Evidence for Rho-Kinase Activation in Patients With Pulmonary Arterial Hypertension

Do.e, Zhulanqiqige; Fukumoto, Yoshihiro; Takaki, Akira; Tawara, Shunsuke; Ohashi, Junko; Nakano, Masataka; Tada, Takeshi; K, Saji; Sugimura, Kazuyuki; Fujita, Hiroshi; Hoshikawa, Yasushi; Nawata, Jun; Kondo, Takashi; Shimokawa, Hiroaki

doi:10.1253/circj.cj-09-0135

Cited by 141 publications

(58 citation statements)

References 54 publications

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“…12,15,27,32,33 Also, there is direct evidence that endothelial vasodilator function is impaired and VSMC contraction enhanced in pulmonary arteries from patients with PAH ( Figure 3). 19 These findings are consistent with previous studies using MCT-induced PH in rats and hypoxiainduced PH in mice, and previous clinical studies of PAH patients. 16-18,24,28,29 Furthermore, the inhibition of Rho-kinase abolishes VSMC hypercontraction of pulmonary arteries from IPAH patients, 19 which is also consistent with a previous clinical study that showed acute inhibition of Rho-kinase improved pulmonary hemodynamics in PAH patients.…”

supporting

confidence: 92%

“…19 These findings are consistent with previous studies using MCT-induced PH in rats and hypoxiainduced PH in mice, and previous clinical studies of PAH patients. 16-18,24,28,29 Furthermore, the inhibition of Rho-kinase abolishes VSMC hypercontraction of pulmonary arteries from IPAH patients, 19 which is also consistent with a previous clinical study that showed acute inhibition of Rho-kinase improved pulmonary hemodynamics in PAH patients. 17,24,29 However, it still remains to be examined whether these functional abnormalities of the pulmonary arteries in patients with PAH can be ameliorated by long-term treatment with a Rho-kinase inhibitor.…”

supporting

confidence: 92%

“…Scale bar, 50 μm. (Summary of the results of Do.e Z et al 19 ) Recent Progress in PH Practice with PAH, it may not be the case with CTEPH. 19 CTEPH is regarded as a consequence of PTE caused by venous thromboembolism; however, the occurrence of CTEPH in patients with acute PTE or deep venous thrombosis is rare.…”

Section: Post-capillary Ph (Left Heart Disease)mentioning

confidence: 98%

“…Enhanced Rho-Kinase Expression and Activity in Patients With PAH Recently, direct evidence for Rho-kinase activation has been demonstrated in patients with PAH, 19 where Rho-kinase activity is enhanced in circulating neutrophils and the pulmonary arteries from patients with PAH, resulting in hypercontraction of the artery ( Figure 3). These findings support the previous findings in animal models of PAH and during right-heart cardiac catheterization in patients with PAH.…”

mentioning

confidence: 99%

“…12,16-18,24,28,29 Thus, increased PVR may be caused, at least in part, by the activated Rho-kinase pathway. 19 In addition, in patients with PAH, eNOS expression is reduced and pulmonary VSMC are hyper-reactive. 19,30,31 Indeed, activated Rho-kinase causes several important abnormalities, including eNOS downregulation in endothelial cells, VSMC hypercontraction through inhibition of myosin phosphatase, VSMC proliferation and migration, and inhibition of VSMC apoptosis ( Figure 2).…”

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confidence: 99%

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Recent Progress in the Management of Pulmonary Hypertension

Fukumoto

Shimokawa

2011

Circ J

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Pulmonary hypertension (PH) is a fatal disease caused by small pulmonary artery obstruction from vascular proliferation and remodeling. PH is characterized by elevated pulmonary arterial pressure and increased pulmonary vascular resistance, frequently leading to right-sided heart failure and death. The classification of PH has been recently updated to include 5 major categories of the disorder, are as: Group 1, pulmonary arterial hypertension (PAH); Group 2, PH due to left heart disease; Group 3, PH due to lung diseases and/or hypoxia; Group 4, chronic thromboembolic PH (CTEPH); and Group 5, others. Recently, significant progress has been made in the understanding of the pathophysiology, diagnosis and treatment of PH. Regarding the pathophysiology of the disorder, direct evidence for Rho-kinase activation in the pulmonary artery from PAH patients has been provided. Regarding diagnosis, optical coherence tomography is useful as a new differential diagnostic tool for distal type CTEPH vs. PAH. Regarding treatment, in addition to the conventional therapy, several new drugs are under clinical trial, including fasudil (a Rho-kinase inhibitor), riosiguat (a soluble guanylate cyclase activator), and imatinib (a tyrosine kinase inhibitor). In addition, pulmonary angioplasty and intensive immunosuppressive therapy may be effective for CTEPH and connective tissue disease-associated PAH, respectively. We briefly review the recent progress in the management of PH. (Circ J 2011; 75: 1801 - 1810

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supporting

confidence: 92%

supporting

confidence: 92%

Section: Post-capillary Ph (Left Heart Disease)mentioning

confidence: 98%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Recent Progress in the Management of Pulmonary Hypertension

Fukumoto

Shimokawa

2011

Circ J

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Pulmonary Vascular Disease Related to Hemodynamic Stress in the Pulmonary Circulation

Chan

Loscalzo

2010

Comprehensive Physiology

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Hemodynamic stress in the pulmonary vessel is directly linked to the development of vascular remodeling and dysfunction, ultimately leading to pulmonary hypertension. Recently, some advances have been made in our molecular understanding of the exogenous upstream stimuli that initiate hemodynamic pertubations as well as the downstream vasoactive effectors that control these responses. However, much still remains unknown regarding how these complex signaling pathways connect in order to result in these characteristic pathophysiological changes. This chapter will describe our current understanding of and needed areas of research into the clinical, physiological, and molecular changes associated with pressure/volume overload in the pulmonary circulation. © 2011 American Physiological Society. Compr Physiol 1:123‐139, 2011.

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Physiological and Pathological Angiogenesis in the Adult Pulmonary Circulation

McLoughlin

Keane

2011

Comprehensive Physiology

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Angiogenesis occurs during growth and physiological adaptation in many systemic organs, for example, exercise-induced skeletal and cardiac muscle hypertrophy, ovulation, and tissue repair. Disordered angiogenesis contributes to chronic inflammatory disease processes and to tumor growth and metastasis. Although it was previously thought that the adult pulmonary circulation was incapable of supporting new vessel growth, over that past 10 years new data have shown that angiogenesis within this circulation occurs both during physiological adaptive processes and as part of the pathogenic mechanisms of lung diseases. Here we review the expression of vascular growth factors in the adult lung, their essential role in pulmonary vascular homeostasis and the changes in their expression that occur in response to physiological challenges and in disease. We consider the evidence for adaptive neovascularization in the pulmonary circulation in response to alveolar hypoxia and during lung growth following pneumonectomy in the adult lung. In addition, we review the role of disordered angiogenesis in specific lung diseases including idiopathic pulmonary fibrosis, acute adult distress syndrome and both primary and metastatic tumors of the lung. Finally, we examine recent experimental data showing that therapeutic enhancement of pulmonary angiogenesis has the potential to treat lung diseases characterized by vessel loss.

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Evidence for Rho-Kinase Activation in Patients With Pulmonary Arterial Hypertension

Cited by 141 publications

References 54 publications

Recent Progress in the Management of Pulmonary Hypertension

Recent Progress in the Management of Pulmonary Hypertension

Pulmonary Vascular Disease Related to Hemodynamic Stress in the Pulmonary Circulation

Physiological and Pathological Angiogenesis in the Adult Pulmonary Circulation

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