Interleukin-6 is independently associated with right ventricular function in pulmonary arterial hypertension

Prins, Kurt W.; Archer, Stephen L.; Pritzker, Marc; Rose, Lauren; Weir, Ε. Kenneth; Sharma, Alok; Thenappan, Thenappan

doi:10.1016/j.healun.2017.08.011

Cited by 78 publications

(71 citation statements)

References 44 publications

(54 reference statements)

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“…We did not further investigate the detailed mechanism of a potential right ventricular maladaptation after injection of EC clones. However, our finding of increased pulmonary expression of IL-6 in the cHx + EC clones group provides one potential explanation for right ventricular maladaptation as increased IL-6 levels have been associated with impaired right ventricular adaption in two studies, including the Multi-Ethnic Study of Atherosclerosis (MESA)-RV study 50,51 . Second, the tail vein injection of in vitro clonally expanded ECs is an artificial means to test our hypothesis that clonally selected CD117 + ECs contribute to the occlusive pulmonary arteriopathy in PAH.…”

Section: Discussionmentioning

confidence: 78%

Clonally selected primitive endothelial cells promote occlusive pulmonary arteriopathy and severe pulmonary hypertension in rats exposed to chronic hypoxia

Bhagwani

Farkas

Harmon

et al. 2020

Sci Rep

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one current concept suggests that unchecked proliferation of clonally selected precursors of endothelial cells (ecs) contribute to severe pulmonary arterial hypertension (pAH). We hypothesized that clonally selected ECs expressing the progenitor marker CD117 promote severe occlusive pulmonary hypertension (PH). The remodelled pulmonary arteries of PAH patients harboured CD117 + ecs. Rat lung CD117 + ecs underwent four generations of clonal expansion to enrich hyperproliferative ecs. The resulting clonally enriched ECs behaved like ECs, as measured by in vitro and in vivo angiogenesis assays. The same primitive ECs showed a limited ability for mesenchymal lineage differentiation. Endothelial differentiation and function were enhanced by blocking TGF-β signalling, promoting bone morphogenic protein (BMP) signalling. The transplantation of the EC clones caused arterio-occlusive PH in rats exposed to chronic hypoxia. these ec clones engrafted in the pulmonary arteries. Yet cessation of chronic hypoxia promoted lung cell apoptosis and resolution of vascular lesions. In conclusion, this is to the best of our knowledge, the first report that clonally enriched primitive ECs promote occlusive pulmonary arteriopathy and severe pH. these primitive ec clones further give rise to cells of endothelial and mesenchymal lineage as directed by BMP and TGF-β signaling. Pulmonary arterial hypertension (PAH) remains a devastating disease with dismal prognosis. The pulmonary arteries of PAH patients have lesions of varying severity including formation of neointima, which obstructs the normal blood flow, and complex multicellular plexiform lesions. A current concept suggests that dysregulated programmed cell death, or apoptosis of ECs causes unchecked proliferation of a subset of apoptosis-resistant ECs 1,2. The ECs retain a hyperproliferative and apoptosis-resistant phenotype even in culture 3. These abnormal ECs in the plexiform lesions of PAH patients may originate from primitive endothelial-like stem cells by clonal selection 4. This concept of primitive cells as source of aberrant ECs in PAH is supported by the findings of markers of primitive stem-like cells in the lung vascular lesions 5-7. Likewise, hyperproliferative pulmonary artery smooth muscle cells may also be derived from progenitor cells in PAH 8,9. During vascular development, primitive ECs

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Section: Discussionmentioning

confidence: 78%

Clonally selected primitive endothelial cells promote occlusive pulmonary arteriopathy and severe pulmonary hypertension in rats exposed to chronic hypoxia

Bhagwani

Farkas

Harmon

et al. 2020

Sci Rep

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“…We found a negative correlation between IL-6 and right ventricular end-diastolic diameter. Recently, relationships between increased circulating IL-6 levels and right ventricular (RV) function in pulmonary arterial hypertension patients have been analyzed [57]. In the cited study, plasma IL-6 levels inversely correlated with echocardiography derived measures of RV function, including RV fractional area change.…”

Section: Discussionmentioning

confidence: 99%

Associations between IL-6 and Echo-Parameters in Patients with Early Onset Coronary Artery Disease

et al. 2019

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Background: Over the last two decades, many studies have investigated the association between interleukin 6 (IL-6) and pathogenesis and progression of coronary artery disease (CAD). Patients with CAD manifested at a young age are a particularly interesting group. They differ from older patients, not only in terms of the severity of coronary artery atherosclerosis, but also risk factor profiles, short- and long-term prognosis after myocardial infarction (MI). The role of IL-6 in younger patients with CAD is less well-known. Therefore, our study aimed to analyze the relationship between IL-6 level and other inflammations, atherosclerosis, and cardiac function parameters in early onset CAD patients. Methods: The study covered 100 patients with early onset CAD and a group of 50 healthy participants. Plasma levels of IL-6 and basic biochemical parameters, anthropometric, echocardiographic, and arteries Doppler ultrasound measurements were performed. Results: We did not observe a significant difference in IL-6 concentration in plasma between patients with early onset CAD and a control group, but IL-6 level was negatively correlated with echocardiographic measurements of ascending aorta diameter, left ventricular shortening fraction, and right ventricular end-diastolic diameter in our patients. Conclusions: In patients with early onset CAD, plasma IL-6 level is associated with other inflammation parameters and with cardiac function, potentially contributing to right ventricular remodeling and left ventricular systolic dysfunction. This suggests possible prognostic benefits of long-time observation of IL-6 level after the acute coronary syndrome.

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“…Elevated circulating levels and enhanced perivascular expression of proinflammatory cytokines (e.g., IL-6) have repeatedly been observed in PAH patients. Indeed, elevated circulating levels of IL-6 correlate with right ventricular function, worse clinical outcome, greater incidence of quality of life-related symptoms, and/or poorer survival in PAH patients (5)(6)(7)(8). Elevated circulating levels of IL-6 have been found even in the non-PAH forms of PH, such as chronic obstructive pulmonary disease-related PH (COPD-PH), and in PH patients with advanced heart failure (9, 10).…”

Section: Il-6 Signaling In Pulmonary Hypertensionmentioning

confidence: 99%

Classical IL-6 signaling: a promising therapeutic target for pulmonary arterial hypertension

Pullamsetti¹,

Seeger²,

Savai³

2018

Journal of Clinical Investigation

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Current therapies for pulmonary arterial hypertension (PAH) provide symptomatic relief and improve prognosis but fall short of improving long-term survival. There is emerging evidence for a role of inflammatory mediators, primarily IL-6, in the pathogenesis of PAH. However, the mechanisms by which IL-6 potentially affects PAH are unknown. In this issue of the JCI, Tamura, Phan, and colleagues identified ectopic upregulation of the membrane-bound IL-6 receptor (IL6R), indicating classical IL-6 signaling in the smooth muscle layer of remodeled vessels in human and experimental PAH. They performed a series of in vitro and in vivo experiments that provide deeper insights into the mechanisms of classical IL-6 signaling and propose interventions directed against IL6R as a potential therapeutic strategy for PAH.

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Interleukin-6 is independently associated with right ventricular function in pulmonary arterial hypertension

Abstract: Serum IL-6 levels are independently associated with RV function and RV-PA coupling in PAH. Patients with higher IL-6 levels have more severe RV dysfunction and diminished RV-PA coupling despite a comparable severity of pulmonary vascular disease.

Cited by 78 publications

References 44 publications

Clonally selected primitive endothelial cells promote occlusive pulmonary arteriopathy and severe pulmonary hypertension in rats exposed to chronic hypoxia

Clonally selected primitive endothelial cells promote occlusive pulmonary arteriopathy and severe pulmonary hypertension in rats exposed to chronic hypoxia

Associations between IL-6 and Echo-Parameters in Patients with Early Onset Coronary Artery Disease

Classical IL-6 signaling: a promising therapeutic target for pulmonary arterial hypertension

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