ROCK Inhibition as Potential Target for Treatment of Pulmonary Hypertension

Montagnoli, Tadeu L.; J, da Silva; Sudo, Susumu Z.; Santos, Aimeé D.; Gomide, Gabriel F; Sá, Mauro Paes Leme de; Zapata‐Sudo, Gisele

doi:10.3390/cells10071648

Cited by 23 publications

(18 citation statements)

References 221 publications

(397 reference statements)

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“…Suppression of MLC phosphorylation via inhibition of Akt can relax the constriction of PASMCs [ 14 ]. Several ROCK inhibitors can suppress the elevation RVSP and the development of vascular remodeling in experimental PAH models induced by hypoxic exposure or MCT treatment [ 26 , 40 , 41 ], which supports our results. Thus, the inhibition of the Akt pathway by H-1337 treatment may be associated with decreased RVSP in Su/Hx rats.…”

Section: Discussionsupporting

confidence: 90%

“…In the present study, 10 μM H-1337M1 suppressed the activation of mTOR and the cell viability of hPASMCs at a level similar to that of LY294002, although the effects of 1 and 10 μM H-1337 and 1 μM H-1337 M1 on mTOR were moderate. It has been known that activated MLC is also responsible for the proliferation of PASMCs [ 26 ]. Therefore, inhibition of both the MLC pathway with H-1337 and H-1337M1 might be related to the suppression of hPASMC proliferation.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, H-1337 and its metabolite H-1337M1 were found to have inhibitory activities on Akt in a preliminary experiment. Although inhibition of ROCK or Akt pathways has been shown to suppress the development of PAH [ 20 , 26 ], the effects of inhibition of both ROCK and Akt pathways on PAH have not been investigated. Thus, we hypothesized that H-1337 may exert antiproliferative effects on vascular lesion cells and pulmonary vasodilative effects via inhibition of both ROCK and Akt signaling.…”

Section: Introductionmentioning

confidence: 99%

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

Shoji

Yoshida

Jujo

et al. 2021

Cells

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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.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Shoji

Yoshida

Jujo

et al. 2021

Cells

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“…Hypoxia increased Cd146, Rgs4, Rgs5, Nox4 , and Rock1 expression in smooth muscle cells [37-40], with Wt and Notch3 -Null cells exhibiting similar profiles (Fig. 3a) [37, 41-43]. Hypoxia increased Bnip3 expression in both endothelial cells and smooth muscle cell clusters, with endothelial cells exhibiting a more robust increase [44].…”

Section: Resultsmentioning

confidence: 99%

Single-Cell RNA Sequencing Reveals Novel Genes Regulated by Hypoxia in the Lung Vasculature

et al. 2022

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Pulmonary arterial hypertension (PAH) is a chronic progressive disease with significant morbidity and mortality. The disease is characterized by vascular remodeling that includes increased muscularization of distal blood vessels and vessel stiffening associated with changes in extracellular matrix deposition. In humans, chronic hypoxia causes PAH, and hypoxia-induced rodent models of PAH have been used for years to study the disease. With the development of single-cell RNA sequencing technology, it is now possible to examine hypoxia-dependent transcriptional changes in vivo at a cell-specific level. In this study, we used single-cell RNA sequencing to compare lungs from wild-type (Wt) mice exposed to hypoxia for 28 days to normoxia-treated control mice. We additionally examined mice deficient for <i>Notch3</i>, a smooth muscle-enriched gene linked to PAH. Data analysis revealed that hypoxia promoted cell number changes in immune and endothelial cell types in the lung, activated the innate immunity pathway, and resulted in specific changes in gene expression in vascular cells. Surprisingly, we found limited differences in lungs from mice deficient for <i>Notch3</i> compared to Wt controls. These findings provide novel insight into the effects of chronic hypoxia exposure on gene expression and cell phenotypes in vivo and identify unique changes to cells of the vasculature.

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“…In addition to the inhibition of RhoA-ROCK directly by fasudil, there are many other potential approaches to inhibit the RhoA-ROCK axis in PAH, such as the aminofurazan derivative drug, SB-772077-B, simvastatin [ 64 ], resveratrol [ 67 ], Compound 3 (trans-6-((4-aminocyclohexyl)amino)-5-fluoro-2-methoxynicotinamide) [ 68 ] and fasudil dichloroacetate [ 69 ]. The roles of RhoA/Rho-kinase signaling in PH and treatment have been reviewed [ 60 , 64 , 70 , 71 , 72 , 73 ]. Recently, new findings have also been established.…”

Section: Ca 2+ Sensitization In Hypertensionmentioning

confidence: 99%

Characterization of Contractile Machinery of Vascular Smooth Muscles in Hypertension

Yang

Hori

2021

Life

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Hypertension is a key risk factor for cardiovascular disease and it is a growing public health problem worldwide. The pathophysiological mechanisms of vascular smooth muscle (VSM) contraction contribute to the development of hypertension. Calcium (Ca2+)-dependent and -independent signaling mechanisms regulate the balance of the myosin light chain kinase and myosin light chain phosphatase to induce myosin phosphorylation, which activates VSM contraction to control blood pressure (BP). Here, we discuss the mechanism of the contractile machinery in VSM, especially RhoA/Rho kinase and PKC/CPI-17 of Ca2+ sensitization pathway in hypertension. The two signaling pathways affect BP in physiological and pathophysiological conditions and are highlighted in pulmonary, pregnancy, and salt-sensitive hypertension.

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ROCK Inhibition as Potential Target for Treatment of Pulmonary Hypertension

Cited by 23 publications

References 221 publications

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

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

Single-Cell RNA Sequencing Reveals Novel Genes Regulated by Hypoxia in the Lung Vasculature

Characterization of Contractile Machinery of Vascular Smooth Muscles in Hypertension

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