ArticleArteriosclerosis, thrombosis, and vascular biology2014
Mixed-lineage kinase 3 deficiency promotes neointima formation through increased activation of the RhoA pathway in vascular smooth muscle cells.
Article in Arteriosclerosis, thrombosis, and vascular biology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 18 citations in OpenAlex.
- Neointimal hyperplasia and vascular restenosis: from molecular mechanisms to therapeutic interventions.Molecular biomedicine · 2026Review
- Mixed lineage kinase 3 contributes to myocardial ischemia/reperfusion injury by regulating neutrophil activation.Basic research in cardiology · 2025Article
- Key Mechanisms of Oxidative Stress-Induced Ferroptosis in Heart Failure with Preserved Ejection Fraction and Potential Therapeutic Approaches.Reviews in cardiovascular medicine · 2025Review
- Myotubularin-Related Protein14 Prevents Neointima Formation and Vascular Smooth Muscle Cell Proliferation by Inhibiting Polo-Like Kinase1.Journal of the American Heart Association · 2022Article
- Mixed lineage kinase 3 requires a functional CRIB domain for regulation of blood pressure, cardiac hypertrophy, and left ventricular function.American journal of physiology. Heart and circulatory physiology · 2022Article
- MLK3 mediates impact of PKG1α on cardiac function and controls blood pressure through separate mechanisms.JCI insight · 2021Article
- Genetic colocalization atlas points to common regulatory sites and genes for hematopoietic traits and hematopoietic contributions to disease phenotypes.BMC medical genomics · 2020Article
- Mixed lineage kinase-3 prevents cardiac dysfunction and structural remodeling with pressure overload.American journal of physiology. Heart and circulatory physiology · 2019Article
- Sustained Activation of Rho GTPases Promotes a Synthetic Pulmonary Artery Smooth Muscle Cell Phenotype in Neprilysin Null Mice.Arteriosclerosis, thrombosis, and vascular biology · 2018Article
- Inhibition of hyaluronan synthesis attenuates pulmonary hypertension associated with lung fibrosis.British journal of pharmacology · 2017Article
- microRNAs Distinctively Regulate Vascular Smooth Muscle and Endothelial Cells: Functional Implications in Angiogenesis, Atherosclerosis, and In-Stent Restenosis.Advances in experimental medicine and biology · 2015Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
objectiveMitogen-activated protein kinase pathways play an important role in neointima formation secondary to vascular injury, in part by promoting proliferation of vascular smooth muscle cells (VSMC). Mixed-lineage kinase 3 (MLK3) is a mitogen-activated protein kinase kinase kinase that activates multiple mitogen-activated protein kinase pathways and has been implicated in regulating proliferation in several cell types. However, the role of MLK3 in VSMC proliferation and neointima formation is unknown. The aim of this study was to determine the function of MLK3 in the development of neointimal hyperplasia and to elucidate the underlying mechanisms. APPROACH AND
resultsNeointima formation was analyzed after endothelial denudation of carotid arteries from wild-type and MLK3-deficient mice. MLK3 deficiency promoted injury-induced neointima formation and increased proliferation of primary VSMC derived from aortas isolated from MLK3-deficient mice compared with wild-type mice. Furthermore, MLK3 deficiency increased the activation of p63Rho guanine nucleotide exchange factor, RhoA, and Rho kinase in VSMC, a pathway known to promote neointimal hyperplasia, and reconstitution of MLK3 expression attenuated Rho kinase activation. Furthermore, cJun NH2-terminal kinase activation was decreased in MLK3-deficient VSMC, and proliferation of wild-type but not MLK3 knockout cells treated with a cJun NH2-terminal kinase inhibitor was attenuated.
conclusionsWe demonstrate that MLK3 limits RhoA activation and injury-induced neointima formation by binding to and inhibiting the activation of p63Rho guanine nucleotide exchange factor, a RhoA activator. In MLK3-deficient cells, activation of p63Rho guanine nucleotide exchange factor proceeds in an unchecked manner, leading to a net increase in RhoA pathway activation. Reconstitution of MLK3 expression restores MLK3/p63Rho guanine nucleotide exchange factor interaction, which is attenuated by feedback from activated cJun NH2-terminal kinase.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.