and vascular remodeling

We read an article in Journal of Cellular Physiology entitled “Visfatin: An emerging adipocytokine bridging the gap in the evolution of cardiovascular diseases” that reviewed the pro-inflammatory and angiogenic actions of visfatin on dysregulated signaling pathways that contribute to pathogenesis of atherosclerosis (Dakroub et al., 2021). However, the mechanisms for the role of visfatin on endothelial dysfunction (ED) were not fully explored. We would like to contribute with findings regarding the potential roles of visfatin on ED in preeclampsia and pathways underlying cardiac and vascular remodeling.

Visfatin/extracellular nicotinamide phosphoribosyltransferase (NAMPT) was proposed as clinical marker of atherosclerosis, ED, and vascular damage (Romacho et al., 2013), and it was shown to produce in vivo ED in mice (Romacho et al., 2020). Notably, dysregulation of adipocytokines was associated with ED in preeclamptic women (Mori et al., 2010), who have an increased risk of future cardiovascular diseases (Ahmed et al., 2014). Antiangiogenic factors released into maternal circulation as a result of placental ischemia/hypoxia contribute to widespread ED and proteinuria in preeclampsia, including the soluble fms-like tyrosine kinase-1 (sFlt-1) (Maynard et al., 2003; Powe et al., 2011). Preeclampsia is characterized by reduced nitric oxide (NO) formation, which was inversely related to sFlt-1 (Sandrim et al., 2008). Although visfatin/NAMPT levels were not different between healthy pregnant and preeclampsia (Luizon et al., 2015), they were inversely related to NO formation and positively related to sFlt-1 levels in preeclamptic women (Pereira et al., 2019) and in the subgroup classified as nonresponsive to antihypertensive therapy, who exhibited higher proteinuria and sFlt-1 levels (Pereira et al., 2021) and the worst clinical outcomes (Luizon, Palei, Belo, et al., 2017; Luizon, Palei, Cavalli, et al., 2017; Pereira et al., 2021). These findings suggest that visfatin/NAMPT inhibits NO formation and upregulates sFlt-1 in preeclampsia. While the impact that adipocytokines have on the endothelium and vascular homeostasis is complex (McElwain et al., 2020), the potential mechanisms underlying the role of visfatin/NAMPT on ED in preeclampsia are detailed below.

Circulating factors contribute to ED by increasing oxidative stress and reducing NO bioavailability in preeclampsia (Kao et al., 2016), and sFlt-1 was suggested to have a role in oxidative stress in placental trophoblasts in preeclampsia (Jiang et al., 2015). Furthermore, an imbalance in pro- and antiangiogenic factors, excessive inflammation, and induction of oxidative stress within the endothelium are major contributors to ED in preeclampsia (Brennan et al., 2014). In this context, visfatin/NAMPT was shown to impair endothelium-dependent relaxation by NADPH oxidase (Vallejo et al., 2011), and upregulation of sFlt-1 may also result from pathways involved in NADPH oxidase induction (Goulopoulou & Davidge, 2015). Moreover, NADPH oxidase activity was crucial for the impaired vasodilation induced by visfatin through the intracellular release of superoxide anions (Vallejo et al., 2011), which scavenge NO to generate peroxynitrite (Goulopoulou & Davidge, 2015). Superoxide also induced the uncoupling of the endothelial NO synthase enzyme, thereby leading to diminished NO bioavailability and increased peroxynitrite production (Brennan et al., 2014). Peroxynitrite may also increase the expression of inducible NO synthase (iNOS) enzyme and intercellular cell adhesion molecule-1 (ICAM-1), a marker of ED due to nuclear factor kappa B (NF-κB) activation (Sankaralingam et al., 2006). Notably, iNOS upregulation was reported in experimental preeclampsia (Amaral et al., 2013), and reviewed in clinical hypertension and preeclampsia (Oliveira-Paula et al., 2014; Sankaralingam et al., 2006). Taken together, these findings support that visfatin/NAMPT inhibit NO formation and upregulate sFlt-1 due to the increased oxidative stress observed in preeclampsia.

Visfatin was also discussed to upregulate matrix metalloproteinases (MMPs) via the MAPK/ERK signaling pathway and other mediators, including NF-κB (Dakroub et al., 2021). Notably, NF-κB is a regulator of several visfatin-induced signaling pathways, including the enhanced expression of inflammatory mediators (ICAM-1 and VCAM-1) in endothelial cells (Kim et al., 2008; Lee et al., 2009) and cytokine production in human leukocytes (Moschen et al., 2007). Since NF-κB is a key transcription factor activated by visfatin, its binding to promoter regions and the regulation of MMP-2/-9 transcription could be considered by further studies. The use of NF-κB inhibitor reinforces this hypothesis by the decrease of MMPs levels/activity and reversal of cardiac and vascular remodeling in hypertension (Cau et al., 2011, 2015; Wu & Schmid-Schonbein, 2011). Moreover, NF-κB inhibition reduced the visfatin-induced MMP-2/-9 mRNA expression, protein levels, and gelatinolytic activity in human vascular endothelial cells (Adya et al., 2008). Therefore, the increased MMP-2/-9 transcription directly by NF-κB could be considered among visfatin-induced pathways underlying vascular remodeling.

Visfatin increased reactive oxygen species (ROS) generation via NF-κB dependent pathway (Kim et al., 2008). Moreover, ROS and peroxynitrite are well-known to activate NF-κB nuclear translocation and by cleavage of the catalytic site, mainly by MMP-2 (Evans et al., 2002; Kandasamy et al., 2010). MMP-2 activation by oxidative stress has been shown in the aorta and hearts of hypertensive rats, thereby resulting in tissue remodeling (Belo et al., 2016; Ceron et al., 2012), and their treatment with antioxidants reduced cardiovascular remodeling and improved endothelial function (Castro et al., 2009; Griendling et al., 2021; Rizzi et al., 2013). Interestingly, increased oxidative stress and hypoxia were shown to induce the formation of a novel N-terminal truncated MMP-2 isoform (NTT-MMP-2) that remains intracellular in or near the mitochondria of cardiac tissue, which expression activates a pro-inflammatory, proapoptotic innate immune response (Lovett et al., 2012). Notably, insights into the epigenetic regulation of the latent promoter of NTT-MMP-2 located in the first MMP-2 intron, including its overlap with a putative active enhancer element, histone modifications, and binding sites for transcription factors which are known to cooperate in hypoxia-induced gene transcription are proposed elsewhere (Cruz et al., 2021). Finally, transfection of NTT-MMP-2 cDNA in cardiomyoblasts resulted in increased luciferase reporter activity for NF-κB (Lovett et al., 2012). Taken together, these findings suggest the existence of a self-perpetuating cycle of ROS generation, NF-κB activation, and increased expression/activity of MMPs by visfatin/NAMPT underlying cardiac and vascular tissue remodeling.

CONFLICT OF INTERESTS

The authors declare that there are no conflict of interests.