RhoA/Rho-kinase and vascular diseases: what is the link?

Nunes, Kênia Pedrosa; Rigsby, Christine S.; Webb, R.

doi:10.1007/s00018-010-0460-1

Cited by 133 publications

(142 citation statements)

References 170 publications

(208 reference statements)

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“…33 Increased RhoA/ROCK activity has been demonstrated in human and experimental hypertension. 34 Antagonizing ROCK using fasudil lowers blood pressure in hypertensive patients. 35,36 Mustafa et al 9 reported that TRPM8-induced gastric fundus contraction is associated with the RhoA/ROCK pathway.…”

Section: Discussionmentioning

confidence: 99%

Activation of Cold-Sensing Transient Receptor Potential Melastatin Subtype 8 Antagonizes Vasoconstriction and Hypertension Through Attenuating RhoA/Rho Kinase Pathway

et al. 2014

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Abstract-Environmental cold is a nonmodifiable hypertension risk factor. Transient receptor potential melastatin subtype 8 (TRPM8) is a cold-sensing cation channel that can be activated by menthol, a compound with a naturally cold sensation in mint. Little is known about the effect of TRPM8 activation on vascular function and blood pressure. Here, we report that TRPM8 is abundantly expressed in the vasculature. TRPM8 activation by menthol attenuated vasoconstriction via RhoA/Rho kinase pathway inhibition in wild-type mice, but the effect was absent in TRPM8 −/− mice. Chronic dietary menthol blunted mesenteric arterial constriction and lowered blood pressure in genetic hypertensive rats via inhibition of RhoA/Rho kinase expression and activity in the vivo study. TRPM8 effect was associated with inhibition of intracellular calcium release from the sarcoplasmic reticulum, RhoA/Rho kinase activity, and sustained arterial contraction in the vitro study. Importantly, 8-week chronic menthol capsule treatment moderately lowered systolic blood pressure and diastolic blood pressure in prehypertensive individuals compared with the placebo group. Furthermore, chronic menthol capsule administration also improved flowmediated dilatation in prehypertensive individuals, but not in the placebo group. In conclusion, our study demonstrates that TRPM8 activation by menthol benefits vascular function and blood pressure by inhibiting calcium signaling-mediated RhoA/ Rho kinase activation in the vasculature. These findings add to the evidence that long-term dietary menthol treatment had Materials and Methods Animal TreatmentWe obtained male spontaneously hypertensive rats (SHR) and WistarKyoto rats (WKY) from Charles Rivers Laboratories (Malvern, PA) and obtained TRPM8 −/− mice from the laboratory of Dr Patapoutian. 6To maintain an isogenic strain, heterozygous knockout mice and their wild type (WT) littermates were maintained and used for experiments, as previously described 7 (online-only Data Supplement). Cell CultureVascular smooth muscle cells (VSMCs) were obtained from the thoracic aortas of mice and cultured by the tissue explant method, as previously described 14 (online-only Data Supplement). Intracellular Calcium MeasurementsFluorescence measurements were performed at 510 nm emission, with excitation wavelengths of 340 and 380 nm (Fluoroskan Ascent Fluorometer; Thermo Helsinki, Finland; online-only Data Supplement). Blood Pressure MeasurementAnimals were implanted surgically with telemetric transmitters (Data Sciences International, MN), and 24-hour ambulatory systolic and diastolic pressures were measured by telemetry in conscious unrestrained animals 16 (online-only Data Supplement). Prehypertensive Participant CharacteristicsPrehypertensive participants aged between 45 to 65 years were included in this study. The prehypertension diagnosis was based on systolic blood pressure (SBP) of 120 to 139 mm Hg or diastolic blood pressure of 80 to 89 mm Hg (online-only Data Supplement). Flow-Mediated VasodilationFlow-mediated vasod...

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Section: Discussionmentioning

confidence: 99%

Activation of Cold-Sensing Transient Receptor Potential Melastatin Subtype 8 Antagonizes Vasoconstriction and Hypertension Through Attenuating RhoA/Rho Kinase Pathway

et al. 2014

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“…In the absence of active myosin phosphatase, myosin light chain remains in the phosphorylated and pro-constrictive state. 16 To investigate the potential role that ROCK may play in the increased ET-1 constrictions after OSA, we pretreated isolated PCAs with the nonspecific ROCK1/2 isoform antagonist Y27632 (1 μmol/L; IC 50 = 140 and 300 nmol/L for ROCK1 and ROCK2, respectively). 17,18 In the presence of Y27632, the constrictor responses to IRL-1620 were abolished in denuded PCAs from OSA rats ( Figure 6A).…”

Section: Resultsmentioning

confidence: 99%

“…Activation of ROCK phosphorylates and inactivates the myosin binding subunit of myosin phosphatase (MYPT1), suppresses myosin phosphatase mediated dephosphorylation of myosin light chain, and enhances vasoconstriction. 16 After pretreatment of vessels with the ROCK inhibitor, Y27632, the increased constriction of OSA PCAs was abolished ( Figure 6A). Furthermore, the ratio of phospho-MYPT1 to total MYPT1 was significantly increased in OSA PCAs ( Figure 6B).…”

Section: Discussionmentioning

confidence: 98%

“…[10][11][12] In a complementary manner, ROCK could contribute to increased contractility through its well-documented capacity to increase sensitivity of the VSM contractile machinery. 16 It should be noted that ET B R has been shown to signal through G q11,12 and 13 , which are involved in the activation of both TRPCs and ROCK. 7,34,35 Given that inhibition of either TRPCs or ROCK alone fully restored vascular contractility to sham levels, we propose that these mechanisms may act in series.…”

Section: Discussionmentioning

confidence: 99%

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Increased Cerebrovascular Sensitivity to Endothelin-1 in a Rat Model of Obstructive Sleep Apnea: A Role for Endothelin Receptor B

Durgan

Crossland

Lloyd

et al. 2015

J Cereb Blood Flow Metab

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Obstructive sleep apnea (OSA) is associated with cerebrovascular diseases. However, little is known regarding the effects of OSA on the cerebrovascular wall. We tested the hypothesis that OSA augments endothelin-1 (ET-1) constrictions of cerebral arteries. Repeated apneas (30 or 60 per hour) were produced in rats during the sleep cycle (8 hours) by remotely inflating a balloon implanted in the trachea. Four weeks of apneas produced a 23-fold increase in ET-1 sensitivity in isolated and pressurized posterior cerebral arteries (PCAs) compared with PCAs from sham-operated rats (EC 50 = 10 − 9.2 mol/L versus 10 − 10.6 mol/L; Po 0.001). This increased sensitivity was abolished by the ET-B receptor antagonist, BQ-788. Constrictions to the ET-B receptor agonist, IRL-1620, were greater in PCAs from rats after 2 or 4 weeks of apneas compared with that from sham-operated rats (P = 0.013). Increased IRL-1620 constrictions in PCAs from OSA rats were normalized with the transient receptor potential channel (TRPC) blocker, SKF96365, or the Rho kinase (ROCK) inhibitor, Y27632. These data show that OSA increases the sensitivity of PCAs to ET-1 through enhanced ET-B activity, and enhanced activity of TRPCs and ROCK. We conclude that enhanced ET-1 signaling is part of a pathologic mechanism associated with adverse cerebrovascular outcomes of OSA.

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“…The Rho-associated serine/threonine kinase family, of which ROCK1 is a member, operates as a key regulator of actin cytoskeleton dynamics and organization (24). ROCK1 has various different roles, including involvement in invasion, metastasis and migration during tumorigenesis (25).…”

Section: Discussionmentioning

confidence: 99%

miR-506 suppresses neuroblastoma metastasis by targeting ROCK1

Cao

et al. 2016

Oncology Letters

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Abstract. Neuroblastoma is a complex form of cancer with highly heterogeneous clinical behavior that arises during childhood from precursor cells of the sympathetic nervous system. In patients with neuroblastoma, mortality often occurs as a result of metastasis. The disease predominantly spreads to bone marrow, with a survival rate of ~40%. The current study demonstrates that microRNA (miR)-506 directly targets and downregulates Rho-associated, coiled-coil containing protein kinase 1 (ROCK1) in transforming growth factor (TGF)-β non-canonical pathways. It may be concluded that ROCK1 contributes to the invasion and migration of neuroblastoma cells by directly downregulating miR-506; thus, leading to the upregulation of ROCK1, which promotes cell invasion and migration. The present results provide a novel understanding of how miR-506 directly regulates TGF-β non-canonical

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RhoA/Rho-kinase and vascular diseases: what is the link?

Cited by 133 publications

References 170 publications

Activation of Cold-Sensing Transient Receptor Potential Melastatin Subtype 8 Antagonizes Vasoconstriction and Hypertension Through Attenuating RhoA/Rho Kinase Pathway

Activation of Cold-Sensing Transient Receptor Potential Melastatin Subtype 8 Antagonizes Vasoconstriction and Hypertension Through Attenuating RhoA/Rho Kinase Pathway

Increased Cerebrovascular Sensitivity to Endothelin-1 in a Rat Model of Obstructive Sleep Apnea: A Role for Endothelin Receptor B

miR-506 suppresses neuroblastoma metastasis by targeting ROCK1

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