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Inhibition of the cyclophilin A-CD147 interaction attenuates right ventricular injury and dysfunction after acute pulmonary embolism in rats.

ABSTRACT: Acute pulmonary embolism (APE)-induced inflammation contributes to cardiomyocyte injury and dysfunction in the right ventricle (RV) of the heart. The interactions of cyclophilin A with its ligand extracellular matrix metalloproteinase inducer (EMMPRIN or CD147) may be involved in this inflammatory process. To this end, here we induced APE by intravenous injections of microspheres in Sprague-Dawley rats. We found that after the APE, cyclophilin A and CD147 levels increased synchronously in RV tissue following APE and peaked at 24 h. The cyclophilin A inhibitor cyclosporine A attenuated the APE-induced cyclophilin A levels, and a monoclonal antibody of CD147 (anti-CD147) abrogated the elevation of CD147 in the RV but not the increase of cyclophilin A. Importantly, treatment with cyclosporine A, anti-CD147, or both attenuated APE-induced increases in RV systolic pressure, plasma cardiac troponin-I (cTnI) concentrations, the RV/left ventricle diameter ratio, and the Tei index, measured by echocardiography 24 h after APE induction. These beneficial effects were associated with reduced RV neutrophil infiltration and prevention of matrix metalloproteinase 9 (MMP-9) and MMP-2 activation. These findings suggested that inhibiting the cyclophilin A-CD147 interaction attenuates APE-associated RV cardiomyocyte injury and dysfunction by suppressing inflammation. We further proposed that cyclophilin A and CD147 might participate in APE-induced pathological processes by partly activating the ERK1/2 kinase-nuclear factor-?B pathway. We conclude that the cyclophilin A-CD147 interaction may represent a potential therapeutic target for managing APE.

SUBMITTER: Lu G

PROVIDER: S-EPMC6078437 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Inhibition of the cyclophilin A-CD147 interaction attenuates right ventricular injury and dysfunction after acute pulmonary embolism in rats.

Lu Guangdong G Jia Zhenyu Z Zu Qingquan Q Zhang Jinxing J Zhao Linbo L Shi Haibin H

The Journal of biological chemistry 20180618 31

Acute pulmonary embolism (APE)-induced inflammation contributes to cardiomyocyte injury and dysfunction in the right ventricle (RV) of the heart. The interactions of cyclophilin A with its ligand extracellular matrix metalloproteinase inducer (EMMPRIN or CD147) may be involved in this inflammatory process. To this end, here we induced APE by intravenous injections of microspheres in Sprague-Dawley rats. We found that after the APE, cyclophilin A and CD147 levels increased synchronously in RV tis ...[more]

PMID: 29914983

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Project description:BackgroundIn acute pulmonary embolism, chest computed tomography angiography derived metrics, such as the right ventricle (RV): left ventricle ratio are routinely used for risk stratification. Paucity of intraparenchymal blood vessels has previously been described, but their association with clinical biomarkers and outcomes has not been studied. We sought to determine if small vascular volumes measured on computed tomography scans were associated with an abnormal RV on echocardiography and mortality. We hypothesized that decreased small venous volume would be associated with greater RV dysfunction and increased mortality.MethodsA retrospective cohort of patients with intermediate risk pulmonary embolism admitted to Brigham and Women's Hospital between 2009 and 2017 was assembled, and clinical and radiographic data were obtained. We performed 3-dimensional reconstructions of vasculature to assess intraparenchymal vascular volumes. Statistical analyses were performed using multivariable regression and cox proportional hazards models, adjusting for age, sex, lung volume, and small arterial volume.ResultsSeven hundred twenty-two subjects were identified of whom 573 had documented echocardiography. A 50% reduction in small venous volume was associated with an increased risk of RV dilation (relative risk: 1.38 [95% CI, 1.18-1.63], P<0.001), RV dysfunction (relative risk: 1.62 [95% CI, 1.36-1.95], P<0.001), and RV strain (relative risk: 1.67 [95% CI, 1.37-2.04], P<0.001); increased cardiac biomarkers, and higher 30-day and 90-day mortality (hazard ratio: 2.50 [95% CI, 1.33-4.67], P=0.004 and hazard ratio: 1.84 [95% CI, 1.11-3.04], P=0.019, respectively).ConclusionsLoss of small venous volume quantified from computed tomography angiography is associated with increased risk of abnormal RV on echocardiography, abnormal cardiac biomarkers, and higher risk of 30- and 90-day mortality. Small venous volume may be a useful marker for assessing disease severity in acute pulmonary embolism.

Project description:BackgroundThe cardioprotective properties of sevoflurane have been reported in studies of the left ventricle. However, whether this volatile anesthetic would also be beneficial for pulmonary vascular remodeling and associated right ventricular hypertrophy (RVH) remained to be explored. Here, we investigated the potential benefit of sevoflurane to right heart function in experimental pulmonary arterial hypertension (PAH).MethodsAdult Wistar rats received one dose peritoneal injection of monocrotaline (MCT, 60 mg/kg) or the equal volume of normal saline. Two weeks later, rats were treated with sevoflurane or sham exposure. PAH status and cardiac function were assessed by echocardiography weekly, and the body weight (BW) was monitored every week. After 6 weeks of exercise, Fulton's index calculation, histological observation, IL-6 and TNF-α immunohistochemical analyses, evaluation of MDA, SOD and GSH-Px levels and NF-κB and MAPK active determination were performed in lung and RV tissue samples.ResultsMCT induced pulmonary vascular remodeling, RVH, increased Fulton's index (P<0.01), and right ventricular failure (RVF) in rats. Animals inhaled sevoflurane had an increased cardiac output (P<0.05) and lower incidence of RVF (P<0.05). Also, these animals had a reduced RVEDD, RVWTd and PAID (P<0.05), increased PV (P<0.05), reduced wall thickness and vascular wall area of pulmonary small vascular (vascular external diameter 50-150 um) (P<0.01), reduced RV fibrosis, and increased RV cardiomyocyte area (P<0.01). Furthermore, sevoflurane reduced IL-6 and TNF-α expression in lungs and heart (P<0.01), decreased level of MDA (P<0.01) and increased activity of SOD and GSH-Px (P<0.01). In addition, it decreased the activities of NF-κB and MAPK pathways (P<0.01).ConclusionSevoflurane reduces pulmonary vascular remodeling and RVH in PAH induced by MCT in rats. This effect is likely due to down-regulation of inflammatory factors IL-6 and TNF-α, reduced level of oxidative stress and the inhibition of NF-κB and MAPK pathways.

Project description:BackgroundRight ventricular dysfunction (RVD) is associated with adverse outcomes of acute pulmonary embolism (PE). However, there are no studies describing the long-term, full-spectrum right ventricular parameters on morphology, pressure and function at certain follow-up time points after PE onset. More exploration of right ventricular function would provide useful clues for long-term management of patients with PE.MethodsFor this systematic review and meta-analysis, we completed a literature search in Pubmed, EMBASE and WebofScience (from Jan 1st, 1998 to April 20th, 2023). Studies of patients with acute PE followed-up longer than 3 months with right ventricle assessment and written in English-language were included. Right ventricular function was assessed by either echocardiography or computed tomographic pulmonary angiography (CTPA). The primary outcome was structural and functional parameters of the right ventricle, and the secondary outcomes were functional assessments [New York Heart Association (NYHA) functional classification and 6-min walk test distance (6 MWD)], at each follow-up time points. Random effect meta-analyses were performed using R software (PROSPERO: CRD42023433332).FindingsA total of 33 studies (3920 patients) were included in the final analysis. The 3-month, 6-month and 1-year prevalence of right ventricular dysfunction (RVD) was 0.34 [95% confidence interval (CI) 0.21-0.48, I2 = 96%], 0.26 (95% CI 0.17-0.36, I2 = 93%) and 0.34 (95% CI 0.19-0.48, I2 = 94%), respectively. Pooled tricuspid annulus plane systolic excursion (TAPSE), right ventricular to left ventricular diameter (RV/LV) ratio and pulmonary artery systolic pressure (PASP) at 1-year was 21.80 mm (95% CI 20.08-23.52, I2 = 93%), 0.64 (95% CI 0.48-0.81, I2 = 92%) and 27.33 mmHg (95% CI 18.88-35.78) (I2 = 96%), respectively. The proportion of NYHA III-IV was 0.06 (95% CI 0.0-0.12) and the pooled 6 MWD was 462.98 m (95% CI 447.55-478.41) over 1 year. Patients treated with thrombolysis had lower prevalence of RVD (1-year 0.17 and 0.07 in systemic thrombolysis and catheter-directed thrombolysis, respectively) than those treated with anticoagulation therapy alone (1-year 0.24) but the pooled risk ratio (RR) was not statistically significant.InterpretationAlthough the conclusion of this study may be limited by its high heterogeneity from varied study designs, inclusion criteria and definition of RVD of each study, our findings suggested that persistent RVD and functional impairment were of considerable high prevalence during long-term follow-up after acute PE. Treatment strategy may influence the prevalence of long-term RVD.FundingThis study is supported by CAMS Innovation Fund for Medical Sciences (CIFMS) (2021-I2M-1-061). The National Key Research and Development Program of China (2016YFC0905600). National High Level Hospital Clinical Research Funding (2022-NHLHCRF-LX-01-02-03). CAMS Institute of Respiratory Medicine Grant for Young Scholars (2023-ZF-8).

Dataset Information

Inhibition of the cyclophilin A-CD147 interaction attenuates right ventricular injury and dysfunction after acute pulmonary embolism in rats.

Publications

Inhibition of the cyclophilin A-CD147 interaction attenuates right ventricular injury and dysfunction after acute pulmonary embolism in rats.

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