Intermedin reduces neointima formation by regulating vascular smooth muscle cell phenotype via cAMP/PKA pathway

Zhu, Qing; Ni, Xian-Qiang; Lu, Weiwei; Zhang, Jinsheng; Ren, Jianjun; Wu, Di; Chen, Yao; Zhang, Lin-Shuang; Yu, Yan-Rong; Tang, Chaoshu; Qi, Yongfen

doi:10.1016/j.atherosclerosis.2017.10.011

Cited by 22 publications

(8 citation statements)

References 39 publications

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“…Primary rats VSMCs were isolated and cultured using previously described methods [12]. After VSMCs migrated from tissue pieces in Dulbecco’s minimum essential medium (DMEM; Gibco, Grand Island, NY) supplemented with 20% fetal bovine serum (FBS; Gemini, West Sacramento, CA), they were collected and cultured in DMEM supplemented with 10% FBS, 100 U/mL penicillin, and 100 mg/mL streptomycin.…”

Section: Methodsmentioning

confidence: 99%

Nrf-2 signaling inhibits intracranial aneurysm formation and progression by modulating vascular smooth muscle cell phenotype and function

Shi

Song

et al. 2019

J Neuroinflammation

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BackgroundOxidative stress and vascular smooth muscle cell (VSMC) phenotypic modulation influence intracranial aneurysm (IA) formation and progression. Oxidative stress plays an important role in phenotype switching, and nuclear factor erythroid 2-related factor 2 (Nrf-2) is one of the main antioxidant systems. Unfortunately, little is known about how Nrf-2 signaling influences VSMC phenotype switches during IA pathogenesis.MethodsWe examined the effect of Nrf-2 activation IA on formation and progression in an elastase-induced rat IA model. We also developed a hydrogen peroxide (H2O2)-induced VSMC oxidative damage model. Then, we analyzed VSMC phenotype changes in the setting of Nrf-2 activation or inhibition in vitro. The proliferation, migration ability, and apoptosis rate of VSMCs were tested. Lastly, we measured the expression levels of antioxidant enzymes and inflammatory cytokines downstream of Nrf-2.ResultsNrf-2 activation suppressed IA formation and progression in vivo. We confirmed Nrf-2 nuclear translocation and a VSMC switch from the contractile to synthetic phenotype. Nrf-2 activation inhibited the proliferation, migratory ability, and apoptosis rate enhanced by H2O2. Quantitative real-time polymerase chain reaction (PCR) and western blot analysis revealed that Nrf-2 activation promoted antioxidant enzymes and VSMC-specific marker gene expressions but decreased pro-inflammatory cytokine levels.ConclusionThese results suggest that Nrf-2 exerts protective effects against IA development by preventing VSMCs from changing to a synthetic phenotype.

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Section: Methodsmentioning

confidence: 99%

Nrf-2 signaling inhibits intracranial aneurysm formation and progression by modulating vascular smooth muscle cell phenotype and function

Shi

Song

et al. 2019

J Neuroinflammation

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“… 31 Meanwhile, cAMP/PKA signalling was able to be involved in the progression of atherosclerosis. 32 , 33 However, the relation between EP3 and cAMP/PKA signalling in atherosclerosis development remains largely unknown. Based on the above backgrounds, we aimed to confirm this relation.…”

Section: Discussionmentioning

confidence: 99%

“…found that GLP‐1 improved the neuronal ability in astrocytes by cAMP/PKA 31 . Meanwhile, cAMP/PKA signalling was able to be involved in the progression of atherosclerosis 32,33 . However, the relation between EP3 and cAMP/PKA signalling in atherosclerosis development remains largely unknown.…”

Section: Discussionmentioning

confidence: 99%

E prostanoid receptor‐3 promotes oxidized low‐density lipoprotein‐induced human aortic smooth muscle cells inflammation

Wang

Huang

et al. 2022

ESC Heart Failure

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Aim The progression of atherosclerosis can lead to the occurrence of multiple cardiovascular diseases (coronary heart disease, etc.). E prostanoid receptor‐3 (EP3) is known to participate in the progression of atherosclerosis. This study aimed to investigate the mechanism by which EP3 modulates the development of atherosclerosis. Methods and results ApoE −/− mice were used to construct in vivo model of atherosclerosis. Human aortic smooth muscle cells (HASMCs) were stimulated with oxidized low‐density lipoprotein (ox‐LDL) to construct in vitro model of atherosclerosis. mRNA expressions were assessed by qRT‐PCR, and western blot was applied to assess the protein levels. CCK‐8 assay was applied to assess the cell viability. The inflammatory cytokines levels were assessed by enzyme‐linked immunosorbent assay, and flow cytometry was applied to assess cell apoptosis. In vivo experiment was constructed to investigate the impact of EP3 in atherosclerosis development. L‐798106 (EP3 inhibitor) significantly inhibited the levels of pro‐inflammatory cytokines in atherosclerosis in vivo . EP3 inhibitor (L‐798106) significantly reversed ox‐LDL‐caused HASMCs injury via inhibiting the apoptosis and inflammatory responses ( P < 0.05). The levels of interleukin‐17 (IL‐17) and intercellular adhesion molecule‐1 (ICAM‐1) in HASMCs were elevated by ox‐LDL, whereas L‐798106 or knockdown of cyclic AMP (cAMP) response element‐binding protein (CREB) notably restored this phenomenon ( P < 0.05). EP3 overexpression further aggravated ox‐LDL‐induced inflammation in HASMCs, and EP3 up‐regulated the levels of IL‐17 and ICAM‐1 in ox‐LDL‐treated HASMCs ( P < 0.05). EP3 up‐regulation promoted the inflammatory responses in ox‐LDL‐treated HASMCs through mediation of cAMP/protein kinase A (PKA)/CREB/IL‐17/ICAM‐1 axis ( P < 0.05). Conclusions EP3 inhibitor alleviates ox‐LDL‐induced HASMC inflammation via mediation of cAMP/PKA/CREB/IL‐17/ICAM‐1 axis. Our study might shed new lights on discovering novel strategies against atherosclerosis.

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“… 31 IMD can inhibit oxidative stress and reduce neointima formation by the SMCs. 32 It also causes vasodilation and inhibits the proliferation of aortic SMCs, 33 which is beneficial to inhibit VV stenosis and maintain tissue perfusion. IMD can attenuate AAA development in Ang-II-induced ApoE -/- mouse aneurysm models by inhibiting oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

K-134, a phosphodiesterase 3 inhibitor, reduces vascular inflammation and hypoxia, and prevents rupture of experimental abdominal aortic aneurysms

Unno

Tanaka

Yata

et al. 2020

JVS-Vascular Science

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Objective Abdominal aortic aneurysm (AAA) is a chronic inflammatory disease, which frequently results in fatal rupture; however, no pharmacologic treatment exists to inhibit AAA growth and prevent rupture. In this study, we investigated whether K-134, a novel phosphodiesterase 3 inhibitor, could limit the progression and rupture of AAA using multiple experimental models. Methods A hypoperfusion-induced AAA rat model was developed by inserting of a small catheter and via tight ligation of the infrarenal aorta. Rats were fed with a 0.15% K-134-containing diet (K-134(+) group) or a normal diet (K-134(-) group) from 7 days before the experiment to 28 days after model creation (pretreatment protocol). After the administration period, elastin fragmentation, macrophage infiltration, reactive oxygen species expression, matrix metalloproteinase levels, aneurysmal tissue hypoxia, and adventitial vasa vasorum (VV) stenosis were assessed. In the delayed treatment protocol, rats with AAA >3 mm were randomly divided to K-134(+) or K-134(-) group 7 days after model creation, and the effect of K-134 on suppressing preexisting AAA was examined. Further, elastase-induced rat model and angiotensin II-infused ApoE -/- mouse model were also used to examine the ability of K-134 to prevent rupture. Results K-134 prevented AAA rupture and significantly improved survival in the pretreatment protocol ( P < .01). In the K-134(+) group, elastin degeneration was prevented; macrophage infiltration and reactive oxygen species production were significantly decreased. At 14 days, the enzymatic activity of matrix metalloproteinase-9 was significantly decreased. Further, K-134 inhibited intimal hyperplasia and VV stenosis. Expressions of hypoxic markers, hypoxia-inducible factor-1α, and pimonidazole, in the aneurysmal wall were also attenuated. In the delayed treatment protocol, K-134 also improved survival of rats with preexisting AAA. Similarly, in the elastase-induced rat model and angiotensin II-infused ApoE -/- mouse model, K-134 inhibited rupture and significantly improved survival ( P < .01). Conclusions K-134 prevented the rupture of AAA and improved survival through suppressing inflammatory reaction. The inhibition of intimal hyperplasia in the adventitial VV may be associated with reduced hypoxia in the aneurysmal tissue. (JVS–Vascular Science 2020;1:219-32.) Clinical Relevance This study shows that K-134, a novel phosphodiesterase 3 inhibitor, suppressed abdominal aortic aneurysm (AAA) rupture. Considering that K-134 had already undergone a phase Ⅱ study in the United States for claudication in peripheral artery occlusive disease patients with good tolerance, K-134 may become a promising new therapeutic option for AAAs and could undergo clinical trials for patients with small AAA.

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Intermedin reduces neointima formation by regulating vascular smooth muscle cell phenotype via cAMP/PKA pathway

Cited by 22 publications

References 39 publications

Nrf-2 signaling inhibits intracranial aneurysm formation and progression by modulating vascular smooth muscle cell phenotype and function

Nrf-2 signaling inhibits intracranial aneurysm formation and progression by modulating vascular smooth muscle cell phenotype and function

E prostanoid receptor‐3 promotes oxidized low‐density lipoprotein‐induced human aortic smooth muscle cells inflammation

K-134, a phosphodiesterase 3 inhibitor, reduces vascular inflammation and hypoxia, and prevents rupture of experimental abdominal aortic aneurysms

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