The role of RhoA and Rho-associated kinase in vascular smooth muscle contraction

Swärd, Karl; Mita, Mitsuo; Wilson, David P.; Deng, Jing; Susnjar, Marija; Walsh, Michael P.

doi:10.1007/s11906-003-0013-1

Cited by 145 publications

(127 citation statements)

References 46 publications

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“…It has been reported that this pyridine derivative is ϳ200 -2,000 times more specific for Rho kinase than other protein kinases including Ca 2ϩ -dependent PKC, MLC kinase, and cAMP-dependent protein kinase that are the major players in regulation of smooth muscle tone (7,16,42). Sakamoto et al (30) demonstrated that Y-27632 has no direct effects on intracellular Ca 2ϩ levels or the activities of MLC phosphatase and MLC kinase at concentrations Ͻ100 M. Studies using Y-27632 have shown Rho kinase to mediate the tonic component of vasoconstrictor responses to agonists including PE, serotonin, ET-1, prostaglandin F 2␣ , and histamine (39,40). In this study, we demonstrate that 1 M Y-27632 abolishes X/XO-induced contractions but not PDBu-induced contractions, suggesting a role for Rho kinase as a mediator of the X/XO-induced contractions (Fig.…”

Section: Discussionmentioning

confidence: 99%

Activation of Rho/Rho kinase signaling pathway by reactive oxygen species in rat aorta

Jin

Zhao

Webb

2004

American Journal of Physiology-Heart and Circulatory Physiology

225

185

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. Activation of Rho/Rho kinase signaling pathway by reactive oxygen species in rat aorta. Am J Physiol Heart Circ Physiol 287: H1495-H1500; 2004; 10.1152/ajpheart.01006.2003.-Evidence indicates that both the Rho/ Rho kinase signaling pathway and reactive oxygen species (ROS) such as superoxide and H 2O2 are involved in the pathogenesis of hypertension. This study aimed to determine whether ROS-induced vascular contraction is mediated through activation of Rho/Rho kinase. Rat aortic rings (endothelium denuded) were isolated and placed in organ chambers for measurement of isometric force development. ROS were generated by a xanthine (X)-xanthine oxidase (XO) mixture. The antioxidants tempol (3 mM) and catalase (1,200 U/ml) or the XO inhibitor allopurinol (400 M) significantly reduced X/XOinduced contraction. A Rho kinase inhibitor, (ϩ)-(R)-trans-4-(1-aminoethyl-N-4-pyridil)cyclohexanecarboxamide dihydrochloride (Y-27632), decreased the contraction in a concentration-dependent manner; however, the Ca 2ϩ -independent protein kinase C inhibitor rottlerin did not have an effect on X/XO-induced contraction. Phosphorylation of the myosin light chain phosphatase target subunit (MYPT1) was increased by ROS, and preincubation with Y-27632 blocked this increased phosphorylation. Western blotting for cytosolic and membrane-bound fractions of Rho showed that Rho was increased in the membrane fraction by ROS, suggesting activation of Rho. These observations demonstrate that ROS-induced Ca 2ϩ sensitization is through activation of Rho and a subsequent increase in Rho kinase activity but not Ca 2ϩ -independent PKC. myosin light chain phosphatase; smooth muscle contraction; antioxidants CONTRACTION OF SMOOTH MUSCLE is regulated by both Ca 2ϩ -dependent and Ca 2ϩ -independent (Ca 2ϩ sensitization) mechanisms. A rise in intracellular Ca 2ϩ levels leads to myosin light chain (MLC) kinase activation, resulting in an increase in MLC phosphorylation. Importantly, MLC phosphorylation can also be increased through inhibition of MLC phosphatase, which augments smooth muscle force generation without a change in intracellular Ca 2ϩ (38).In recent years, studies have revealed that the small GTPase Rho and its downstream target Rho kinase mediate the Ca 2ϩ sensitization of smooth muscle contraction (37). The exchange of bound GDP for GTP activates Rho and stimulates its translocation from cytosol to membrane. Rho-GTP phosphorylates Rho kinase, which inhibits MLC phosphatase activity by phosphorylation of the MLC phosphatase target subunit (MYPT1). A decrease in MLC phosphatase activity increases phosphorylation of myosin and therefore contributes to smooth muscle contraction at low levels of intracellular Ca 2ϩ concentration. Strong evidence suggests that increased Rho/Rho kinase-dependent Ca 2ϩ sensitization contributes to hypertension and inhibition of Rho or Rho kinase reduces blood pressure (33, 42). Some heterotrimetric G protein-coupled receptor (GPCR) agonists, including angiotensin II (ANG II) and endothelin (ET)-1, induce smooth mus...

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Section: Discussionmentioning

confidence: 99%

Activation of Rho/Rho kinase signaling pathway by reactive oxygen species in rat aorta

Jin

Zhao

Webb

2004

American Journal of Physiology-Heart and Circulatory Physiology

225

185

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“…This, in turn, suppresses stress fiber formation and dramatically augments hypertension in rat models (28). There are numerous other pivotal actin-associated effectors that are downstream of Rho GTPase signaling, including myristolated alanine-rich C kinase substrate (MARCKS), the LIM kinases, and their downstream phosphoeffector capable of promoting actin filament disassembly, cofilin (11,26). These observable pathways that converge on actinbased cytoskeletal remodeling represent a limited molecular understanding of Rho GTPase function and cytoskeletal signal transduction.…”

Section: Discussionmentioning

confidence: 99%

Rho GTPase signaling modulates cell shape and contractile phenotype in an isoactin-specific manner

Kolyada

Riley

Herman

2003

American Journal of Physiology-Cell Physiology

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Rho family small GTPases (Rho, Rac, and Cdc42) play an important role in cell motility, adhesion, and cell division by signaling reorganization of the actin cytoskeleton. Here, we report an isoactin-specific, Rho GTPase-dependent signaling cascade in cells simultaneously expressing smooth muscle and nonmuscle actin isoforms. We transfected primary cultures of microvascular pericytes, cells related to vascular smooth muscle cells, with various Rho-related and Rho-specific expression plasmids. Overexpression of dominant positive Rho resulted in the formation of nonmuscle actin-containing stress fibers. At the same time, α-vascular smooth muscle actin (αVSMactin) containing stress fibers were disassembled, resulting in a dramatic reduction in cell size. Rho activation also yielded a disassembly of smooth muscle myosin and nonmuscle myosin from stress fibers. Overexpression of wild-type Rho had similar but less dramatic effects. In contrast, dominant negative Rho and C3 exotransferase or dominant positive Rac and Cdc42 expression failed to alter the actin cytoskeleton in an isoform-specific manner. The loss of smooth muscle contractile protein isoforms in pericyte stress fibers, together with a concomitant decrease in cell size, suggests that Rho activation influences “contractile” phenotype in an isoactin-specific manner. This, in turn, should yield significant alteration in microvascular remodeling during developmental and pathologic angiogenesis.

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“…20 Phosphorylation and inhibition of small GTPase RhoA will inhibit Rho kinase which, in turn, dephosphorylates the MYPT1 and then increases the myosin light chain phosphatases activity. [20][21][22] rHBD2 inhibited MLC 20 and MYPT1 phosphorylation and increased RhoA phosphorylation (Figure 1B-1D). These results suggest that rHBD2 dephosphorylates MLC 20 and MYPT1 by inhibiting RhoA and, thus, relaxes smooth muscle and lowers blood pressure.…”

Section: Discussionmentioning

confidence: 90%

Human β-Defensin 2 Is a Novel Opener of Ca ²⁺ -Activated Potassium Channels and Induces Vasodilation and Hypotension in Monkeys

Zhang

Liu

et al. 2013

Hypertension

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Human β-defensin 2 (HBD2) is a cysteine-rich cationic antimicrobial peptide known for its important role in innate immune system. Intensive studies have demonstrated its antimicrobial and chemotactic activities in vitro. In this study, ELISA analysis showed that HBD2 was significantly downregulated in sera of patients with hypertension. It relaxed vessel smooth muscle by acting on the major regulatory pathways, contributing to vessel smooth muscle contraction. Electrophysiology analysis indicated that HBD2 acted as an opener of large-conductance Ca 2+ -activated potassium (BK Ca )-mSlo+hβ1 channels and increased BK Ca currents. Mutation analysis revealed that HBD2 activated BK Ca -mSlo+hβ1 channels via interacting with Leu41 and Gln43 of β1-loop. In vivo experiments suggested that HBD2 at 4× to 6× of physiological concentration exerted hypotensive effect in monkeys significantly, whereas the selective blocker of BK Ca channels, Paxilline, inhibited the effect. HBD2 is the first peptide opener of BK Ca -mSlo+hβ1 channels. It may be a novel regulator of blood pressure and provides a new therapeutic target for the treatment of hypertension. The HBD2 blockade of the BK Ca channels may represent a new type of cross-talk between immune and cardiovascular systems.

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The role of RhoA and Rho-associated kinase in vascular smooth muscle contraction

Cited by 145 publications

References 46 publications

Activation of Rho/Rho kinase signaling pathway by reactive oxygen species in rat aorta

Activation of Rho/Rho kinase signaling pathway by reactive oxygen species in rat aorta

Rho GTPase signaling modulates cell shape and contractile phenotype in an isoactin-specific manner

Human β-Defensin 2 Is a Novel Opener of Ca ²⁺ -Activated Potassium Channels and Induces Vasodilation and Hypotension in Monkeys

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The role of RhoA and Rho-associated kinase in vascular smooth muscle contraction

Cited by 145 publications

References 46 publications

Activation of Rho/Rho kinase signaling pathway by reactive oxygen species in rat aorta

Activation of Rho/Rho kinase signaling pathway by reactive oxygen species in rat aorta

Rho GTPase signaling modulates cell shape and contractile phenotype in an isoactin-specific manner

Human β-Defensin 2 Is a Novel Opener of Ca 2+ -Activated Potassium Channels and Induces Vasodilation and Hypotension in Monkeys

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Human β-Defensin 2 Is a Novel Opener of Ca ²⁺ -Activated Potassium Channels and Induces Vasodilation and Hypotension in Monkeys