The Role of the Transcription Factor KLF2 in Vascular Development and Disease

Novodvorský, Peter; Chico, Timothy J. A.

doi:10.1016/b978-0-12-386930-2.00007-0

Cited by 95 publications

(83 citation statements)

References 181 publications

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“…The endothelium plays an important role in maintaining vascular homeostasis and regulating blood vessel tone, inflammation, vessel permeability, thrombosis, and vasculogenesis/angiogenesis processes 1, 2. Endothelial dysfunction, typically characterized by impaired vasoreactivity, enhanced permeability to plasma lipoproteins, and selective adhesiveness for mononuclear leukocytes, is implicated in atherosclerosis, diabetes mellitus, hypertension, and coronary artery disease 2, 3…”

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confidence: 99%

“…Kruppel‐like factor 2 (KLF2) is a zinc‐finger transcription factor preferentially expressed in vascular endothelium, lung, and lymphocytes 1, 4, 5. It functions as a master regulator to maintain endothelial homeostasis5 and control multiple genes critical for anti‐inflammatory, ‐thrombotic, ‐oxidative, and ‐proliferative effects in endothelial cells (ECs) 1, 4, 5, 6, 7, 8, 9, 10.…”

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confidence: 99%

“…It functions as a master regulator to maintain endothelial homeostasis5 and control multiple genes critical for anti‐inflammatory, ‐thrombotic, ‐oxidative, and ‐proliferative effects in endothelial cells (ECs) 1, 4, 5, 6, 7, 8, 9, 10. For example, KLF2 potently induces the expression of vasodilatory and anti‐inflammatory genes such as endothelial nitric oxide synthase, inhibits vasoconstrictive factors such as endothelin‐1 expression, and represses expression of adhesion molecules, such as vascular cell adhesion molecule 1 (VCAM1) 1, 8, 10. Experimental studies have demonstrated that shear stress11 along with small molecules such as lipid‐lowering statins10, 12 and resveratrol are capable of exerting vasoprotective effects by promoting KLF2 activation 4, 12, 13.…”

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confidence: 99%

“…Experimental studies have demonstrated that shear stress11 along with small molecules such as lipid‐lowering statins10, 12 and resveratrol are capable of exerting vasoprotective effects by promoting KLF2 activation 4, 12, 13. The molecular mechanisms involved in the regulation of endothelial KLF2 expression includes the AMP‐activated protein kinase/dual specificity mitogen‐activated protein kinase kinase 5/extracellular‐signal related kinase 5/MEF2 (myocyte enhancing factor 2) pathway and the histone deacetylase (HDAC) 5 pathway 1, 14, 15. Recent studies have demonstrated that deletion of 1 KLF2 allele in mice increases atherosclerosis,16 and KLF2 controls endothelial and vascular integrity 17.…”

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confidence: 99%

“…In light of the potent vasoprotective effects mediated by KLF2, modulating KLF2 expression or function might be a novel therapeutic strategy for a wide range of human diseases, including cardiovascular diseases 1. Therefore, we aimed to identify novel KLF2 activators using a luciferase assay based high‐throughput drug screening and hoped that these activators would have endothelial protective functions.…”

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confidence: 99%

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Suberanilohydroxamic Acid as a Pharmacological Kruppel‐Like Factor 2 Activator That Represses Vascular Inflammation and Atherosclerosis

Yang

Liu

et al. 2017

JAHA

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BackgroundKruppel‐like factor 2 (KLF2) is an important zinc‐finger transcription factor that maintains endothelial homeostasis by its anti‐inflammatory, ‐thrombotic, ‐oxidative, and ‐proliferative effects in endothelial cells. In light of the potent vasoprotective effects of KLF2, modulating KLF2 expression or function could give rise to new therapeutic strategies to treat cardiovascular diseases.Methods and ResultsHigh‐throughput drug screening based on KLF2 promoter luciferase reporter assay was performed to screen KLF2 activators. Real‐time PCR and western blot were used to detect gene and protein expression. Identified KLF2 activator was orally administered to ApoE−/− mice to evaluate anti‐atherosclerotic efficacy. By screening 2400 compounds in the Spectrum library, we identified suberanilohydroxamic (SAHA) acid, also known as vorinostat as a pharmacological KLF2 activator through myocyte enhancer factor 2. We found that SAHA exhibited anti‐inflammatory effects and attenuated monocyte adhesion to endothelial cells inflamed with tumor necrosis factor alpha. We further showed that the inhibitory effect of SAHA on endothelial inflammation and ensuing monocyte adhesion was KLF2 dependent using KLF2‐deficient mouse lung endothelial cells or KLF2 small interfering RNA– depleted human endothelial cells. Importantly, we observed that oral administration of SAHA reduced diet‐induced atherosclerotic lesion development in ApoE−/− mice without significant effect on serum lipid levels.ConclusionsThese results demonstrate that SAHA has KLF2‐dependent anti‐inflammatory effects in endothelial cells and provide the proof of concept that KLF2 activation could be a promising therapeutic strategy for treating atherosclerosis.

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confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Suberanilohydroxamic Acid as a Pharmacological Kruppel‐Like Factor 2 Activator That Represses Vascular Inflammation and Atherosclerosis

Yang

Liu

et al. 2017

JAHA

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TRPM7 promotes lipopolysaccharide‐induced inflammatory dysfunction in renal tubular epithelial cells

Sun

Chen

Xie

et al. 2022

Immunity Inflam & Disease

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Background: Sepsis-associated acute kidney injury (S-AKI) has been reported to affect 30%-50% of all sepsis patients; this condition is associated with a notable fatality rate. Following lipopolysaccharide (LPS) stimulation, the expression of transient receptor potential cation channel subfamily M member 7 (TRPM7), a nonselective cation channel expressed by the renal tubular epithelial cells (RTECs) was found to be upregulated. We aimed to determine how TRPM7 functions in S-AKI. Methods: To establish an in vitro model of S-AKI, RTECs were treated with LPS. The effect of TRPM7 knockdown on cell viability, lactate dehydrogenase (LDH) release, apoptosis, inflammation, and oxidative stress was studied. The binding site between Kruppel-like factor 2 (KLF2) and TRPM7 was predicted using JASPAR. The influence of KLF2 on the regulatory roles of TRPM7 in cells, as well as the effect of their knockdown on the MAPK signaling pathway, was investigated. Results: TRPM7 was upregulated in LPS-treated cells, and knocking improved cell viability, reduced LDH levels, and minimized apoptosis, inflammation, and oxidative stress. KLF2 was shown to be associated with TRPM7 and its level decreased in LPS-treated cells. KLF2 knockdown increased TRPM7 expression and reversed the effects of TRPM7 knockdown in LPS-treated cells, including suppression of p38 MAPK, ERK1/2, and JNK activation. Conclusion:Taken together, our results show that TRPM7 is negatively regulated by KLF2 and promotes LPS-induced inflammatory dysfunction by activating the MAPK pathway in RTECs. The theoretical foundation for the prevention and management of S-AKI is laid out in this article.

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TRPC3‐mediated Ca²⁺ signals as a promising strategy to boost therapeutic angiogenesis in failing hearts: The role of autologous endothelial colony forming cells

Moccia

Lucariello

Guerra³

2017

Journal Cellular Physiology

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Endothelial progenitor cells (EPCs) are a sub-population of bone marrow-derived mononuclear cells that are released in circulation to restore damaged endothelium during its physiological turnover or rescue blood perfusion after an ischemic insult. Additionally, they may be mobilized from perivascular niches located within larger arteries' wall in response to hypoxic conditions. For this reason, EPCs have been regarded as an effective tool to promote revascularization and functional recovery of ischemic hearts, but clinical application failed to exploit the full potential of patients-derived cells. Indeed, the frequency and biological activity of EPCs are compromised in aging individuals or in subjects suffering from severe cardiovascular risk factors. Rejuvenating the reparative phenotype of autologous EPCs through a gene transfer approach has, therefore, been put forward as an alternative approach to enhance their therapeutic potential in cardiovascular patients. An increase in intracellular Ca concentration constitutes a pivotal signal for the activation of the so-called endothelial colony forming cells (ECFCs), the only known truly endothelial EPC subset. Studies from our group showed that the Ca toolkit differs between peripheral blood- and umbilical cord blood (UCB)-derived ECFCs. In the present article, we first discuss how VEGF uses repetitive Ca spikes to regulate angiogenesis in ECFCs and outline how VEGF-induced intracellular Ca oscillations differ between the two ECFC subtypes. We then hypothesize about the possibility to rejuvenate the biological activity of autologous ECFCs by transfecting the cell with the Ca -permeable channel Transient Receptor Potential Canonical 3, which selectively drives the Ca response to VEGF in UCB-derived ECFCs.

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The Role of the Transcription Factor KLF2 in Vascular Development and Disease

Cited by 95 publications

References 181 publications

Suberanilohydroxamic Acid as a Pharmacological Kruppel‐Like Factor 2 Activator That Represses Vascular Inflammation and Atherosclerosis

Suberanilohydroxamic Acid as a Pharmacological Kruppel‐Like Factor 2 Activator That Represses Vascular Inflammation and Atherosclerosis

TRPM7 promotes lipopolysaccharide‐induced inflammatory dysfunction in renal tubular epithelial cells

TRPC3‐mediated Ca²⁺ signals as a promising strategy to boost therapeutic angiogenesis in failing hearts: The role of autologous endothelial colony forming cells

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The Role of the Transcription Factor KLF2 in Vascular Development and Disease

Cited by 95 publications

References 181 publications

Suberanilohydroxamic Acid as a Pharmacological Kruppel‐Like Factor 2 Activator That Represses Vascular Inflammation and Atherosclerosis

Suberanilohydroxamic Acid as a Pharmacological Kruppel‐Like Factor 2 Activator That Represses Vascular Inflammation and Atherosclerosis

TRPM7 promotes lipopolysaccharide‐induced inflammatory dysfunction in renal tubular epithelial cells

TRPC3‐mediated Ca2+ signals as a promising strategy to boost therapeutic angiogenesis in failing hearts: The role of autologous endothelial colony forming cells

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TRPC3‐mediated Ca²⁺ signals as a promising strategy to boost therapeutic angiogenesis in failing hearts: The role of autologous endothelial colony forming cells