Roles of KLF4 and AMPK in the inhibition of glycolysis by pulsatile shear stress in endothelial cells

Han, Yanyan; He, Ming; Marin, Traci; Shen, Hui; Wang, Wei‐Ting; Lee, Tzong-Yi; Hong, Hsiao-Chin; Jiang, Zong‐Lai; Garland, Theodore; Shyy, John Y.‐J.; Gongol, Brendan; Chien, Shu

doi:10.1073/pnas.2103982118

Cited by 32 publications

(27 citation statements)

References 36 publications

(48 reference statements)

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“…However, we cannot rule out the possibility that presence of various complexes of KLF4 and KLF2 might also be indicative of different phases of cell cycle. Nevertheless, KLF4 and KLF2 are expressed in quiescent ECs and these two proteins are known to associate directly with p300, a nuclear protein that acts as a histone acetyltransferase (HAT) to transcriptionally regulate targets through chromatin remodeling (34)(35)(36). That is, p300 acetylates KLF4 to regulate gene transcription via the modulation of histone acetylation.…”

Section: Discussionmentioning

confidence: 99%

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A requirement for Krüppel-Like Factor-4 in the maintenance of endothelial cell quiescence

Mastej

Axen

Wary

et al. 2022

Preprint

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Rationale and GoalEndothelial cells (ECs) are quiescent and critical for maintaining homeostatic functions of the mature vascular system, while disruption of quiescence is at the heart of endothelial to mesenchymal transition (EndMT) and tumor angiogenesis. Here, we addressed the hypothesis that KLF4 maintains the EC quiescence.Methods and ResultsIn ECs, KLF4 bound to KLF2, and the KLF4-transctivation domain (TAD) interacted directly with KLF2. KLF4-depletion increased KLF2 expression, accompanied by phosphorylation of SMAD3, increased expression of alpha-smooth muscle actin (αSMA), VCAM-1, TGF-β1 and ACE2, but decreased VE-cadherin expression. In the absence of Klf4, Klf2 bound to the Klf2-promoter/enhancer region and autoregulated its own expression. Loss of EC-Klf4 in RosamT/mG::Klf4fl/fl::Cdh5CreERT2 engineered mice, increased Klf2 levels and these cells underwent EndMT.ConclusionIn quiescent ECs, KLF2 and KLF4 partnered to regulate a combinatorial mechanism. The loss of KLF4 disrupted this combinatorial mechanism, thereby upregulating KLF2 as an adaptive response. However, increased KLF2 expression overdrives for the loss of KLF4, giving rise to an EndMT phenotype.Key PointsAdult endothelial cells (ECs) are quiescent in that these cells are arrested at G0-phase of the cell cycle, but mechanisms of EC quiescence are not well understood.The Krüppel-like factors (KLFs) -2 and -4 are transcriptional regulators, highly expressed in quiescent ECs, however, their roles in this process have not been addressed.Elucidation of the mechanisms of KLF function in quiescent ECs should provide clues to the translational discoveries intended for the treatment of EC-dysfunction, such as endothelial to mesenchymal transition (EndMT) associated with several vascular diseases including tumor angiogenesis.Graphical Abstract

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Section: Discussionmentioning

confidence: 99%

“…Transcription factors (TFs) KLF2 and KLF4 are highly expressed in quiescent ECs (30)(31)(32)(33)(34)(35)(36). To this end, KLF4 is known to inhibit cell cycle progression, while KLF2 inhibited VEGF-induced hyperpermeability.…”

Section: Introductionmentioning

confidence: 99%

A requirement for Krüppel-Like Factor-4 in the maintenance of endothelial cell quiescence

Mastej

Axen

Wary

et al. 2022

Preprint

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“…2 reflects an elevated AMPK activity and corresponds with the time course of changes in cellular lactate content. Interestingly, elevated activity of AMPK was implicated as one of the factors in a down-regulation of glycolysis in vascular endothelial cells subjected to pulsatile shear stress [Han et al, 2021]. However, in our stable experiments, shear stress was not considered.…”

Section: Discussionmentioning

confidence: 99%

Effect of lipopolysaccharide (LPS) on HAEC cells. Does nicotinamide N-methyltransferase sensitize HAEC cells to LPS?

Stepinska

Dymkowska

Mateuszuk

et al. 2021

Preprint

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Treatment of endothelial cells with bacterial lipopolysaccharide (LPS) evokes a number of metabolic and functional consequences which built a multifaceted physiological response of endothelium to bacterial infection. Here effects of LPS on human aortic endothelial cells (HAEC) have been investigated. Among the spectrum of biochemical changes substantially elevated N-nicotinamide methyltransferase (NNMT) protein level was particularly intriguing. It has been shown that silencing of the NNMT-encoding gene prevented several changes which are observed in control HAECs due to treatment with LPS. They include significantly increased cytosolic Ca2+ concentration and abnormally strong calcium response to thapsigargin, altered energy metabolism which is switched to anaerobic glycolysis and rearrangement of the mitochondrial network organization. Biochemical mechanisms behind protecting effect of partial NNMT deficiency remains unknown but we speculate that the primary role in this phenomenon is attributed to normalized Ca2+ response in cells partially deprived of the NNMT gene. However, this assumption needs to be verified experimentally. Nevertheless, this paper focuses the reader attention on NNMT, which is an important enzyme that potentially may affect cellular metabolism by two means: direct influence based on a regulation of NAD+ synthesis through modulation of nicotinamide availability, and a regulation of S-adenosylmethionine concentration and therefore controlling of methylation processes including modification of chromatin and epigenetic effects

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“… 14 If the angiogenic response is insufficient to provide oxygen, chronic hypoxia initiates low-grade inflammation in adipose tissue. 15 An increase in pro-inflammatory gene expression leads to adipose tissue fibrosis, 16 impairment of endothelial angiogenic potentials, 17 and, in more severe cases, necrosis. Angiogenesis serves as an important immediate response mechanism against hypoxic conditions in expanding adipose tissue.…”

Section: Factors Affecting Healthy Vs Unhealthy Adipose Tissue Expansionmentioning

confidence: 99%

“… 103 Interestingly, exercise and high LSS activate the AMPK pathway in the abdominal aorta and the endothelial cells, respectively. 17 , 92 , 97 This implies that exercise renders endothelial mitochondria more protective via AMPK activation. Mitochondrial adaptation to exercise in obese subjects has not yet been extensively studied.…”

Section: Exercise and Mitochondrial Remodelingmentioning

confidence: 99%

Healthy versus Unhealthy Adipose Tissue Expansion: the Role of Exercise

Meister

Hong

Shin

et al. 2022

Journal of Obesity & Metabolic Syndrome

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Although the hallmark of obesity is the expansion of adipose tissue, not all adipose tissue expansion is the same. Expansion of healthy adipose tissue is accompanied by adequate capillary angiogenesis and mitochondria-centered metabolic integrity, whereas expansion of unhealthy adipose tissue is associated with capillary and mitochondrial derangement, resulting in deposition of immune cells (M1-stage macrophages) and excess production of pro-inflammatory cytokines. Accumulation of these dysfunctional adipose tissues has been linked to the development of obesity comorbidities, such as type 2 diabetes, hypertension, dyslipidemia, and cardiovascular disease, which are leading causes of human mortality and morbidity in modern society. Mechanistically, vascular rarefaction and mitochondrial incompetency (for example, low mitochondrial content, fragmented mitochondria, defective mitochondrial respiratory function, and excess production of mitochondrial reactive oxygen species) are frequently observed in adipose tissue of obese patients. Recent studies have demonstrated that exercise is a potent behavioral intervention for preventing and reducing obesity and other metabolic diseases. However, our understanding of potential cellular mechanisms of exercise, which promote healthy adipose tissue expansion, is at the beginning stage. In this review, we hypothesize that exercise can induce unique physiological stimuli that can alter angiogenesis and mitochondrial remodeling in adipose tissues and ultimately promote the development and progression of healthy adipogenesis. We summarize recent reports on how regular exercise can impose differential processes that lead to the formation of either healthy or unhealthy adipose tissue and discuss key knowledge gaps that warrant future research.

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Roles of KLF4 and AMPK in the inhibition of glycolysis by pulsatile shear stress in endothelial cells

Cited by 32 publications

References 36 publications

A requirement for Krüppel-Like Factor-4 in the maintenance of endothelial cell quiescence

A requirement for Krüppel-Like Factor-4 in the maintenance of endothelial cell quiescence

Effect of lipopolysaccharide (LPS) on HAEC cells. Does nicotinamide N-methyltransferase sensitize HAEC cells to LPS?

Healthy versus Unhealthy Adipose Tissue Expansion: the Role of Exercise

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