Targeting RhoA/ROCK pathway in pulmonary arterial hypertension

Antoniu, Sabina A

doi:10.1517/14728222.2012.671811

Cited by 53 publications

(41 citation statements)

References 57 publications

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“…These cholesterol-independent ‘pleiotropic’ effects are mediated by the depletion of crucial isoprenoid intermediates of the cholesterol biosynthetic pathway, namely FPP and GGPP. Statin treatment has been shown to abrogate membrane localization of small GTPases and interfere with, among others, Rho-ROCK signaling in various types of cells and diseases, including cancer (Riganti et al, 2008; Wiemer et al, 2009; Roy et al, 2011; Mardilovich et al, 2012), diabetes (Zhou and Li, 2011), cardiovascular disease (Reddy et al, 2005; Nakamura et al, 2006; Zhou and Liao, 2009; Zhou et al, 2011; Lopez-Pedrera et al, 2012), endothelial dysfunction (Tesfamariam, 2006; Noma et al, 2012), pulmonary hypertension (Oka et al, 2008; Antoniu, 2012), heart failure and ischemic stroke (Sawada and Liao, 2009; Miyamoto et al, 2010), bronchial asthma (Chiba et al, 2010), Alzheimer disease (Tang, 2005), and kidney disease (Fried, 2008). To what extent Rho-ROCK activity is inhibited in these respective patients upon statin therapy is unclear.…”

Section: The Selectivity Of Rho/rock Inhibition In Human Diseasesmentioning

confidence: 99%

Rho-kinase: regulation, (dys)function, and inhibition

Amin

Dubey²,

Zhang

et al. 2013

Biological Chemistry

157

133

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In a variety of normal and pathological cell types, Rho-kinases I and II (ROCKI/II) play a pivotal role in the organization of the nonmuscle and smooth muscle cytoskeleton and adhesion plaques as well as in the regulation of transcription factors. Thus, ROCKI/II activity regulates cellular contraction, motility, morphology, polarity, cell division, and gene expression. Emerging evidence suggests that dysregulation of the Rho-ROCK pathways at different stages is linked to cardiovascular, metabolic, and neurodegenerative diseases as well as cancer. This review focuses on the current status of understanding the multiple functions of Rho-ROCK signaling pathways and various modes of regulation of Rho-ROCK activity, thereby orchestrating a concerted functional response.

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Section: The Selectivity Of Rho/rock Inhibition In Human Diseasesmentioning

confidence: 99%

Rho-kinase: regulation, (dys)function, and inhibition

Amin

Dubey²,

Zhang

et al. 2013

Biological Chemistry

157

133

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show abstract

“…A wide variety of cellular actions, including proliferation, apoptosis, motility, migration, inflammation, and vasoconstriction are influenced and regulated by the Rho-A/Rho-kinase signaling pathway [76–79]. All these effects are related to its activation (which can occur in response to many ligands implicated in the pathogenesis of PAH, including endothelin-1, thromboxane-A 2 , and serotonin) and subsequent inhibition of the myosin light chain phosphatase activity [76–79].…”

Section: Expected Novel Drugs and Future Therapeutic Targetsmentioning

confidence: 99%

“…All these effects are related to its activation (which can occur in response to many ligands implicated in the pathogenesis of PAH, including endothelin-1, thromboxane-A 2 , and serotonin) and subsequent inhibition of the myosin light chain phosphatase activity [76–79]. …”

Section: Expected Novel Drugs and Future Therapeutic Targetsmentioning

confidence: 99%

Pulmonary Arterial Hypertension in Adults: Novel Drugs and Catheter Ablation Techniques Show Promise? Systematic Review on Pharmacotherapy and Interventional Strategies

Rosanio

Pelliccia

Gaudio

et al. 2014

BioMed Research International

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This systematic review aims to provide an update on pharmacological and interventional strategies for the treatment of pulmonary arterial hypertension in adults. Currently US Food and Drug Administration approved drugs including prostanoids, endothelin-receptor antagonists, phosphodiesterase type-5 inhibitors, and soluble guanylate-cyclase stimulators. These agents have transformed the prognosis for pulmonary arterial hypertension patients from symptomatic improvements in exercise tolerance ten years ago to delayed disease progression today. On the other hand, percutaneous balloon atrioseptostomy by using radiofrequency perforation, cutting balloon dilatation, or insertion of butterfly stents and pulmonary artery catheter-based denervation, both associated with very low rate of major complications and death, should be considered in combination with specific drugs at an earlier stage rather than late in the progression of pulmonary arterial hypertension and before the occurrence of overt right-sided heart failure.

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“…In experimental animal models, activation of the GTPbinding protein RhoA and its downstream target ROCK plays a role in the pathogenesis of pulmonary hypertension, as evidenced by attenuation of pulmonary hypertension by inhibition of the Rho/ROCK pathway (Antoniu, 2012;Raja, 2012). In line with these observations, preliminary data in humans suggest that the Rock inhibitor Fasudil reduces pulmonary artery pressure in patients with severe idiopathic pulmonary arterial hypertension (PAH) and high-altitude dwellers suffering from hypoxic pulmonary hypertension .…”

Section: Other Mechanismsmentioning

confidence: 99%

Mechanisms and Drug Therapy of Pulmonary Hypertension at High Altitude

Scherrer

Allemann

Rexhaj

et al. 2013

High Altitude Medicine & Biology

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Pulmonary vasoconstriction represents a physiological adaptive mechanism to high altitude. If exaggerated, however, it is associated with important morbidity and mortality. Recent mechanistic studies using short-term acute high altitude exposure have provided insight into the importance of defective vascular endothelial and respiratory epithelial nitric oxide (NO) synthesis, increased endothelin-1 bioavailability, and overactivation of the sympathetic nervous system in causing exaggerated hypoxic pulmonary hypertension in humans. Based on these studies, drugs that increase NO bioavailability, attenuate endothelin-1 induced pulmonary vasoconstriction, or prevent exaggerated sympathetic activation have been shown to be useful for the treatment/prevention of exaggerated pulmonary hypertension during acute short-term high altitude exposure. The mechanisms underpinning chronic pulmonary hypertension in high altitude dwellers are less well understood, but recent evidence suggests that they differ in some aspects from those involved in short-term adaptation to high altitude. These differences have consequences for the choice of the treatment for chronic pulmonary hypertension at high altitude. Finally, recent data indicate that fetal programming of pulmonary vascular dysfunction in offspring of preeclampsia and children generated by assisted reproductive technologies represents a novel and frequent cause of pulmonary hypertension at high altitude. In animal models of fetal programming of hypoxic pulmonary hypertension, epigenetic mechanisms play a role, and targeting of these mechanisms with drugs lowers pulmonary artery pressure. If epigenetic mechanisms also are operational in the fetal programming of pulmonary vascular dysfunction in humans, such drugs may become novel tools for the treatment of hypoxic pulmonary hypertension.

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Targeting RhoA/ROCK pathway in pulmonary arterial hypertension

Cited by 53 publications

References 57 publications

Rho-kinase: regulation, (dys)function, and inhibition

Rho-kinase: regulation, (dys)function, and inhibition

Pulmonary Arterial Hypertension in Adults: Novel Drugs and Catheter Ablation Techniques Show Promise? Systematic Review on Pharmacotherapy and Interventional Strategies

Mechanisms and Drug Therapy of Pulmonary Hypertension at High Altitude

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