Inhaled Rho Kinase Inhibitors Are Potent and Selective Vasodilators in Rat Pulmonary Hypertension

Nagaoka, Tetsutaro; Fagan, Karen A.; Gebb, Sarah A.; Morris, Kenneth G.; Suzuki, Tsutomu; Shimokawa, Hiroaki; McMurtry, Ivan F.; Oka, Masahiko

doi:10.1164/rccm.200405-637oc

Cited by 218 publications

(199 citation statements)

References 46 publications

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“…This assertion was challenged, however, by striking studies demonstrating that inhibitors of Rho kinase (ROCK), an important mediator of smooth muscle cell contractility, acutely normalized P PA in chronically hypoxic rats when administered systemically 34,35 or via inhalation, 36 indicating that active contraction may, in fact, be the most important factor determining P PA . This hypothesis was supported by morphological studies demonstrating that with CH, the increase in smooth muscle cells extended outward and did not, in fact, cause luminal narrowing.…”

Section: Mechanisms Of Hph: Lessons From Animal Modelsmentioning

confidence: 99%

Pulmonary Vascular and Ventricular Dysfunction in the Susceptible Patient (2015 Grover Conference Series)

2016

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Pulmonary blood vessel structure and tone are maintained by a complex interplay between endogenous vasoactive factors and oxygen-sensing intermediaries. Under physiological conditions, these signaling networks function as an adaptive interface between the pulmonary circulation and environmental or acquired perturbations to preserve oxygenation and maintain systemic delivery of oxygen-rich hemoglobin. Chronic exposure to hypoxia, however, triggers a range of pathogenetic mechanisms that include hypoxia-inducible factor 1α (HIF-1α)-dependent upregulation of the vasoconstrictor peptide endothelin 1 in pulmonary endothelial cells. In pulmonary arterial smooth muscle cells, chronic hypoxia induces HIF-1α-mediated upregulation of canonical transient receptor potential proteins, as well as increased Rho kinase-Ca 2+ signaling and pulmonary arteriole synthesis of the profibrotic hormone aldosterone. Collectively, these mechanisms contribute to a contractile or hypertrophic pulmonary vascular phenotype. Genetically inherited disorders in hemoglobin structure are also an important etiology of abnormal pulmonary vasoreactivity. In sickle cell anemia, for example, consumption of the vasodilator and antimitogenic molecule nitric oxide by cell-free hemoglobin is an important mechanism underpinning pulmonary hypertension. Contemporary genomic and transcriptomic analytic methods have also allowed for the discovery of novel risk factors relevant to sickle cell disease, including GALNT13 gene variants. In this report, we review cutting-edge observations characterizing these and other pathobiological mechanisms that contribute to pulmonary vascular and right ventricular vulnerability.Keywords: hypoxia, pulmonary hypertension, genetics. In the autumn of 2015 at the Lost Valley Ranch in Sedalia, Colorado, the 34th Grover Conference, on pulmonary circulation in the "omics" era, convened for a 4-day symposium to discuss contemporary scientific concepts in the genetics, genomics, proteomics, and epigenetics of pulmonary vascular diseases. This biannual meeting, sponsored by the American Thoracic Society and co-led this year by Drs. C. Gregory Elliot, Wendy K. Chung, D. Hunter Best, and Eric D. Austin, commemorates the perpetual and transformative scientific contributions of Dr. Robert Grover 1 to the fields of high-altitude medicine and pulmonary vascular disease. This review is part of an ongoing Pulmonary Circulation thematic series that aims to provide a synopsis of key concepts presented at this year's Grover Conference.Here, we summarize the discussions that constituted a section of the conference emphasizing novel genetic and molecular mechanisms underpinning "pulmonary vascular and ventricular dysfunction in the susceptible patient." To accomplish this, three concepts are reviewed in detail: the functional relevance of chronic hypoxia (CH), discovered through genomic analyses; novel molecular mechanisms and phenotypic signatures of pulmonary vascular disease in sickle cell disease; and hormonal regulation of vascular f...

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Section: Mechanisms Of Hph: Lessons From Animal Modelsmentioning

confidence: 99%

Pulmonary Vascular and Ventricular Dysfunction in the Susceptible Patient (2015 Grover Conference Series)

2016

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“…ROCK has been described in pathologic processes, including endothelial dysfunction, vasoconstriction, and inflammation. 37,38 Ma et al 39 have described a key role for 15-HETE in pulmonary vascular remodeling and vascular angiogenesis in a hypoxia model of PAH. In their investigation, 15-HETE regulated cell cycle progression and induced EC and PASMC proliferation via increase in messenger RNA and protein expression of ROCK in PASMCs.…”

Section: Discussionmentioning

confidence: 99%

Proinflammatory High‐Density Lipoprotein Results from Oxidized Lipid Mediators in the Pathogenesis of Both Idiopathic and Associated Types of Pulmonary Arterial Hypertension

et al. 2015

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Pulmonary arterial hypertension (PAH) is characterized by abnormal elaboration of vasoactive peptides, endothelial cell dysfunction, vascular remodeling, and inflammation, which collectively contribute to its pathogenesis. We investigated the potential for highdensity lipoprotein (HDL) dysfunction (i.e., proinflammatory effects) and abnormal plasma eicosanoid levels to contribute to the pathobiology of PAH and assessed ex vivo the effect of treatment with apolipoprotein A-I mimetic peptide 4F on the observed HDL dysfunction. We determined the "inflammatory indices" HII and LII for HDL and low-density lipoprotein (LDL), respectively, in subjects with idiopathic PAH (IPAH) and associated PAH (APAH) by an in vitro monocyte chemotaxis assay. The 4F was added ex vivo, and repeat LII and HII values were obtained versus a sham treatment. We further determined eicosanoid levels in plasma and HDL fractions from patients with IPAH and APAH relative to controls. The LIIs were significantly higher for IPAH and APAH patients than for controls. Incubation of plasma with 4F before isolation of LDL and HDL significantly reduced the LII values, compared with sham-treated LDL, for IPAH and APAH. The increased LII values reflected increased states of LDL oxidation and thereby increased proinflammatory effects in both cohorts. The HIIs for both PAH cohorts reflected a "dysfunctional HDL phenotype," that is, proinflammatory HDL effects. In contrast to "normal HDL function," the determined HIIs were significantly increased for the IPAH and APAH cohorts. Ex vivo 4F treatment significantly improved the HDL function versus the sham treatment. Although there was a significant "salutary effect" of 4F treatment, this did not entirely normalize the HII. Significantly increased levels for both IPAH and APAH versus controls were evident for the eicosanoids 9-HODE, 13-HODE, 5-HETE, 12-HETE, and 15-HETE, while no statistical differences were evident for comparisons of IPAH and APAH for the determined plasma eicosanoid levels in the HDL fractions. Our study has further implicated the putative role of "oxidant stress" and inflammation in the pathobiology of PAH. Our data suggest the influences on the "dysfunctional HDL phenotype" of increased oxidized fatty acids, which are paradoxically proinflammatory. We speculate that therapies that target either the "inflammatory milieu" or the "dysfunctional HDL phenotype," such as apoA-I mimetic peptides, may be valuable avenues of further research in pulmonary vascular diseases.Keywords: pulmonary arterial hypertension, low-density lipoprotein, high-density lipoprotein, inflammatory index, hydroxyeicosatetraenoic acids, hydroxyoctadecadienoic acids, pulmonary arterial endothelial cells, pulmonary arterial smooth muscle cells.

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“…Indeed, ROCK inhibitors improved pulmonary hypertension, right ventricular remodeling and pulmonary vascular remodeling. Alternatively, inhaled delivery of ROCK inhibitors was also able to reduce pulmonary artery pressure in animal models of pulmonary hypertension [84]. Clinically, treatment with fasudil lowered pulmonary artery vascular resistance in patients with pulmonary hypertension [85].…”

Section: Rock In Pulmonary Hypertensionmentioning

confidence: 99%

ROCKs as therapeutic targets in cardiovascular diseases

Rikitake

Liao

2005

Expert Review of Cardiovascular Therapy

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There is growing evidence that Rho-kinases (ROCKs), the immediate downstream targets of the small guanosine triphosphate-binding protein Rho, may contribute to cardiovascular disease. ROCKs play a central role in diverse cellular functions such as smooth muscle contraction, stress fiber formation and cell migration and proliferation. Overactivity of ROCKs is observed in cerebral ischemia, coronary vasospasm, hypertension, vascular inflammation, arteriosclerosis and atherosclerosis. ROCKs, therefore, may be an important and still relatively unexplored therapeutic target in cardiovascular disease. Recent experimental and clinical studies using ROCK inhibitors such as Y-27632 and fasudil have revealed a critical role of ROCKs in embryonic development, inflammation and oncogenesis. This review will focus on the potential role of ROCKs in cellular functions and discuss the prospects of ROCK inhibitors as emerging therapy for cardiovascular diseases. Keywords contraction; endothelium; hypertension; inflammation; leukocyte; remodeling; Rho-kinase; smooth muscleThe small guanosine triphosphate (GTP)-binding proteins belonging to the Rho family regulate various aspects of cell shape, motility, proliferation and apoptosis [1]. Rho-kinases (ROCKs), which were one of the first downstream effectors of Rho to be discovered [2-4], were found to mediate RhoA-induced actin cytoskeletal changes through effects on myosin light-chain (MLC) phosphorylation [5,6]. ROCKs are protein serine/threonine kinases that share 45-50% homology with other actin cytoskeletal kinases such as myotonic dystrophy kinase (DMPK), myotonic dystrophy-related cdc42-binding kinase (MRCK) and citron kinase [1]. ROCKs consist of an amino-terminal kinase domain, followed by a mid-coiled-coil-forming region containing a Rho-binding domain (RBD) and a carboxy-terminal cysteine-rich domain (CRD) located within the pleckstrin homology (PH) motif (FIGURE 1). In mammalian systems, two ROCK isoforms have been identified. ROCK1, which is also known as ROKβ, and p160ROCK, which is located on chromosome 18 and encodes a 1354 amino acid protein [4,5]. ROCK2, which is also known as ROKα and sometimes confusingly called Rho-kinase, is located on chromosome 12 and contains 1388 amino acids [2,7,8]. ROCK1 and 2 share an overall 65% homology in amino acid sequence and 92% homology in their kinase domains

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Inhaled Rho Kinase Inhibitors Are Potent and Selective Vasodilators in Rat Pulmonary Hypertension

Cited by 218 publications

References 46 publications

Pulmonary Vascular and Ventricular Dysfunction in the Susceptible Patient (2015 Grover Conference Series)

Pulmonary Vascular and Ventricular Dysfunction in the Susceptible Patient (2015 Grover Conference Series)

Proinflammatory High‐Density Lipoprotein Results from Oxidized Lipid Mediators in the Pathogenesis of Both Idiopathic and Associated Types of Pulmonary Arterial Hypertension

ROCKs as therapeutic targets in cardiovascular diseases

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