The cyclic adenosine monophosphate elevating medicine, forskolin, reduces neointimal formation and atherogenesis in mice

Hao, Huifeng; Ma, Xiaoyan; Chen, Hong; Zhu, Liyuan; Xu, Zhenyu; Li, Qiaoling; Xu, Chuansheng; Zhang, Yuze; Peng, Zekun; Wang, Miao

doi:10.1111/jcmm.15476

Cited by 13 publications

(9 citation statements)

References 25 publications

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“…Notably, in 12 patients with stage III (NYHA) congestive cardiomyopathy, forskolin dose-dependently reduced cardiac pre-and afterload values, and led to a reduction in systolic, diastolic, and mean pulmonary artery pressures as well as pulmonary wedge pressure by >50% concomitant with an increase in cardiac output (Baumann et al, 1990). Consistent with a recent report (Hao et al, 2020) from Hao et al, this study demonstrates the ability of forskolin to promote endothelial recovery from vascular injury and indicates its therapeutic applications in disorders associated with vascular injuries, such as in-stent restenosis after treatment for coronary stenosis.…”

Section: Discussionsupporting

confidence: 88%

Zyxin Mediates Vascular Repair via Endothelial Migration Promoted by Forskolin in Mice

et al. 2021

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Background and Purpose: Endothelial repair upon vascular injury is critical for the protection of vessel integrity and prevention of the development of vascular disorders, but the underlying mechanisms remain poorly understood. In this study, we investigated the role of zyxin and its associated cyclic adenosine monophosphate (cAMP) signaling in the regulation of re-endothelialization after vascular injury.Experimental Approach: In zyxin-/- and wild-type mice, wire injury of the carotid artery was carried out, followed by Evans blue staining, to evaluate the re-endothelialization. Mice with endothelium-specific zyxin knockout were used to further determine its role. An in vitro wound-healing assay was performed in primary human endothelial cells (ECs) expressing zyxin-specific short-hairpin RNAs (shRNAs) or scrambled controls by measuring cell migration and proliferation. The effects of the cAMP signaling agonist forskolin were assessed.Key Results: The re-endothelialization of the injured carotid artery was impaired in zyxin-deficient mice, whereas the rate of cell proliferation was comparable with that in wild-type controls. Furthermore, endothelium-specific deletion of zyxin led to similar phenotypes. Knockdown of zyxin by shRNAs in primary human ECs significantly reduced cell migration in the wound-healing assay. Notably, forskolin enhanced endothelial migration in a dose-dependent manner, and this was dependent on zyxin through its interaction with vasodilator-stimulated phosphoprotein. In addition, forskolin promoted the re-endothelialization of the injured carotid artery, and this was compromised by zyxin deficiency.Conclusion and Implications: This study reveals zyxin as a new player in endothelial repair, which is promoted by forskolin, after vascular injury. Thus, zyxin-mediated signaling might be a potential treatment target for diseases involving vascular injury.

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Section: Discussionsupporting

confidence: 88%

Zyxin Mediates Vascular Repair via Endothelial Migration Promoted by Forskolin in Mice

et al. 2021

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“…It has been reported that only free cholesterol can be transported by cholesterol transporters in the lysosome such as Niemann–Pick type C related protein 1 or 2 (NPC-1 or NPC-2) for further metabolism and efflux intracellularly; once the free cholesterol is converted into CCs, they cannot be transported by NPC-1 or NPC-2, leading to the accumulation of massive CCs in the lysosome and cell apoptosis. , Therefore, the prevention of CC formation or the dissolution of CCs to free cholesterol in the lysosome to enhance the disposal of cholesterol will be of great clinical significance for atherosclerotic therapy. As confirmed by a recent study, the development of atherosclerosis can be halted by the treatment of cAMP-enhancing agents (such as forskolin, which catalyzes the production of cAMP, , and rolipram, which prevents the degradation of cAMP) to inhibit the formation of CCs and promote cholesterol efflux in endothelial cells . However, for macrophages or foam cells, which are the major cholesterol-laden cells in atherosclerotic plaque, none of the clinical drugs have been used to remove lysosomal CCs in macrophages or foam cells for the treatment of atherosclerosis.…”

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confidence: 99%

Poly-β-cyclodextrin Supramolecular Nanoassembly with a pH-Sensitive Switch Removing Lysosomal Cholesterol Crystals for Antiatherosclerosis

Zhang

Gong

et al. 2021

Nano Lett.

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Cholesterol crystals (CCs), originally accumulating in the lysosome of cholesterol-laden cells, can aggravate the progression of atherosclerosis. β-cyclodextrin (CD) is a potent cholesterol acceptor or CC solubilizer. However, the random extraction of cholesterol impedes the in vivo application of CD for removing lysosomal CCs. Here, we exploit poly-β-cyclodextrin (pCD) as a lysosomal CC solubilizer and dextran sulfate grafted with benzimidazole (BM) as a pH-sensitive switch (pBM) to selfassemble into a supramolecular nanoassembly (pCD/pBM-SNA). The CD cavity in pCD/pBM-SNA can be efficiently sealed by hydrophobic BM at pH 7.4 (OFF). After it enters the lysosome, pCD/pBM-SNA disassembles, recovers the CD cavity to dissolve CCs into free cholesterol due to the protonation of BM (ON), and reduces CCs, finally enhancing the cholesterol efflux and promoting atherosclerosis regression. Our findings provide an "OFF−ON" tactic to remove lysosomal CCs for antiatherosclerosis as well as other diseases such as Niemann−Pick type C diseases with excessive cholesterol accumulation in the lysosome.

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“…To examine the effect of RIPK1 inhibition on the development of advanced atherogenesis, we used a mouse model ( ApoE SA / SA ) that exhibits both hypercholesterolemia and hypertension upon induction and develop advanced atherosclerotic lesions including those in coronary arteries ( 20 ). Eight-week-old male ApoE SA / SA mice were administered with a western diet (21% fat and 0.2% cholesterol) mixed with or without GSK547 at a dose of 10 mg/kg/day, and with doxycycline (Dox)-containing water to induce hypertension.…”

Section: Resultsmentioning

confidence: 99%

“…Eight-weeks-old male and female ApoE SA / SA mice on C57BL/6J background, which are deficient in Apoe gene and with SR-BI knockdown and inducible angiotensin II expression (by doxycycline administration) were used in the present study ( 20 ). For atherosclerosis study, ApoE SA / SA mice were fed a Western diet (TD 88137; Harlan Teklad) which contains GSK547 powder [GlaxoSmithKline; 10 mg/kg/day (0.083 g/kg food)].…”

Section: Methodsmentioning

confidence: 99%

Stage-Dependent Impact of RIPK1 Inhibition on Atherogenesis: Dual Effects on Inflammation and Foam Cell Dynamics

Zhang

Huang

et al. 2021

Front. Cardiovasc. Med.

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Objective: Atherosclerosis is an arterial occlusive disease with hypercholesterolemia and hypertension as common risk factors. Advanced-stage stenotic plaque, which features inflammation and necrotic core formation, is the major reason for clinical intervention. Receptor interacting serine/threonine-protein kinase 1 (RIPK1) mediates inflammation and cell death and is expressed in atherosclerotic lesions. The role of RIPK1 in advanced-stage atherosclerosis is unknown.Approach and Results: To investigate the effect of RIPK1 inhibition in advanced atherosclerotic plaque formation, we used ApoESA/SA mice, which exhibit hypercholesterolemia, and develop angiotensin-II mediated hypertension upon administration of doxycycline in drinking water. These mice readily develop severe atherosclerosis, including that in coronary arteries. Eight-week-old ApoESA/SA mice were randomized to orally receive a highly selective RIPK1 inhibitor (RIPK1i, GSK547) mixed with a western diet, or control diet. RIPK1i administration reduced atherosclerotic plaque lesion area at 2 weeks of treatment, consistent with suppressed inflammation (MCP-1, IL-1β, TNF-α) and reduced monocyte infiltration. However, administration of RIPK1i unexpectedly exacerbated atherosclerosis at 4 weeks of treatment, concomitant with increased macrophages and lipid deposition in the plaques. Incubation of isolated macrophages with oxidized LDL resulted in foam cell formation in vitro. RIPK1i treatment promoted such foam cell formation while suppressing the death of these cells. Accordingly, RIPK1i upregulated the expression of lipid metabolism-related genes (Cd36, Ppara, Lxrα, Lxrb, Srebp1c) in macrophage foam cells with ABCA1/ABCG1 unaltered. Furthermore, RIPK1i treatment inhibited ApoA1 synthesis in the liver and reduced plasma HDL levels.Conclusion: RIPK1 modulates the development of atherosclerosis in a stage-dependent manner, implicating both pro-atherosclerotic (monocyte infiltration and inflammation) and anti-atherosclerotic effects (suppressing foam cell accumulation and promoting ApoA1 synthesis). It is critical to identify an optimal therapeutic duration for potential clinical use of RIPK1 inhibitor in atherosclerosis or other related disease indications.

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The cyclic adenosine monophosphate elevating medicine, forskolin, reduces neointimal formation and atherogenesis in mice

Cited by 13 publications

References 25 publications

Zyxin Mediates Vascular Repair via Endothelial Migration Promoted by Forskolin in Mice

Zyxin Mediates Vascular Repair via Endothelial Migration Promoted by Forskolin in Mice

Poly-β-cyclodextrin Supramolecular Nanoassembly with a pH-Sensitive Switch Removing Lysosomal Cholesterol Crystals for Antiatherosclerosis

Stage-Dependent Impact of RIPK1 Inhibition on Atherogenesis: Dual Effects on Inflammation and Foam Cell Dynamics

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