Fasudil dichloroacetate (FDCA), an orally available agent with potent therapeutic efficiency on monocrotaline-induced pulmonary arterial hypertension rats

Qi, Lei; Lv, Tian; Cheng, Yusheng; Yu, Min; Han, Honghao; Kong, Hui; Xie, Wei; Wang, Hong; Zhang, Yihua; Huang, Zhangjian

doi:10.1016/j.bmcl.2019.05.006

Cited by 18 publications

(17 citation statements)

References 24 publications

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“…Strong evidence from cell studies indicates that ROCK is activated [ 19 ] and contributes to PH pathogenesis and its modulation could interfere with the alterations induced in different PH experimental models, using monocrotaline (MCT) [ 49 , 193 , 194 , 195 , 196 , 197 , 198 , 199 , 200 , 201 , 202 , 203 ] or hypoxia [ 35 , 126 , 162 , 198 , 202 , 204 , 205 , 206 ].…”

Section: Rock In Preclinical Models Of Phmentioning

confidence: 99%

ROCK Inhibition as Potential Target for Treatment of Pulmonary Hypertension

Montagnoli

Sudo

et al. 2021

Cells

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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.

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Section: Rock In Preclinical Models Of Phmentioning

confidence: 99%

ROCK Inhibition as Potential Target for Treatment of Pulmonary Hypertension

Montagnoli

Sudo

et al. 2021

Cells

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“…As a positive control, bosentan inhibited SuHxinduced PAH, with significant reductions in RVSP, accompanied by significant reductions in pulmonary vascular remodeling and RV hypertrophy, confirming the validity and reliability of our experimental system. In our previous research, FDCA exhibited a therapeutic effect on monocrotaline-induced PAH in rats, demonstrating a more potent effect than equimolar doses of fasudil or DCA, 19 but the mechanism remained unknown. In this study, by using the SuHx-induced PAH rat model, we observed that FDCA also alleviated the PAH-related hemodynamic and pathological changes mentioned above, confirming the reliable effect of FDCA on pulmonary vascular and RV remodeling in vivo.…”

Section: Discussionmentioning

confidence: 95%

“…Our previous pharmacokinetic parameters demonstrated that FDCA enhanced the plasma concentrations of fasudil, and slightly prolonged the half-life. 19 Compared to the traditional fasudil hydrochloride, salifying with dichloroacetic acid may slightly influence the binding of fasudil with the ROCK protein. 19 However, the effects of FDCA on pulmonary vascular remodeling and vasoconstriction in PAH are still not well understood.…”

Section: Introductionmentioning

confidence: 99%

“…19 Compared to the traditional fasudil hydrochloride, salifying with dichloroacetic acid may slightly influence the binding of fasudil with the ROCK protein. 19 However, the effects of FDCA on pulmonary vascular remodeling and vasoconstriction in PAH are still not well understood. Therefore, we investigated the effects of FDCA on pulmonary hemodynamics, and PA and RV remodeling in a SU5416 plus hypoxia (SuHx)-induced rat model of PAH.…”

Section: Introductionmentioning

confidence: 99%

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Fasudil Dichloroacetate Alleviates SU5416/Hypoxia-Induced Pulmonary Arterial Hypertension by Ameliorating Dysfunction of Pulmonary Arterial Smooth Muscle Cells

Liu¹,

Huang²,

Ding³

et al. 2021

DDDT

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Background: Pulmonary arterial hypertension (PAH) is an incurable disease that urgently needs therapeutic approaches. Based on the therapeutic effects of fasudil and dichloroacetate (DCA) on PAH, we aimed to explore the effects and potential mechanism of a new salt, fasudil dichloroacetate (FDCA), in a SU5416 plus hypoxia (SuHx)-induced rat model of PAH. Methods: The rat model of PAH was established by a single subcutaneous injection of SU5416 (20 mg/kg) followed by hypoxia (10% O 2 ) exposure for 3 weeks. FDCA (15, 45, or 135 mg/kg i.g. daily) or the positive control, bosentan (100 mg/kg i.g. daily), were administered from the first day after SU5416 injection. After 3-week hypoxia, hemodynamic parameters, and histological changes of the pulmonary arterial vessels and right ventricle (RV) were assessed. Additionally, in vitro, the effects of FDCA (50 μM), compared with equimolar doses of fasudil, DCA, or fasudil+DCA, on the proliferation, migration, and contraction of human pulmonary arterial smooth muscle cell (PASMC) under hypoxia (1% O 2 ) were evaluated. Results: FDCA dose-dependently attenuated SuHx-induced PAH, with significant reductions in RV systolic pressure, pulmonary artery wall thickness, pulmonary vessel muscularization, perivascular fibrosis, as well as RV hypertrophy and fibrosis. In vitro, FDCA inhibited hypoxia-induced PASMC proliferation, migration, and contraction to a greater degree than fasudil or DCA alone by restoring mitochondrial function, reducing intracellular Ca 2+ , and inhibiting calcium/calmodulin-dependent kinase (Ca 2+ /CaMK) activity as well as Rho-kinase activity. Conclusion: FDCA ameliorates hypoxia-induced PASMC dysfunction by inhibiting both Ca 2+ /CaMK and Rho-kinase signaling pathways, as well as maintaining mitochondrial homeostasis, thus alleviating SuHx-induced PAH.

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“…Mean pulmonary artery pressure or systolic pulmonary artery pressure were decreased after receiving intravenous or inhaled fasudil treatment in patients with high-altitude PAH, congenital heart diseases or connective tissue diseases associated with PAH [ 66 ]. 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 ].…”

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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Fasudil dichloroacetate (FDCA), an orally available agent with potent therapeutic efficiency on monocrotaline-induced pulmonary arterial hypertension rats

Cited by 18 publications

References 24 publications

ROCK Inhibition as Potential Target for Treatment of Pulmonary Hypertension

ROCK Inhibition as Potential Target for Treatment of Pulmonary Hypertension

Fasudil Dichloroacetate Alleviates SU5416/Hypoxia-Induced Pulmonary Arterial Hypertension by Ameliorating Dysfunction of Pulmonary Arterial Smooth Muscle Cells

Characterization of Contractile Machinery of Vascular Smooth Muscles in Hypertension

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