scholarly journals ROCK Inhibition as Potential Target for Treatment of Pulmonary Hypertension

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1648
Author(s):  
Tadeu L. Montagnoli ◽  
Jaqueline S. da Silva ◽  
Susumu Z. Sudo ◽  
Aimeé D. Santos ◽  
Gabriel F. Gomide ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Cell Proliferation ◽  
Pulmonary Hypertension ◽  
Right Ventricle ◽  
Vascular Remodeling ◽  
Cell Biology ◽  
Vascular Cell ◽  
Preclinical And Clinical Studies ◽  
Rock Inhibition ◽  
Review Current

Pulmonary hypertension (PH) is a cardiovascular disease caused by extensive vascular remodeling in the lungs, which ultimately leads to death in consequence of right ventricle (RV) failure. While current drugs for PH therapy address the sustained vasoconstriction, no agent effectively targets vascular cell proliferation and tissue inflammation. Rho-associated protein kinases (ROCKs) emerged in the last few decades as promising targets for PH therapy, since ROCK inhibitors demonstrated significant anti-remodeling and anti-inflammatory effects. In this review, current aspects of ROCK inhibition therapy are discussed in relation to the treatment of PH and RV dysfunction, from cell biology to preclinical and clinical studies.

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.

NPS2143 Modulates the Phenotypic Switching of PASMCs by Inhibiting Autophagy in Hypoxia-Induced Pulmonary Hypertension

2021 ◽  
Vol 8 (2) ◽  
Author(s):  
Wang L ◽  
◽  
Shao H ◽  
Che B ◽  
Wang N ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Pulmonary Hypertension ◽  
Pulmonary Artery ◽  
Western Blot ◽  
Vascular Remodeling ◽  
Pulmonary Artery Hypertension ◽  
Phenotypic Switching ◽  
Pulmonary Vascular Remodeling

Background and Objectives: Pulmonary Artery Hypertension (PAH) is considered as a malignant tumor in cardiovascular disease. Our previous study found that Calcium-Sensing Receptor (CaSR) is involved in pulmonary vascular remodeling in hypoxic pulmonary hypertension (HPH). However, the relationship of Pulmonary Artery Smooth Muscle Cell (PASMC) phenotypic switching, proliferation, and autophagy in CaSR-related HPH remain unclear. The purpose of this study was to detect the role of a CaSR antagonist, NPS2143, on the vascular remodeling by autophagy modulation under hypoxia. Methods: Hypoxic rat PAH model were simulated in vivo. Meanwhile, mean Pulmonary Artery Pressure (mPAP) was measured while RVI, WT%, and WA% indices were calculated. Immunohistochemistry and Western blot were used to detect phenotypic switching and cell proliferation in pulmonary arteriole. Cell viability was determined in vitro by CCK8 and cell cycle. Cell proliferation, phenotypic switching, autophagy level and PI3K/Akt/mTOR pathways were investigated in human PASMCs through mRNA or Western blot methods. Results: Rats with hypoxic-induced PAH had an increased mPAP, RVI, WT% and WA%. Moreover, expression of CaSR was significantly increased, followed by activation of autophagy (increased LC3b and decreased p62), phenotypic switching of PASMCs (reduced calponin, SMA-a and increased OPN) and pulmonary vascular remodeling. However, NPS2143 weakened these hypoxic effects. The results using hypoxic-induced human PASMCs confirmed that NPS2143 suppressed autophagy and reversed phenotypic switching in vitro by inhibiting PI3K/Akt/mTOR pathways. Conclusions: Our study demonstrates that NPS2143 was conducive to inhibit the proliferation and reverse phenotypic switching of PASMCs by regulating autophagy levels in HPH and vascular remodeling.

scholarly journals Deficiency of Akt1, but not Akt2, attenuates the development of pulmonary hypertension

2015 ◽  
Vol 308 (2) ◽  
pp. L208-L220 ◽  
Author(s):  
Haiyang Tang ◽  
Jiwang Chen ◽  
Dustin R. Fraidenburg ◽  
Shanshan Song ◽  
Justin R. Sysol ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Vascular Remodeling ◽  
Pulmonary Vascular Remodeling ◽  
Akt Isoforms ◽  
Cell Proliferation And Migration ◽  
Pulmonary Arterial ◽  
And Migration ◽  
Proliferation And Migration

Pulmonary vascular remodeling, mainly attributable to enhanced pulmonary arterial smooth muscle cell proliferation and migration, is a major cause for elevated pulmonary vascular resistance and pulmonary arterial pressure in patients with pulmonary hypertension. The signaling cascade through Akt, comprised of three isoforms (Akt1–3) with distinct but overlapping functions, is involved in regulating cell proliferation and migration. This study aims to investigate whether the Akt/mammalian target of rapamycin (mTOR) pathway, and particularly which Akt isoform, contributes to the development and progression of pulmonary vascular remodeling in hypoxia-induced pulmonary hypertension (HPH). Compared with the wild-type littermates, Akt1 −/− mice were protected against the development and progression of chronic HPH, whereas Akt2 −/− mice did not demonstrate any significant protection against the development of HPH. Furthermore, pulmonary vascular remodeling was significantly attenuated in the Akt1 −/− mice, with no significant effect noted in the Akt2 −/− mice after chronic exposure to normobaric hypoxia (10% O2). Overexpression of the upstream repressor of Akt signaling, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), and conditional and inducible knockout of mTOR in smooth muscle cells were also shown to attenuate the rise in right ventricular systolic pressure and the development of right ventricular hypertrophy. In conclusion, Akt isoforms appear to have a unique function within the pulmonary vasculature, with the Akt1 isoform having a dominant role in pulmonary vascular remodeling associated with HPH. The PTEN/Akt1/mTOR signaling pathway will continue to be a critical area of study in the pathogenesis of pulmonary hypertension, and specific Akt isoforms may help specify therapeutic targets for the treatment of pulmonary hypertension.

scholarly journals The Isoquinoline-Sulfonamide Compound H-1337 Attenuates SU5416/Hypoxia-Induced Pulmonary Arterial Hypertension in Rats

Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 66
Author(s):  
Hiroki Shoji ◽  
Yoko Yoshida ◽  
Takayuki Jujo Sanada ◽  
Akira Naito ◽  
Junko Maruyama ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Right Ventricle ◽  
Arterial Hypertension ◽  
Vascular Remodeling ◽  
Myosin Light Chain ◽  
Pulmonary Vasculature ◽  
Pulmonary Vascular Remodeling ◽  
Pulmonary Arterial ◽  
Sulfonamide Compound

Pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary arterial pressure and right heart failure. Selective pulmonary vasodilators have improved the prognosis of PAH; however, they are not able to reverse pulmonary vascular remodeling. Therefore, a search for new treatment agents is required. H-1337 is an isoquinoline-sulfonamide compound that inhibits multiple serine/threonine kinases, including Rho-associated protein kinase (ROCK) and mammalian target of rapamycin (mTOR). Here, we investigated the effects of H-1337 on pulmonary hypertension and remodeling in the pulmonary vasculature and right ventricle in experimental PAH induced by SU5416 and hypoxia exposure. H-1337 and H-1337M1 exerted inhibitory effects on ROCK and Akt. H-1337 inhibited the phosphorylation of myosin light chain and mTOR and suppressed the proliferation of smooth muscle cells in vitro. H-1337 treatment also suppressed the phosphorylation of myosin light chain and mTOR in the pulmonary vasculature and decreased right ventricular systolic pressure and the extent of occlusive pulmonary vascular lesions. Furthermore, H-1337 suppressed aggravation of right ventricle hypertrophy. In conclusion, our data demonstrated that inhibition of ROCK and mTOR pathways with H-1337 suppressed the progression of pulmonary vascular remodeling, pulmonary hypertension, and right ventricular remodeling.

scholarly journals 2-Methoxyestradiol Attenuates the Development and Retards the Progression of Hypoxia-And Alpha-Naphthylthiourea-Induced Pulmonary Hypertension

PRILOZI ◽  
2021 ◽  
Vol 42 (1) ◽  
pp. 41-51
Author(s):  
Stevan P. Tofovic ◽  
Xinchen Zhang ◽  
Tom J. Jones ◽  
Gordana Petruševska
Keyword(s):  
Pulmonary Hypertension ◽  
Acute Lung Injury ◽  
Pleural Effusion ◽  
Lung Injury ◽  
Right Ventricle ◽  
Vascular Remodeling ◽  
Chronic Hypoxia ◽  
Biological Effects ◽  
Systolic Pressure ◽  
Pulmonary Vascular Remodeling

Abstract Pulmonary arterial hypertension (PH), a progressive, incurable, and deadly disease, predominantly develops in women. Growing body of evidence suggest that dysregulated estradiol (E2) metabolism influences the development of PH and that some of the biological effects of E2 are mediated by its major non-estrogenic metabolite, 2-metyhoxyestradiol (2ME). The objective of this study was to examine effects of 2ME in chronic hypoxia (CH)-induced PH and alpha-naphthylthiourea (ANTU)-induced acute lung injury and PH. In addition, we investigated the effects of exposure to different levels of CH on development of PH. Chronic exposure to 15% or 10% oxygen produced similar increases in right ventricle peak systolic pressure (RVPSP) and pulmonary vascular remodeling, but oxygen concentration-dependent increase in hematocrit. Notably, right ventricle (RV) hypertrophy correlated with level of hypoxia and hematocrit, rather than with magnitude of RVPSP. The latter suggests that, in addition to increased afterload, hypoxia (via increased hematocrit) significantly contributes to RV hypertrophy in CH model of PH. In CH-PH rats, preventive and curative 2ME treatments reduced both elevated RVPSP and pulmonary vascular remodeling. Curative treatment with 2ME was more effective in reducing hematocrit and right ventricular hypertrophy, as compared to preventive treatment. Single ANTU injection produced lung injury, i.e., increased lungs weight and induced pleural effusion. Treatment with 2ME significantly reduced pleural effusion and, more importantly, eliminated acute mortality induced by ANTU (33% vs 0%, ANTU vs. ANTU+2ME group). Chronic treatment with ANTU induced PH and RV hypertrophy and increased lungs weight. 2-ME significantly attenuated severity of disease (i.e., reduced RVPSP, RV hypertrophy and pulmonary vascular injury). This study demonstrates that 2ME has beneficial effects in chronic hypoxia- and acute lung injury-induced PH and provides preclinical justification for clinical evaluation of 2ME in pulmonary hypertension.

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 Inhibition of mTOR attenuates store-operated Ca2+ entry in cells from endarterectomized tissues of patients with chronic thromboembolic pulmonary hypertension

2009 ◽  
Vol 297 (4) ◽  
pp. L666-L676 ◽  
Author(s):  
Aiko Ogawa ◽  
Amy L. Firth ◽  
Weijuan Yao ◽  
Michael M. Madani ◽  
Kim M. Kerr ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Pulmonary Hypertension ◽  
Vascular Remodeling ◽  
Chronic Thromboembolic Pulmonary Hypertension ◽  
Receptor Expression ◽  
Wall Thickening ◽  
Pulmonary Thromboendarterectomy ◽  
Pulmonary Vascular Remodeling ◽  
Phosphorylated Akt ◽  
Thromboembolic Pulmonary Hypertension

Pulmonary vascular remodeling occurs in patients with chronic thromboembolic pulmonary hypertension (CTEPH). One factor contributing to this vascular wall thickening is the proliferation of pulmonary artery smooth muscle cells (PASMC). Store-operated Ca2+ entry (SOCE) and cytosolic free Ca2+ concentration ([Ca2+]cyt) in PASMC are known to be important in cell proliferation and vascular remodeling in pulmonary hypertension. Rapamycin is widely known for its antiproliferative effects in injured coronary arteries. Although several reports have suggested favorable effects of rapamycin in animal models of pulmonary hypertension, no reports have been published to date in human tissues. Here we report that rapamycin has an inhibitory effect on SOCE and an antiproliferative effect on PASMC derived from endarterectomized tissues of CTEPH patients. Cells were isolated from endarterectomized tissues obtained from patients undergoing pulmonary thromboendarterectomy (PTE). Immunohistochemical analysis indicated high deposition of platelet-derived growth factor (PDGF) in tissue sections from PTE tissues and increased PDGF receptor expression. PDGF transiently phosphorylated Akt, mammalian target of rapamycin (mTOR), and p70S6 kinase in CTEPH cells from CTEPH patients. Acute treatment (30 min) with rapamycin (10 nM) slightly increased cyclopiazonic acid (10 μM)-induced Ca2+ mobilization and significantly reduced SOCE. Chronic treatment (24 h) with rapamycin reduced Ca2+ mobilization and markedly inhibited SOCE. The inhibitory effects of rapamycin on SOCE were less prominent in control cells. Rapamycin also significantly reduced PDGF-stimulated cell proliferation. In conclusion, the data from this study indicate the importance of the mTOR pathway in the development of pulmonary vascular remodeling in CTEPH and suggest a potential therapeutic benefit of rapamycin (or inhibition of mTOR) in these patients.

The monocrotaline model of pulmonary hypertension in perspective

2012 ◽  
Vol 302 (4) ◽  
pp. L363-L369 ◽  
Author(s):  
Jose G. Gomez-Arroyo ◽  
Laszlo Farkas ◽  
Aysar A. Alhussaini ◽  
Daniela Farkas ◽  
Donatas Kraskauskas ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Animal Models ◽  
Right Ventricle ◽  
Vascular Remodeling ◽  
Therapeutic Strategies ◽  
Relevant Model ◽  
Right Ventricle Dysfunction ◽  
Ventricular Afterload ◽  
Pulmonary Arterial

Severe forms of pulmonary arterial hypertension (PAH) are characterized by various degrees of remodeling of the pulmonary arterial vessels, which increases the pulmonary vascular resistance and right ventricular afterload, thus contributing to the development of right ventricle dysfunction and failure. Recent years have seen advances in the understanding of the pathobiology of PAH; however, many important questions remain unanswered. Elucidating the pathobiology of PAH continues to be critical to design new effective therapeutic strategies, and appropriate animal models of PAH are necessary to achieve the task. Although the monocrotaline rat model of PAH has contributed to a better understanding of vascular remodeling in pulmonary hypertension, we question the validity of this model as a preclinically relevant model of severe plexogenic PAH. Here we review pertinent publications that either have been forgotten or ignored, and we reexamine the monocrotaline model in the context of human forms of PAH.

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