RhoGTPase in Vascular Disease

Strassheim, Derek; Gerasimovskaya, Evgenia; Irwin, David; Dempsey, Edward C.; Stenmark, Kurt R.; Karoor, Vijaya

doi:10.3390/cells8060551

Cited by 72 publications

(46 citation statements)

References 204 publications

(243 reference statements)

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“…Genes such as RHO, CADM1, ELOVL4, GNAT1, GUCY2F, RP1 , and SLC24A1 were inductive in this group. Most of them play an important role in development and metabolism in retinal rod and cone photoreceptors by mediating the protection of the retina from nutrient delivery, oxidative stress, ionic homeostasis, growth factors release, and ocular immune privilege establishment [ 13 , 25 – 27 ]. Besides, nervous system development and function genes showed the most significant change in perspective of physiological system development and functions.…”

Section: Discussionmentioning

confidence: 99%

Identification of Key Genes and Pathways Associated with Age-Related Macular Degeneration

Zhang

Zhou

2020

Journal of Ophthalmology

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Age-related macular degeneration (AMD) is the leading cause of severe, permanent vision loss among the elderly in the developed world. The cellular and molecular pathogenesis of initiation and development of AMD remain poorly delineated. The limited resources of the human AMD RPE/choroid tissues impeded the extensive study of the disease. To better understand the molecular and pathway changes in human AMD RPE/choroid tissues, we searched the literature and found three independent studies using high-throughput technology to analyze gene expression in 54 human AMD RPE/choroid tissues and 46 age-matched healthy controls. We downloaded these data, pooled them together, and reanalyzed the difference between molecular and pathways by the Ingenuity Pathway Analysis (IPA) database. Totally, 353 differentially expressed genes (DEGs) were identified, among which 181 genes were downregulated and 172 genes were upregulated in RPE/choroid of AMD patients. Furthermore, several significantly enriched biological processes, including cancer, organismal injury and abnormalities, and ophthalmic disease, were identified associated with these DEGs. By analysis of canonical pathway, the phototransduction pathway and atherosclerosis signaling were the top two significant canonical pathways altered in RPE/choroid tissues in human AMD. As expected, several ophthalmic disease-related molecules, including RHO, PDE6A, 3′,5′-cyclic-GMP phosphodiesterase, and G protein alpha, were in the central nodes of disease network. The bioinformatics technology combined with the existing high-throughput data was applied to evaluate the underlying key genes and pathways in human AMD tissues, which may predict downstream and upstream biological processes and identify potential therapeutic intervention targets in human AMD.

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Section: Discussionmentioning

confidence: 99%

Identification of Key Genes and Pathways Associated with Age-Related Macular Degeneration

Zhang

Zhou

2020

Journal of Ophthalmology

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“…Depending on the context (i.e., cell type or the stimulus), activated GTPases lead to cellular responses such as proliferation, differentiation, motility, survival, or apoptosis [ 2 , 3 ]. Taking into account the importance of these responses at a cellular physiology level, mutations or alterations in the Ras superfamily of GTPases have been associated with different diseases, such as cancer [ 8 ], as well as vascular [ 9 ] and neurodegenerative diseases [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Small GTPases of the Ras and Rho Families Switch on/off Signaling Pathways in Neurodegenerative Diseases

Sastre

Montoro

Gálvez‐Martín

et al. 2020

IJMS

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Small guanosine triphosphatases (GTPases) of the Ras superfamily are key regulators of many key cellular events such as proliferation, differentiation, cell cycle regulation, migration, or apoptosis. To control these biological responses, GTPases activity is regulated by guanine nucleotide exchange factors (GEFs), GTPase activating proteins (GAPs), and in some small GTPases also guanine nucleotide dissociation inhibitors (GDIs). Moreover, small GTPases transduce signals by their downstream effector molecules. Many studies demonstrate that small GTPases of the Ras family are involved in neurodegeneration processes. Here, in this review, we focus on the signaling pathways controlled by these small protein superfamilies that culminate in neurodegenerative pathologies, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Specifically, we concentrate on the two most studied families of the Ras superfamily: the Ras and Rho families. We summarize the latest findings of small GTPases of the Ras and Rho families in neurodegeneration in order to highlight these small proteins as potential therapeutic targets capable of slowing down different neurodegenerative diseases.

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“…The role of ROCK in airway smooth muscle contractility has been widely studied (Sakai et al, 2017). RhoA is a small GTPase that binds to several surface receptors that activate ROCK when it is bound to GTP (Strassheim et al, 2019). Expression of this kinase is increased in the airways of patients with asthma (Wang et al, 2020) and some drugs that inhibit ROCK signaling, such as Y27632, Y39983, H1152, and fasudil (Table 1), are highly important because they induce airway smooth muscle relaxation.…”

Section: Rho-associated Kinase (Rock) Is a Key Regulator Of Airway Smmentioning

confidence: 99%

Regulation of Myosin Light-Chain Phosphatase Activity to Generate Airway Smooth Muscle Hypercontractility

et al. 2020

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Smooth muscle is a central structure involved in the regulation of airway tone. In addition, it plays an important role in the development of some pathologies generated by alterations in contraction, such as hypercontractility and the airway hyperresponsiveness observed in asthma. The molecular processes associated with smooth muscle contraction are centered around myosin light chain (MLC) phosphorylation, which is controlled by a balance in the activity of myosin light-chain kinase (MLCK) and myosin light-chain phosphatase (MLCP). MLCK activation depends on increasing concentrations of intracellular Ca 2+ , while MLCP activation is independent of Ca 2+. MLCP contains a phosphatase subunit (PP1c) that is regulated through myosin phosphatase target subunit 1 (MYPT1) and other subunits, such as glycogenassociated regulatory subunit and myosin-binding subunit 85 kDa. Interestingly, MLCP inhibition may contribute to exacerbation of smooth muscle contraction by increasing MLC phosphorylation to induce hypercontractility. Many pathways inhibiting MLCP activity in airway smooth muscle have been proposed and are focused on inhibition of PP1c, inhibitory phosphorylation of MYPT1 and dissociation of the PP1c-MYPT1 complex.

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RhoGTPase in Vascular Disease

Cited by 72 publications

References 204 publications

Identification of Key Genes and Pathways Associated with Age-Related Macular Degeneration

Identification of Key Genes and Pathways Associated with Age-Related Macular Degeneration

Small GTPases of the Ras and Rho Families Switch on/off Signaling Pathways in Neurodegenerative Diseases

Regulation of Myosin Light-Chain Phosphatase Activity to Generate Airway Smooth Muscle Hypercontractility

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