Irisin Protects the Human Placenta from Oxidative Stress and Apoptosis via Activation of the Akt Signaling Pathway

Abstract

Irisin is a newly discovered exercise-mediated polypeptide hormone. Irisin levels increase during pregnancy however, women with preeclampsia (PE) have significantly lower levels of Irisin compared to women of healthy pregnancies. Even though many studies suggest a role of Irisin in pregnancy, its function in the human placenta is unclear. In the current study, we aimed to understand key roles of Irisin through its ability to protect against apoptosis is the preeclamptic placenta and in ex vivo and in vitro models of hypoxia/re-oxygenation (H/R) injury. Our studies show that Irisin prevents cell death by reducing pro-apoptotic signaling cascades, reducing cleavage of PARP to induce DNA repair pathways and reducing activity of Caspase 3. Irisin caused an increase in the levels of anti-apoptotic BCL2 to pro-apoptotic BAX and reduced ROS levels in an in vitro model of placental ischemia. Furthermore, we show that Irisin treatment acts through the Akt signaling pathway to prevent apoptosis and enhance cell survival. Our findings provide a novel understanding for the anti-apoptotic and pro-survival properties of Irisin in the human placenta under pathological conditions. This work yields new insights into placental development and disease and points towards intervention strategies for placental insufficiencies, such as PE, by protecting and maintaining placental function through inhibiting hypoxic ischemia-induced apoptosis.

Injectable Self-Healing Oxidized Starch/Gelatin Hybrid Hydrogel for Preventing Aseptic Loosening of Bone Tissue Engineering

“…In contrast, EdU staining revealed that Ti particles markedly inhibited BMSC proliferation, which was restored by the addition of irisin (Figure S9f–g). Previous studies have reported that wear particles upregulate the expression of apoptosis-related genes such as caspase-1, caspase-3, bax, and P53, leading to apoptosis in preosteoblasts. , These compelling results suggest that irisin not only counteracts the inhibition of BMSC osteogenic differentiation caused by Ti particles but also enhances cell proliferation and reduces apoptosis, consistent with findings from other studies. − Subsequently, to further elucidate the regulatory mechanism of irisin on osteogenic differentiation, the expression levels of integrin αV, the Wnt/β-catenin signaling pathway, and genes associated with osteogenic differentiation were assessed using rt-PCR and immunofluorescence staining. As shown in Figure S10b, after 21 days of osteogenic differentiation, Ti particles suppressed the expression of osteogenic differentiation-related genes ( alp , runx2 , ocn , and sp - 7) and Wnt/β-catenin signaling pathway-related genes (β -catenin , lef- 1, and tcf- 4).…”

Adrenomedullin has a pivotal role in trophoblast differentiation: A promising nanotechnology-based therapeutic target for early-onset preeclampsia

“…ADM is best known to activate the PI3K-AKT pathway, which has been implicated in trophoblast differentiation ( 62 ). AKT inactivation results in disrupted trophoblast cell differentiation toward EVT ( 63 ). ADM-null TSC displayed reduced expression of genes related to PI3K-AKT signaling upon differentiation.…”

Irisin ameliorates diabetic kidney disease by restoring autophagy in podocytes

“…A salient question that arises is how irisin suppresses PI3K-AKT signaling in podocytes, especially considering evidence suggesting that irisin can activate Akt signaling. 44,45 We have previously reported sin counters TGFb1-Smad3 signaling. 11 Since TGFb1 is known to engage in crosstalk with Akt signaling, 46,47 it stands to reason that the inhibition of TGFb1 signaling by irisin could also result in the suppression of Akt activity.…”

“…A salient question that arises is how irisin suppresses PI3K‐AKT signaling in podocytes, especially considering existing evidence suggesting that irisin can activate Akt signaling 44,45 . We have previously reported that irisin counters TGFb1‐Smad3 signaling 11 .…”