RhoA/Rho-kinase signaling: a therapeutic target in pulmonary hypertension

Barman, Scott A.; Zhu, Shu; White, Richard E.

doi:10.2147/vhrm.s4711

Cited by 57 publications

(41 citation statements)

References 105 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In addition to the STAT3-NFAT axis, the antiproliferative and proapoptotic effect of SHP2 inhibition by siRNA or miR-204 mimic could also be attributed to the inhibition of the RhoA-ROCK (Rho-associated, coiled-coilcontaining protein kinase) pathway (Fig. S6 D; Lee and Chang, 2008;Kimura and Eguchi, 2009), which is increased and implicated in PAH-PASMC proliferation (Barman et al, 2009). Based on the fact that miR-204 is encoded within TRPM3 (Wang et al, 2010) (Fig.…”

Section: Src Activation By Mir-204 Promotes Stat3 and Nfat Activationmentioning

confidence: 99%

Role for miR-204 in human pulmonary arterial hypertension

Courboulin¹,

Paulin²,

Giguère³

et al. 2011

J Cell Biol

148

219

View full text Add to dashboard Cite

Pulmonary arterial hypertension (PAH) is characterized by enhanced proliferation and reduced apoptosis of pulmonary artery smooth muscle cells (PASMCs). Because microRNAs have been recently implicated in the regulation of cell proliferation and apoptosis, we hypothesized that these regulatory molecules might be implicated in the etiology of PAH. In this study, we show that miR-204 expression in PASMCs is down-regulated in both human and rodent PAH. miR-204 down-regulation correlates with PAH severity and accounts for the proliferative and antiapoptotic phenotypes of PAH-PASMCs. STAT3 activation suppresses miR-204 expression, and miR-204 directly targets SHP2 expression, thereby SHP2 up-regulation, by miR-204 down-regulation, activates the Src kinase and nuclear factor of activated T cells (NFAT). STAT3 also directly induces NFATc2 expression. NFAT and SHP2 were needed to sustain PAH-PASMC proliferation and resistance to apoptosis. Finally, delivery of synthetic miR-204 to the lungs of animals with PAH significantly reduced disease severity. This study uncovers a new regulatory pathway involving miR-204 that is critical to the etiology of PAH and indicates that reestablishing miR-204 expression should be explored as a potential new therapy for this disease. role of miR-204 in the etiology of PAH. Interestingly, using in silico and microarray gene expression analyses, we observed that among the 461 predicted targets of miR-204 (TargetScan 5.1), only 165 were increased by artificial miR-204 inhibition in control human PASMCs (n = 2 patients; Fig. S1 C). In accordance with the pro-proliferative and antiapoptotic phenotypes seen in PAH, several Src-STAT3-and NFAT-related genes were identified (Fig. S1 C). miR-204 expression is decreased in human PAH and correlates with PAH severityTo investigate the expression pattern of miR-204 in normal and pulmonary hypertensive lungs, we examined miR-204 expression levels in (a) lung biopsies from 8 individuals with nonfamilial PAH compared with biopsies from 8 individuals without pulmonary hypertension, (b) lungs from 6 mice with hypoxia-induced pulmonary hypertension compared with 5 control littermates, and (c) lungs from 5 rats with monocrotaline (MCT)-induced pulmonary hypertension compared with 10 control littermates ( Fig. 1 A). We found decreased levels of miR-204 in human and rodent pulmonary hypertensive lung tissues compared with normotensive lung samples. To characterize whether down-regulated miR-204 levels were specific to the lung in rats with pulmonary hypertension, we compared organ-specific levels of miR-204 between normal and pulmonary hypertensive rats (Fig. 1 B). Even if we were able to detect minimal amounts of miR-204 in most organs, miR-204 levels were only down-regulated in the lung and PAs but not in the aorta, liver, heart, and kidney in rats 3 wk after MCT injection (pulmonary hypertensive rats) compared with non-pulmonary hypertensive rats (Fig. 1 B).To test whether miR-204 down-regulation correlated with disease progression, we studied humans, mice, a...

show abstract

Section: Src Activation By Mir-204 Promotes Stat3 and Nfat Activationmentioning

confidence: 99%

Role for miR-204 in human pulmonary arterial hypertension

Courboulin¹,

Paulin²,

Giguère³

et al. 2011

J Cell Biol

148

219

View full text Add to dashboard Cite

show abstract

“…29 RhoA and Rho kinase have long been associated with the development of PAH and this pathway has been proposed as a potential target for PAH therapy. 30 …”

Section: Discussionmentioning

confidence: 99%

Protein expression by human pulmonary artery smooth muscle cells containing a BMPR2 mutation and the action of ET-1 as determined by proteomic mass spectrometry

Yao

Taylor

et al. 2015

International Journal of Mass Spectrometry

View full text Add to dashboard Cite

Pulmonary arterial hypertension (PAH) is a disease characterized by increased pulmonary vascular resistance and remodeling. Increase in the population of vascular smooth muscle cells is among the key events contributing to the remodeling. Endothelin-1 (ET-1), a potent vasoconstrictor, is linked to the etiology and progression of PAH. Here we analyze changes in protein expressions in response to ET-1 in pulmonary arterial smooth muscle cells (PASMC) from a healthy Control (non-PAH) and a PAH subject presenting a bone morphogenetic protein type II receptor (BMPR2) mutation with exon 1–8 deletion. Protein expressions were analyzed by proteomic mass spectrometry using label-free quantitation and the correlations were subjected to Ingenuity™ Pathway Analysis. The results point to eIF2/mTOR/p70S6K, RhoA/actin cytoskeleton/integrin and protein unbiquitination as canonical pathways whose protein expressions increase with the development of PAH. These pathways have an intimal function in the PAH-related physiology of smooth muscle proliferation, apoptosis, contraction and cellular stress. Exposure of the cells to ET-1 further increases protein expression within these pathways. Thus our results show changes in signaling pathways as a consequence of PAH and the effect of ET-1 interference on Control and PAH-affected cells.

show abstract

“…Blood vessel contraction induced by agonist is mainly due to an increase in intracellular Ca 2+ concentration by increased membrane depolarization or phospholipase C (PLC)-mediated Ca 2+ release from the sarcoplasmic reticulum (24,25). It has been reported that the RhoA/Rho kinase pathway acts as a Ca 2+ sensitizer during smooth muscle contraction and that abnormal Ca 2+ sensitization provokes the pathophysiology of hypertension, arterial restenosis, and pulmonary hypertension (26)(27)(28). A thromboxane-A2 mimic compound, U46619, activates the RhoA/Rho kinase pathway, which phosphorylates and activates the myosin phosphatase inhibitor CPI17 in VSMCs, resulting in inhibition of myosin light chain phosphatase (MLCP), which induces vasodilation (23).…”

Section: Discussionmentioning

confidence: 99%

Glucosamine increases vascular contraction through activation of RhoA/Rho kinase pathway in isolated rat aorta

Kim¹,

Seok²,

Kim³

et al. 2011

BMB Reports

View full text Add to dashboard Cite

Diabetes is a well-known independent risk factor for vascular disease. However, its underlying mechanism remains unclear. It has been reported that increased influx of the hexosamine biosynthesis pathway (HBP) induces O-GlcNAcylation of proteins, leading to insulin resistance. In this study, we determined whether or not O-GlcNAc modification of proteins could increase vessel contraction. Using an endothelium-denuded aortic ring, we observed that glucosamine induced OGlcNAcylation of proteins and augmented vessel contraction stimulated by U46619, a thromboxane A2 agonist, via augmentation of the phosphorylation of MLC20, MYPT1(Thr855), and CPI17, but not phenylephrine. Pretreatment with OGT inhibitor significantly ameliorated glucosamine-induced vessel constriction. Glucosamine treatment also increased RhoA activity, which was also attenuated by OGT inhibitor. In conclusion, glucosamine, a product of glucose influx via the HBP in a diabetic state, increases vascular contraction, at least in part, through activation of the RhoA/Rho kinase pathway, which may be due to O-GlcNAcylation. [BMB reports 2011; 44(6): 415-420]

show abstract

RhoA/Rho-kinase signaling: a therapeutic target in pulmonary hypertension

Cited by 57 publications

References 105 publications

Role for miR-204 in human pulmonary arterial hypertension

Role for miR-204 in human pulmonary arterial hypertension

Protein expression by human pulmonary artery smooth muscle cells containing a BMPR2 mutation and the action of ET-1 as determined by proteomic mass spectrometry

Glucosamine increases vascular contraction through activation of RhoA/Rho kinase pathway in isolated rat aorta

Contact Info

Product

Resources

About