Lithium is a therapeutic agent commonly used to treat bipolar disorder and its beneficial effects are thought to be due to a combination of activation of the Wnt/β‐catenin pathway via inhibition of glycogen synthase kinase‐3β and depletion of the inositol pool via inhibition of the inositol monophosphatase‐1. We demonstrated that lithium in primary endothelial cells induced an increase in mitochondrial mass leading to an increase in ATP production without any significant change in mitochondrial efficiency. This increase in mitochondrial mass was associated with an increase in the mRNA levels of mitochondrial biogenesis transcription factors: nuclear respiratory factor‐1 and ‐2β, as well as mitochondrial transcription factors A and B2, which lead to the coordinated upregulation of oxidative phosphorylation components encoded by either the nuclear or mitochondrial genome. These effects of lithium on mitochondrial biogenesis were independent of the inhibition of glycogen synthase kinase‐3β and independent of inositol depletion. Also, expression of the coactivator PGC‐1α was increased, whereas expression of the coactivator PRC was not affected. Lithium treatment rapidly induced a decrease in activating Akt‐Ser473 phosphorylation and inhibitory Forkhead box class O (FOXO1)‐Thr24 phosphorylation, as well as an increase in activating c‐AMP responsive element binding (CREB)‐Ser133 phosphorylation, two mechanisms known to control PGC‐1α expression. Together, our results show that lithium induces mitochondrial biogenesis via CREB/PGC‐1α and FOXO1/PGC‐1α cascades, which highlight the pleiotropic effects of lithium and reveal also novel beneficial effects via preservation of mitochondrial functions.

Endothelial cell (EC) senescence and dysfunction occurring after chronic injury and inflammation are highly associated with the development and progression of cardiovascular diseases. However, the factors involved in the establishment of EC senescence remain poorly understood. We have previously shown that lithium, an inhibitor of glycogen synthase kinase (GSK)-3␤ and activator of the Wnt/␤-catenin signaling pathway, induces an EC senescent-like phenotype. Herein, we show that lithium induces a rapid and pronounced up-regulation of the matrix metalloproteinase (MMP)-1, an inflammation and senescent cell marker, at the mRNA and protein levels, whereas the induction of two other senescent cell markers is either weak (interleukin-8) or delayed (plasminogen activator inhibitor-1). Lithium effect on MMP-1 expression is also specific among other Endothelial cell (EC)2 senescence and dysfunctions are the hallmarks of cardiovascular degenerative diseases such as atherosclerosis (1, 2). Senescent EC are characterized by changes in cell morphology and metabolism as well as by an irreversible cell cycle arrest and reduced migratory behavior (2), which account for impaired wound healing and slower tumor growth in the elderly (3). The senescent EC, like other cell types, display also changes in their secretory pattern with in particular, an increase of proinflammatory and proangiogenic factors, which in turn alters the tissue microenvironment and activity of neighboring cells (2-4). Although the effects of these proinflammatory and angiogenic factors on enabled-proliferative EC have been extensively studied, less is known about their effects on cell cycle-arrested and pre-senescent EC.The human matrix metalloproteinase (MMP)-1 and the plasminogen-activator inhibitor (PAI)-1 belong to this class of proinflammatory and proangiogenic factors, which control vascular remodeling and angiogenesis by regulating extracellular matrix (ECM) degradation and release of growth factors such as transforming growth factor-␤ and vascular endothelial growth factor (5, 6). By inducing both angiogenesis and changes in the ECM microenvironment, MMP-1 up-regulation has been associated with increased tumor growth and metastasis (6, 7). PAI-1 has a dual effect on angiogenesis depending upon its level of expression and the status of the ECM proteolytic system (5). On the other hand, the expressions of MMP-1 and PAI-1 are increased in senescent EC in culture (8, 9) and in vivo within atherosclerotic lesions (10). MMP-1 activity is in particular associated with instability of the atherosclerotic plaque and subsequently with infarct events in humans (11). Increased PAI-1 levels are also associated with a poor prognostic in atherosclerosis and cardiovascular disease progression (12).Interestingly, PAI-1 up-regulation has been associated with the establishment of cell senescence both in vitro and in vivo (13). PAI-1 is a downstream target gene of the tumor suppressor p53 (14) and is required for p53-induced cell senescence in primary fibroblasts via its ...

TCF7L2 transcription factor is a downstream effector of the canonical Wnt/β-catenin signaling, which controls cell fate and homeostasis. However, the complexity of TCF7L2 expression with numerous mRNA isoforms coding for proteins with distinct N-and C-termini allows variability in TCF7L2 functions and regulations. Here, we show that although TCF7L2 mRNA isoforms distinguish fetal, immortalized and adult differentiated endothelial cells (EC), they cannot explain the lack of significant β-catenin/TCF7 activities in ECs. Lithium, a Wnt-signaling activator, increases TCF7L2 mRNA levels and induces an RNA isoform switch favoring the expression of TCF7L2-short forms lacking the C-termini domains. Although the latter occurs in different cell types, its extent depends on the overall increase of TCF7L2 transcription, which correlates with cell-responsiveness to Wnt/β-catenin signaling. While GSK3β down-regulation increases TCF7L2 expression, there is no concomitant change in TCF7L2 mRNA isoforms, which demonstrate the dual effects of lithium on TCF7L2 expression via a GSK3β-dependent up-regulation and a GSK3β-independent modulation of RNA-splicing. TCF7L2E-long forms display a repressor activity on TCF7L2-promoter reporters and lithium induces a decrease of the endogenous TCF7L2 forms bound to native TCF7L2-promoter chromatin at two novel distal TCF7-binding sites. Altogether our data reveal a lithium-induced RNA switch favoring the expression of TCF7L2-short forms, which results in a transcriptional de-repression of lithium-target genes negatively regulated by TCF7L2-long forms, like TCF7L2, and thus to an amplification of Wnt-signaling in responsive cells.

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Wnt proteins control cell survival and cell fate during development. Although Wnt expression is tightly regulated in a spatio-temporal manner, the mechanisms involved both at the transcriptional and translational levels are poorly defined. We have identified a downstream translation initiation codon, AUG(+74), in Wnt13B and Wnt13C mRNAs responsible for the expression of Wnt13 nuclear forms. In this report, we demonstrate that the expression of the nuclear Wnt13C form is translationaly regulated in response to stress and apoptosis. Though the 5'-leaders of both Wnt13C and Wnt13B mRNAs have an inhibitory effect on translation, they did not display an internal ribosome entry site activity as demonstrated by dicistronic reporter assays. However, mutations or deletions of the upstream AUG(−99) and AUG(+1) initiation codons abrogate these translation inhibitory effects, demonstrating that Wnt13C expression is controlled by upstream open reading frames. Since long 5'-untranslated region with short upstream open reading frames characterize other Wnt transcipts, our present data on the translational control of Wnt13 expression open the way to further studies on the translation control of Wnt expression as a modulator of their subcellular localization and activity.