Abstract P091: New Rho-kinase Inhibitors Reduce Cardiac Dysfunction And Vascular Remodeling In Pulmonary Hypertension In Rats

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Tadeu L Montagnoli ◽  
Jaqueline S Da Silva ◽  
Bruna S Rocha ◽  
Marina Silva ◽  
Bianca Santos-Carlos ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Vascular Remodeling ◽  
Kinase Inhibitors ◽  
Rho Kinase ◽  
Cardiomyocyte Hypertrophy ◽  
Ejection Time ◽  
Arterial Elastance ◽  
Morphological Alterations ◽  
Male Wistar Rats ◽  
Rock Inhibition

Pulmonary hypertension (PH) is characterized by extensive pulmonary vascular remodeling, leading to right ventricle (RV) hypertrophy and dysfunction. Since Rho kinases (ROCK) play a key role in smooth muscle proliferation and cardiomyocyte hypertrophy, this work evaluated the effects of ROCK inhibition by LASSBio-2020 and LASSBio-2065 on monocrotaline (MCT)-induced PH. After single injection of MCT (60 mg/kg i.p.), male Wistar rats were randomly divided in groups and treated with vehicle, LASSBio-2020 or LASSBio-2065 (60 μmol/kg/day, i.p.). Table 1 shows summarized data. After 14 days, ROCK inhibitors reduced pulmonary vascular resistance, indicated by the ratio of pulmonary acceleration time and ejection time (PAT/TET; p< 0.05) and medial wall thickness of distal pulmonary arterioles (p< 0.05). LASSBio-2020 and LASSBio-2065 also reduced Fulton index of RV hypertrophy (p< 0.05) and RV afterload, as shown by recovery of RV cardiac output (p< 0.05) and arterial elastance (p< 0.05). ROCK inhibitors improved diastolic function since both compounds reduced RV end-diastolic pressures (RVEDP) and Tau, measured through catheterization. Therefore, ROCK inhibition by LASSBio-2020 and LASSBio-2065 reverted functional and morphological alterations in PH rats and may represent a useful alternative for management of PH-associated RV dysfunction.

scholarly journals Peroxisome proliferator activated receptor-γ-Rho-kinase interactions contribute to vascular remodeling after chronic intrauterine pulmonary hypertension

2014 ◽  
Vol 306 (3) ◽  
pp. L299-L308 ◽  
Author(s):  
Jason Gien ◽  
Nancy Tseng ◽  
Gregory Seedorf ◽  
Gates Roe ◽  
Steven H. Abman
Keyword(s):  
Pulmonary Hypertension ◽  
Protein Expression ◽  
Vascular Remodeling ◽  
Rho Kinase ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Cell Counts ◽  
Expression Activity ◽  
Rock Inhibition ◽  
Rock Activity

Peroxisome proliferator-activated receptor-γ (PPARγ) and Rho-kinase (ROCK) regulate smooth muscle cell (SMC) proliferation and contribute to vascular remodeling in adult pulmonary hypertension. Whether these pathways interact to contribute to the development of vascular remodeling in persistent pulmonary hypertension of the newborn (PPHN) remains unknown. We hypothesized that ROCK-PPARγ interactions increase SMC proliferation resulting in vascular remodeling in experimental PPHN. Pulmonary artery SMCs (PASMCs) were harvested from fetal sheep after partial ligation of the ductus arteriosus in utero (PPHN) and controls. Cell counts were performed daily for 5 days with or without PPARγ agonists and ROCK inhibition. PPARγ and ROCK protein expression/activity were measured by Western blot in normal and PPHN PASMCs. We assessed PPARγ-ROCK interactions by studying the effect of ROCK activation on PPARγ activity and PPARγ inhibition (siRNA) on ROCK activity and PASMC proliferation. At baseline, PPHN PASMC cell number was increased by 38% above controls on day 5. ROCK protein expression/activity were increased by 25 and 34% and PPARγ protein/activity decreased by 40 and 50% in PPHN PASMC. ROCK inhibition and PPARγ activation restored PPHN PASMC growth to normal values. ROCK inhibition increased PPARγ activity by 50% in PPHN PASMC, restoring PPARγ activity to normal. In normal PASMCs, ROCK activation decreased PPARγ activity and PPARγ inhibition increased ROCK activity and cell proliferation, resulting in a PPHN hyperproliferative PASMC phenotype. PPARγ-ROCK interactions regulate SMC proliferation and contribute to increased PPHN PASMC proliferation and vascular remodeling in PPHN. Restoring normal PPARγ-ROCK signaling may prevent vascular remodeling and improve outcomes in PPHN.

scholarly journals Thyroxine Induces Acute Relaxation of Rat Skeletal Muscle Arteries via Integrin αvβ3, ERK1/2 and Integrin-Linked Kinase

2021 ◽  
Vol 12 ◽  
Author(s):  
Ekaterina K. Selivanova ◽  
Dina K. Gaynullina ◽  
Olga S. Tarasova
Keyword(s):  
Skeletal Muscle ◽  
Kinase Inhibitors ◽  
Isometric Force ◽  
Rho Kinase ◽  
Integrin Αvβ3 ◽  
Acute Effects ◽  
Rat Skeletal Muscle ◽  
Subsequent Decrease ◽  
Adrenoceptor Agonist ◽  
Male Wistar Rats

Aim: Hyperthyroidism is associated with a decreased peripheral vascular resistance, which could be caused by the vasodilator genomic or non-genomic effects of thyroid hormones (TH). Non-genomic, or acute, effects develop within several minutes and involve a wide tissue-specific spectrum of molecular pathways poorly studied in vasculature. We aimed to investigate the mechanisms of acute effects of TH on rat skeletal muscle arteries.Methods: Sural arteries from male Wistar rats were used for isometric force recording (wire myography) and phosphorylated protein content measurement (Western blotting).Results: Both triiodothyronine (T3) and thyroxine (T4) reduced contractile response of sural arteries to α1-adrenoceptor agonist methoxamine. The effect of T4 was more prominent than T3 and not affected by iopanoic acid, an inhibitor of deiodinase 2. Endothelium denudation abolished the effect of T3, but not T4. Integrin αvβ3 inhibitor tetrac abolished the effect of T4 in endothelium-denuded arteries. T4 weakened methoxamine-induced elevation of phospho-MLC2 (Ser19) content in arterial samples. The effect of T4 in endothelium-denuded arteries was abolished by inhibiting ERK1/2 activation with U0126 as well as by ILK inhibitor Cpd22 but persisted in the presence of Src- or Rho-kinase inhibitors (PP2 and Y27632, respectively).Conclusion: Acute non-genomic relaxation of sural arteries induced by T3 is endothelium-dependent and that induced by T4 is endothelium-independent. The effect of T4 on α1-adrenergic contraction is stronger compared to T3 and involves the suppression of extracellular matrix signaling via integrin αvβ3, ERK1/2 and ILK with subsequent decrease of MLC2 (Ser19) phosphorylation.

Acute vasodilator effects of Rho-kinase inhibitors in neonatal rats with pulmonary hypertension unresponsive to nitric oxide

2008 ◽  
Vol 294 (2) ◽  
pp. L205-L213 ◽  
Author(s):  
Patrick J. McNamara ◽  
Prashanth Murthy ◽  
Crystal Kantores ◽  
Lilian Teixeira ◽  
Doreen Engelberts ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Kinase Inhibitors ◽  
Pulmonary Arteries ◽  
Rho Kinase ◽  
Neonatal Rat ◽  
Rock Inhibitor ◽  
No Donor ◽  
Rat Models ◽  
Pulmonary Hemodynamic

Pulmonary hypertension (PHT) in neonates is often refractory to the current best therapy, inhaled nitric oxide (NO). The utility of a new class of pulmonary vasodilators, Rho-kinase (ROCK) inhibitors, has not been examined in neonatal animals. Our objective was to examine the activity and expression of RhoA/ROCK in normal and injured pulmonary arteries and to determine the short-term pulmonary hemodynamic (assessed by pulse wave Doppler) effects of ROCK inhibitors (15 mg/kg ip Y-27632 or 30 mg/kg ip fasudil) in two neonatal rat models of chronic PHT with pulmonary vascular remodeling (chronic hypoxia, 0.13 FiO2, or 1 mg·kg−1·day−1 ip chronic bleomycin for 14 days from birth). Activity of the RhoA/ROCK pathway and ROCK expression were increased in hypoxia- and bleomycin-induced PHT. In both models, severe PHT [characterized by raised pulmonary vascular resistance (PVR) and impaired right ventricular (RV) performance] did not respond acutely to inhaled NO (20 ppm for 15 min) or to a single bolus of a NO donor, 3-morpholinosydnonimine hydrochloride (SIN-1; 2 μg/kg ip). In contrast, a single intraperitoneal bolus of either ROCK inhibitor (Y-27632 or fasudil) completely normalized PVR but had no acute effect on RV performance. ROCK-mediated vasoconstriction appears to play a key role in chronic PHT in our two neonatal rat models. Inhibitors of ROCK have potential as a testable therapy in neonates with PHT that is refractory to NO.

scholarly journals Involvement of RhoA/Rho kinase signaling in protection against monocrotaline-induced pulmonary hypertension in pneumonectomized rats by dehydroepiandrosterone

2008 ◽  
Vol 295 (1) ◽  
pp. L71-L78 ◽  
Author(s):  
Noriyuki Homma ◽  
Tetsutaro Nagaoka ◽  
Vijaya Karoor ◽  
Masatoshi Imamura ◽  
Laimute Taraseviciene-Stewart ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Artery ◽  
Protein Expression ◽  
Vascular Remodeling ◽  
Rho Kinase ◽  
Related Protein ◽  
Pulmonary Vascular Remodeling ◽  
Naturally Occurring ◽  
Dhea Treatment ◽  
Induced Changes

RhoA/Rho kinase (ROCK) signaling plays a key role in the pathogenesis of experimental pulmonary hypertension (PH). Dehydroepiandrosterone (DHEA), a naturally occurring steroid hormone, effectively inhibits chronic hypoxic PH, but the responsible mechanisms are unclear. This study tested whether DHEA was also effective in treating monocrotaline (MCT)-induced PH in left pneumonectomized rats and whether inhibition of RhoA/ROCK signaling was involved in the protective effect of DHEA. Three weeks after MCT injection, pneumonectomized rats developed PH with severe vascular remodeling, including occlusive neointimal lesions in pulmonary arterioles. In lungs from these animals, we detected cleaved (constitutively active) ROCK I as well as increases in activities of RhoA and ROCK and increases in ROCK II protein expression. Chronic DHEA treatment (1%, by food for 3 wk) markedly inhibited the MCT-induced PH (mean pulmonary artery pressures after treatment with 0% and 1% DHEA were 33 ± 5 and 16 ± 1 mmHg, respectively) and severe pulmonary vascular remodeling in pneumonectomized rats. The MCT-induced changes in RhoA/ROCK-related protein expression were nearly normalized by DHEA. A 3-wk DHEA treatment (1%) started 3 wk after MCT injection completely inhibited the progression of PH (mean pulmonary artery pressures after treatment with 0% and 1% DHEA were 47 ± 3 and 30 ± 3 mmHg, respectively), and this treatment also resulted in 100% survival in contrast to 30% in DHEA-untreated rats. These results suggest that inhibition of RhoA/ROCK signaling, including the cleavage and constitutive activation of ROCK I, is an important component of the impressive protection of DHEA against MCT-induced PH in pneumonectomized rats.

scholarly journals Kinase-dependent activation of voltage-gated Ca2+ channels by ET-1 in pulmonary arterial myocytes during chronic hypoxia

2012 ◽  
Vol 302 (10) ◽  
pp. L1128-L1139 ◽  
Author(s):  
Trevor Luke ◽  
Julie Maylor ◽  
Clark Undem ◽  
J. T. Sylvester ◽  
Larissa A. Shimoda
Keyword(s):  
Pulmonary Hypertension ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Chronic Hypoxia ◽  
Fluorescent Microscopy ◽  
Rho Kinase ◽  
Rho Kinase Inhibitors ◽  
Voltage Dependent ◽  
Pulmonary Arterial ◽  
Microscopy Techniques

Exposure to chronic hypoxia (CH) causes pulmonary hypertension. The vasoconstrictor endothelin-1 (ET-1) is thought to play a role in the development of hypoxic pulmonary hypertension. In pulmonary arterial smooth muscle cells (PASMCs) from chronically hypoxic rats, ET-1 signaling is altered, with the ET-1-induced change in intracellular calcium concentration (Δ[Ca2+]i) occurring through activation of voltage-dependent Ca2+ channels (VDCC) even though ET-1-induced depolarization via inhibition of K+ channels is lost. The mechanism underlying this response is unclear. We hypothesized that activation of VDCCs by ET-1 following CH might be mediated by protein kinase C (PKC) and/or Rho kinase, both of which have been shown to phosphorylate and activate VDCCs. To test this hypothesis, we examined the effects of PKC and Rho kinase inhibitors on the ET-1-induced Δ[Ca2+]i in PASMCs from rats exposed to CH (10% O2, 3 wk) using the Ca2+-sensitive dye fura 2-AM and fluorescent microscopy techniques. We found that staurosporine and GF109203X, inhibitors of PKC, and Y-27632 and HA 1077, Rho kinase inhibitors, reduced the ET-1-induced Δ[Ca2+]i by >70%. Inhibition of tyrosine kinases (TKs) with genistein or tyrphostin A23, or combined inhibition of PKC, TKs, and Rho kinase, reduced the Δ[Ca2+]i to a similar extent as inhibition of either PKC or Rho kinase alone. The ability of PKC or Rho kinase to activate VDCCs in our cells was verified using phorbol 12-myristate 13-acetate and GTP-γ-S. These results suggest that following CH, the ET-1-induced Δ[Ca2+]i in PASMCs occurs via Ca2+ influx through VDCCs mediated primarily by PKC, TKs, and Rho kinase.

scholarly journals Pulmonary microvascular remodeling in chronic thrombo-embolic pulmonary hypertension

2018 ◽  
Vol 315 (6) ◽  
pp. L951-L964 ◽  
Author(s):  
Kelly Stam ◽  
Richard W. van Duin ◽  
André Uitterdijk ◽  
Ilona Krabbendam-Peters ◽  
Oana Sorop ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Vascular Remodeling ◽  
Rho Kinase ◽  
Pulmonary Vasculature ◽  
Swine Model ◽  
No Production ◽  
Pulmonary Vascular Remodeling ◽  
Small Arteries ◽  
Microvascular Remodeling ◽  
Ventricular Afterload

Pulmonary vascular remodeling in pulmonary arterial hypertension involves perturbations in the nitric oxide (NO) and endothelin-1 (ET-1) pathways. However, the implications of pulmonary vascular remodeling and these pathways remain unclear in chronic thrombo-embolic pulmonary hypertension (CTEPH). The objective of the present study was to characterize changes in microvascular morphology and function, focussing on the ET-1 and NO pathways, in a CTEPH swine model. Swine were chronically instrumented and received up to five pulmonary embolizations by microsphere infusion, whereas endothelial dysfunction was induced by daily administration of the endothelial NO synthase inhibitor Nω-nitro-l-arginine methyl ester until 2 wk before the end of study. Swine were subjected to exercise, and the pulmonary vasculature was investigated by hemodynamic, histological, quantitative PCR, and myograph experiments. In swine with CTEPH, the increased right-ventricular afterload, decreased cardiac index, and mild ventilation-perfusion-mismatch were exacerbated during exercise. Pulmonary microvascular remodeling was evidenced by increased muscularization, which was accompanied by an increased maximal vasoconstriction. Although ET-1-induced vasoconstriction was increased in CTEPH pulmonary small arteries, the ET-1 sensitivity was decreased. Moreover, the contribution of the ETA receptor to ET-1 vasoconstriction was increased, whereas the contribution of the ETB receptor was decreased and the contribution of Rho-kinase was lost. A reduction in endogenous NO production was compensated in part by a decreased phosphodiesterase 5 (PDE5) activity resulting in an apparent increased NO sensitivity in CTEPH pulmonary small arteries. These findings suggest that pulmonary microvascular remodeling with a reduced activity of PDE5 and Rho-kinase may contribute to the lack of therapeutic efficacy of PDE5 inhibitors and Rho-kinase inhibitors in CTEPH.

Involvement of asymmetric dimethylarginine and Rho kinase in the vascular remodeling in monocrotaline-induced pulmonary hypertension

2010 ◽  
Vol 53 (5-6) ◽  
pp. 223-229 ◽  
Author(s):  
Xiao-Hui Li ◽  
Jun Peng ◽  
Na Tan ◽  
Wei-Hua Wu ◽  
Ting-Ting Li ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Vascular Remodeling ◽  
Asymmetric Dimethylarginine ◽  
Rho Kinase
Sign in / Sign up

Export Citation Format

Share Document