Extracellular Cyclophilin A, Especially Acetylated, Causes Pulmonary Hypertension by Stimulating Endothelial Apoptosis, Redox Stress, and Inflammation

Xue, Chao; Sowden, Mark P.; Berk, Bradford C.

doi:10.1161/atvbaha.117.309212

Cited by 57 publications

(52 citation statements)

References 39 publications

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“…Our results showed significant upregulation of CLDN1 (Figure f,g; p < 0.01) in PAH models. Moreover, cell inflammatory signals like IkBα have been used to access cell dysfunction in PAH model in Xue, Sowden, and Berk () research too. We measured the protein expression of IkBα and p‐IkBα.…”

Section: Resultsmentioning

confidence: 99%

MicroRNA‐140‐5p targeting tumor necrosis factor‐α prevents pulmonary arterial hypertension

Zhu

Zhang

Yin

et al. 2018

Journal Cellular Physiology

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Background Pulmonary arterial hypertension (PAH) is characterized by the apoptosis resistance and hyperproliferation of pulmonary artery smooth muscle cells (PASMCs). Its pathogenesis has not been revealed. Here, we carried out experiments to investigate the functions of miR‐140‐5p and tumor necrosis factor‐α (TNF‐α). Methods We selected GSE703 from Gene Expression Omnibus (GEO) Database to conduct microarray analysis using R software and Gene Set Enrichment Analysis (GSEA). Combing bioinformatics results, the upregulation of miR‐140‐5p inhibited PAH progression through targeting TNF‐α. RNA expression was measured by quantitative real‐time polymerase chain reaction (RT‐qPCR) and protein level was measured by western blot analysis and enzyme‐linked immunosorbent assays (ELISA). We conducted monocrotaline (MCT) injection to rats to form PAH animal models. The lung tissues were observed by hematoxylin–eosin (HE) staining and Sirius red‐picric acid staining. Right ventricular systolic pressure (RVSP) and the ratio of right ventricle (RV)‐to‐left ventricle (LV) plus septum (S) weight (RV/[LV + S]) were measured in MCT‐induced animal models. Overexpression of miR‐140‐5p and TNF‐α were utilized to research the proliferation, migration, and phenotypic variation of hypoxia‐mediated PASMCs. The binding between miR‐140‐5p and TNF‐α 3′‐untranslated region (3′‐UTR) was confirmed via luciferase reporter assay. Results Downregulation of miR‐140‐5p and upregulation of TNF‐α were observed in PAH rat model and hypoxia‐mediated PASMCs. And we proved that overexpression of miR‐140‐5p could suppress the proliferation, migration, and phenotypic variation of PASMCs, therefore inhibiting PAH pathogenesis. Luciferase assay verified that miR‐140‐5p targeted TNF‐α directly. A converse correlation was also shown between miR‐140‐5p and TNF‐α in PASMCs. Conclusions miR‐140‐5p and TNF‐α are important regulators in PAH pathology and may serve as a therapeutic target for PAH.

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Section: Resultsmentioning

confidence: 99%

MicroRNA‐140‐5p targeting tumor necrosis factor‐α prevents pulmonary arterial hypertension

Zhu

Zhang

Yin

et al. 2018

Journal Cellular Physiology

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“…To this end, several experiments have been conducted. Xue et al 63 demonstrated that endothelium-specific overexpression of cyclophilin A, which has been shown to induce vascular injury through multiple mechanisms, including endothelial dysfunction and vascular smooth muscle proliferation, caused spontaneous PAH in mice in vivo. Mechanistically, extracellular cyclophilin A induced endothelial cell dysfunction via endothelial apoptosis, inflammation, and oxidative stress production.…”

Section: Pulmonary Hypertensionmentioning

confidence: 99%

“…Mechanistically, extracellular cyclophilin A induced endothelial cell dysfunction via endothelial apoptosis, inflammation, and oxidative stress production. 63 Meloche et al 64 proposed a mechanism by which coronary artery disease develops in PAH patients; expression of bromodomaincontaining protein 4, which promotes atherogenic processes through inflammatory responses in endothelial cells, was increased not only in the lungs of PAH patients but also in their coronary arteries, promoting vascular remodeling through enhanced proliferation and suppressed apoptosis in vascular smooth muscle cells. These findings provide a clue for understanding why PAH patients are likely to be complicated by coronary artery disease even in the absence of metabolic disorders.…”

Section: Pulmonary Hypertensionmentioning

confidence: 99%

Endothelial Functions

Godo

Shimokawa

2017

ATVB

395

258

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e108T he endothelium plays important roles in modulating vascular tone by synthesizing and releasing an array of endothelium-derived relaxing factors, including vasodilator prostaglandins, NO, and endothelium-dependent hyperpolarization (EDH) factors, as well as endothelium-derived contracting factors.1,2 Such redundant mechanisms, like endogenous hyperglycemic hormones, are advantageous for ensuring proper maintenance of vascular tone under pathological conditions, where one of the vasoactive factor-mediated responses is compromised favoring a vasoconstrictor, prothrombotic, and proinflammatory state. Endothelial dysfunction is mainly caused by reduced production or action of endothelium-derived relaxing factors and could be an initial step toward cardiovascular disease.1 Indeed, evaluation of endothelial functions in humans has attracted much attention in the clinical settings because it serves as an excellent surrogate marker of cardiovascular events. For instance, endothelial dysfunction, as evaluated by impaired flow-mediated dilation of the brachial artery or digital reactive hyperemia index in peripheral arterial tonometry, is associated with future cardiovascular events in patients with coronary artery disease, 3-5 and 1-SD decrease in flow-mediated dilation or reactive hyperemia index is associated with doubling of cardiovascular event risk. 6 These observations suggest that endothelial function in peripheral vascular beds could predict future cardiovascular events.In this review, we will sum up the current advances and trends in the research on endothelial functions from bench to bedside with particular focus on recent publications in Arteriosclerosis, Thrombosis, and Vascular Biology. Earlier highlights of the journal on endothelial biology are extensively summarized in some review articles. 7-9 Emerging Modulators of Endothelial Functions Shear StressAs Lüscher and Corti 10 described in an editorial, flow is the signal of life. This physical force is sensed by the endothelium lining internal surface of the whole cardiovascular system to be translated into numerous downstream signaling pathways in a moment to moment manner in response to diverse physiological demands in the body. Indeed, shear stress is one of the important physiological cues that make endothelial cells synthesize and release endothelium-derived relaxing factors to cause relaxation of underlying vascular smooth muscle and vasodilatation. In this context, novel mechanisms of endothelial mechanotransduction in health and disease have been unveiled and summarized in a review series published recently in Arteriosclerosis, Thrombosis, and Vascular Biology. 11,12 Briefly, Zhou et al 12 emphasized the distinct roles of atheroprotective laminar or pulsatile shear stress versus atheroprone oscillatory shear stress or disturbed flow and discussed in detail the underlying molecular mechanisms that are dependent on these patterns of flow. Abe and Berk 11 further reviewed the current knowledge on the dual roles of shear stress with emphasis plac...

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“…In addition, CyPA and Bsg were also up-regulated in the lung from cROCK1 −/− mice after pressure overload, in which vascular remodeling and postcapillary PH were significantly developed. Both CyPA and Bsg are known to accelerate PH by stimulating oxidative stress and inflammation (33,48). Similarly, CyPA and Bsg in the lung may also contribute to the development of postcapillary PH, which is primarily caused by the passive backward transmission of elevated filling pressure induced by LV dysfunction.…”

Section: Different Roles Of Rock1 and Rock2 In Ros Production Inmentioning

confidence: 99%

“…Celastrol suppresses the activity of NF-κB, which up-regulates inflammatory genes and enhances cardiac hypertrophy (52) and pulmonary vascular remodeling (53). As CyPA and Bsg activate NF-κB (48,54), the effect of celastrol on HF may have been due to the inhibition of CyPA/Bsg-NF-κB axis, which enhances ROS generation and inflammatory status. However, the beneficial effects of celastrol may involve mechanisms other than reducing CyPA and Bsg.…”

Section: Celastrol As a Novel Therapeutic Agent For Hf Patients With mentioning

confidence: 99%

Different roles of myocardial ROCK1 and ROCK2 in cardiac dysfunction and postcapillary pulmonary hypertension in mice

Sunamura

Satoh

Kurosawa

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Although postcapillary pulmonary hypertension (PH) is an important prognostic factor for patients with heart failure (HF), its pathogenesis remains to be fully elucidated. To elucidate the different roles of Rho-kinase isoforms, ROCK1 and ROCK2, in cardiomyocytes in response to chronic pressure overload, we performed transverse aortic constriction (TAC) in cardiac-specific ROCK1-deficient () and ROCK2-deficient () mice. Cardiomyocyte-specific ROCK1 deficiency promoted pressure-overload-induced cardiac dysfunction and postcapillary PH, whereas cardiomyocyte-specific ROCK2 deficiency showed opposite results. Histological analysis showed that pressure-overload-induced cardiac hypertrophy and fibrosis were enhanced in mice compared with controls, whereas cardiac hypertrophy was attenuated in mice after TAC. Consistently, the levels of oxidative stress were up-regulated in hearts and down-regulated in hearts compared with controls after TAC. Furthermore, cyclophilin A (CyPA) and basigin (Bsg), both of which augment oxidative stress, enhanced cardiac dysfunction and postcapillary PH in mice, whereas their expressions were significantly lower in mice. In clinical studies, plasma levels of CyPA were significantly increased in HF patients and were higher in patients with postcapillary PH compared with those without it. Finally, high-throughput screening demonstrated that celastrol, an antioxidant and antiinflammatory agent, reduced the expressions of CyPA and Bsg in the heart and the lung, ameliorating cardiac dysfunction and postcapillary PH induced by TAC. Thus, by differentially affecting CyPA and Bsg expressions, ROCK1 protects and ROCK2 jeopardizes the heart from pressure-overload HF with postcapillary PH, for which celastrol may be a promising agent.

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Extracellular Cyclophilin A, Especially Acetylated, Causes Pulmonary Hypertension by Stimulating Endothelial Apoptosis, Redox Stress, and Inflammation

Cited by 57 publications

References 39 publications

MicroRNA‐140‐5p targeting tumor necrosis factor‐α prevents pulmonary arterial hypertension

MicroRNA‐140‐5p targeting tumor necrosis factor‐α prevents pulmonary arterial hypertension

Endothelial Functions

Different roles of myocardial ROCK1 and ROCK2 in cardiac dysfunction and postcapillary pulmonary hypertension in mice

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