Abstract 13535: The Synergistic Effects of Incretin-related Drugs for the Treatment of Pulmonary Arterial Hypertension

Introduction: A growing body of evidence suggests that inflammation plays a crucial role in the development of pulmonary arterial hypertension (PAH). Dipeptidyl peptidase-4 (DPP-4; also known as CD26), a protease which degrades incretin hormones such as glucagon-like peptide-1 (GLP-1), modulates inflammatory processes by regulating activity of T cells through co-stimulatory pathway. Hypothesis: Incretin-related drugs, including both DPP-4 inhibitors and GLP-1 receptor agonists, suppress the progression of PAH by attenuating inflammatory response of PA. Methods: Sprague Dawley rats were injected monocrotaline to induce PAH (N=80). After 14 days from PAH induction, these rats were treated with alogliptin, a DPP-4 inhibitor (M+A, N=20), liraglutide, a GLP-1 receptor agonist (M+L, N=20), both of these drugs (M+A+L, N=20), or vehicle (M, N=20). Results: A significant increase of survival was observed on days 30 after PAH induction both in the M+A and M+L compared to the M (M+A: 45%* vs. M+L: 60%* vs. M: 5%, * p <0.05). Both alogliptin and liraglutide markedly improved right ventricular pressure (M+A: 33±4.1mmHg* vs. M+L: 26±1.9mmHg* vs. M: 85.9±1.2mmHg, * p <0.05). mRNA levels of both CD28 and CD86, co-stimulators of T cells, significantly decreased and the level of caveolin-1 markedly increased in lung tissues of the M+A compared to those in the M. mRNA levels of both Tissue Factor (TF) and PAI-1 significantly decreased in lung tissues of the M+L than those in the M. Consistently, survival of rats in the M+A+L was the highest (65%) among all of the groups of PAH rats. Coimmunoprecipitation assays revealed that CD26 in T cells physically interacted with caveolin-1 in rat pulmonary vascular smooth muscle cells (rPASMCs). Immunoblot analyses showed that alogliptin suppressed caveolin-1 phosphorylation in rPASMCs. Furthermore, reporter gene assays demonstrated that alogliptin significantly inhibited the transcriptional activity of NF-κB. Conclusions: These results suggest that DPP-4 inhibition and stimulation of GLP-1 receptors synergistically mediate salutary effects on monocrotaline-induced PAH by modulating T cell activity and TF-associated signaling pathway. Thus, incretin-related drugs have a potential as a novel therapeutic tool for PAH.

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Circulating CD4+T/methylation signatures of network-oriented SOCS3, ITGAL, NFIC, NCOR2, PGK1 genes associate with hemodynamics in pulmonary arterial hypertension patients

European Heart Journal ◽

10.1093/eurheartj/ehab724.1952 ◽

2021 ◽

Vol 42 (Supplement_1) ◽

Author(s):

G Benincasa ◽

B A Maron ◽

O Affinito ◽

M D'Alto ◽

M Franzese ◽

...

Keyword(s):

T Cells ◽

Pulmonary Arterial Hypertension ◽

Cardiac Index ◽

Arterial Hypertension ◽

Cd4 T Cells ◽

Right Atrial ◽

Potential Candidate ◽

Mrna Levels ◽

Non Invasive ◽

Pulmonary Arterial

Abstract Background CD4+ T cells are associated with pulmonary arterial hypertension (PAH) pathogenesis but mechanistic insights are limited. Purpose To identify differential CD4+ T methylation signatures in healthy controls vs PAH and evaluate a putative association with the cardiopulmonary hemodynamic profile of affected patients. Methods We used RRBS platform to profile CD4+ T DNA methylome in the CLEOPAHTRA clinical trial. Results Differentially methylated CpG sites (N=631) annotated to N=408 genes (DMGs). Most of them (65%) were hypermethylated and localized in distal intergenic (36%) and promoter regions (31%). Promoter-related network analysis established the PAH subnetwork highlighting 5 hub DMGs (SOCS3, GNAS, ITGAL, NCOR2, NFIC) and 5 non-hub DMGs (NR4A2, GRM2, PGK1, STMN1, LIMS2) as potential candidate genes (Figure 1). The Infinium Human MethylationEPIC BeadChip on CD4+ T cells from an independent study population confirmed the global RRBS-methylation trends. Both in idiopathic and Associated-PAH, each of these 10 network-oriented DMGs was strongly correlated with at least one hemodynamic parameter such as right atrial pressure (RAP), cardiac index (CI), mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), and pulmonary capillary wedge pressure (PCWP) (Figure 2). In addition, mRNA levels of the ITGAL, NFIC, NCOR2, PGK1 genes and the IL-6-STAT3-SOCS3 signaling axis were significantly upregulated in PBMCs from patients with PAH vs controls suggesting putative drug targets. Furthermore, both SOCS3 methylation and mRNA levels were positively correlated with cardiac index (CI) in idiopathic PAH whereas both PGK1 methylation and mRNA levels were positively correlated with RAP and inversely with CI in Associated PAH suggesting putative non-invasive biomarkers. Conclusions This hypothesis-generating study shows for the first time that circulating CD4+ T methylation signatures, inclusive of SOCS3, ITGAL, NFIC, NCOR2, and PGK1 genes may yield insight into pro-inflammatory mechanisms that exacerbate vascular remodeling in PAH and suggest non-invasive biomarkers to optimize patient phenotyping and, possibly, prognostication in PAH. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): PRIN2017F8ZB89 from Italian Ministry of University and Research (MIUR) (PI Prof Napoli) and Ricerca Corrente (RC) 2019 from Italian Ministry of Health (PI Prof. Napoli). Figure 1 Figure 2

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Abstract 13715: Pathophysiological Role of Dexmedetomidine for Monocrotaline-induced Pulmonary Arterial Hypertension in Rats

Circulation ◽

10.1161/circ.142.suppl_3.13715 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Yohei Yamaguchi ◽

Susumu Hosokawa ◽

Yusuke Kajikawa ◽

Yasuhiro Maejima ◽

Mitsuaki Isobe ◽

...

Keyword(s):

Survival Rate ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Inflammatory Responses ◽

Systolic Pressure ◽

Mrna Levels ◽

Sprague Dawley ◽

Pulmonary Arterial ◽

Anti Inflammatory ◽

Inflammatory Effect

Introduction: The abnormal proliferation of pulmonary arterial smooth muscle cells (PASMCs) is one of pathological characteristics of pulmonary arterial hypertension (PAH). Inflammation is thought to play an important role for PASMCs proliferation in PAH. Dexmedetomidine (DEX) is a selective α2-adrenergic receptor agonist that is used as a sedative in clinical settings. It has been reported that DEX regulates certain inflammatory responses. Hypothesis: DEX ameliorates Monocrotaline (MCT)-induced PAH in rats through its anti-inflammatory effect. Methods: In vivo, 6-week-old male Sprague-Dawley rats were injected 60 mg/kg of MCT subcutaneously. At day 14 after MCT injection, continuous infusions of DEX (2μg/kg/hour) by osmotic pumps were started in one group (MCT + DEX group), and not in another group (MCT group). We performed cardiac catheterization to measure right ventricular systolic pressure (RVSP) and prepared rats paraffin embedded lung tissues for Immunohistochemistry at day 23. In vitro, we analyzed the effect of DEX on human PASMCs (hPASMCs) proliferation stimulated with fibroblast growth factor 2 (FGF2). In addition, we examined mRNA levels of proinflammatory cytokines in hPASMCs by FGF2 stimuation with/without DEX. Results: Both RVSP and survival rate markedly improved in MCT + DEX group compared with those in MCT group (RVSP; 34mmHg ± 4mmHg vs. 70mmHg ± 10mmHg, survival rate 42% vs. 0% at day 29). In histological analysis, medial hypertrophy of pulmonary arterioles and phosphorylated-p65 positive PASMCs significantly reduced in MCT + DEX group. DEX also inhibited hPASMCs proliferation dose dependently. Furthermore, IL-6 mRNA expression was suppressed by DEX in hPASMCs stimulated with FGF2. Conclusions: DEX improved MCT-induced PAH in rats by suppressing PASMCs proliferation through the anti-inflammatory effect, which may result from inhibition of NF-κB activation induced by IL-6. DEX can be a new therapeutic tool for PAH.

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Understanding the Role of CD4+CD25high (So-Called Regulatory) T Cells in Idiopathic Pulmonary Arterial Hypertension

Respiration ◽

10.1159/000114655 ◽

2008 ◽

Vol 75 (3) ◽

pp. 253-256 ◽

Cited By ~ 8

Author(s):

Frédéric Perros ◽

Sylvia Cohen-Kaminsky ◽

Marc Humbert

Keyword(s):

T Cells ◽

Pulmonary Arterial Hypertension ◽

Regulatory T Cells ◽

Arterial Hypertension ◽

Idiopathic Pulmonary Arterial Hypertension ◽

Pulmonary Arterial

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Faculty Opinions recommendation of Whole exome sequencing to identify a novel gene (caveolin-1) associated with human pulmonary arterial hypertension.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718024844.793479573 ◽

2013 ◽

Author(s):

Vinicio de Jesus Perez

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Caveolin 1 ◽

Novel Gene ◽

Whole Exome ◽

Pulmonary Arterial

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Abstract 15120: Nanoparticle-Mediated Delivery of Pitavastatin into Small Pulmonary Arteies by Intravenous Administration Attenuated the Progression of Already Established Monocrotaline-induced Pulmonary Arterial Hypertension in Rats

Circulation ◽

10.1161/circ.130.suppl_2.15120 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Kenzo Ichimura ◽

Tetsuya Matoba ◽

Ryoji Nagahama ◽

Kaku Nakano ◽

Kenji Sunagawa ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Pulmonary Artery ◽

Arterial Hypertension ◽

Intravenous Administration ◽

Pulmonary Arteries ◽

Intratracheal Instillation ◽

Poly Lactic Acid ◽

Bolus Administration ◽

Sprague Dawley ◽

Pulmonary Arterial

Background: Pulmonary arterial hypertension (PAH) is an intractable disease of small pulmonary artery in which multiple pathogenetic factors are involved. We have previously reported that poly(lactic acid/glycolic acid) (PLGA) nanoparticle (NP)-mediated targeting of pitavastatin into lungs by intratracheal instillation attenuated the development of PAH. In the present study we examined the effects of intravenous treatment with pitavastatin-NPs on the progression of already established PAH induced by monocrotaline (MCT). Methods and Results: Male Sprague-Dawley rats (200 to 230 g) were injected subcutaneously with 60 mg/kg MCT to induce PAH. At day 17 after MCT injection when PAH had been already established, animals were randomly divided into 4 groups, which treated with intravenous daily bolus administration of the following drugs for consecutive 4 days from 17 to 20 days after MCT injection; 1) vehicle, 2) FITC-NPs, 3) pitavastatin alone (1, 3, 10 or 30 mg/kg), or 4) pitavastatin-NPs (containing 1 or 3 mg/kg pitavastatin). Treatment with pitavastatin-NPs, but not with pitavastatin alone attenuated the progression of established PAH (Fig. A) associated with the reduction of inflammation and small pulmonary artery remodeling (stenosis and obstruction of pulmonary arterial branches) (Fig. B). In trace experiments, intravenous administration of FITC-NPs revealed the targeting of FITC-NPs into small pulmonary artery in rats with MCT-induced PAH, but not in normal animals. Importantly, in a separate protocol, treatment with pitavastatin-NPs improved the survival rate at day 35 (30% in pitavastatin-NP group vs. 61% in FITC-NP group, P<0.05 by Kaplan-Meier). Conclusion: A novel NP-mediated targeting of pitavastatin into small pulmonary arteries by intravenous administration attenuated the progression of established PAH and improved survival associated with anti-inflammatory and anti-remodeling effects in a rat model of MCT-induced PAH.

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Protection against monocrotaline-induced pulmonary arterial hypertension and caveolin-1 downregulation by fluvastatin in rats

Molecular Medicine Reports ◽

10.3892/mmr.2017.8345 ◽

2017 ◽

Author(s):

Shaoping Zhu ◽

Junyu Wang ◽

Xianguo Wang ◽

Jinping Zhao

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Caveolin 1 ◽

Pulmonary Arterial

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The Role of Regulatory T Cells in Pulmonary Arterial Hypertension

Journal of the American Heart Association ◽

10.1161/jaha.119.014201 ◽

2019 ◽

Vol 8 (23) ◽

Cited By ~ 2

Author(s):

Haihua Qiu ◽

Yi He ◽

Fan Ouyang ◽

Ping Jiang ◽

Shuhong Guo ◽

...

Keyword(s):

T Cells ◽

Pulmonary Arterial Hypertension ◽

Regulatory T Cells ◽

Arterial Hypertension ◽

Pulmonary Arterial

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Absence of T Cells Confers Increased Pulmonary Arterial Hypertension and Vascular Remodeling

American Journal of Respiratory and Critical Care Medicine ◽

10.1164/rccm.200608-1189oc ◽

2007 ◽

Vol 175 (12) ◽

pp. 1280-1289 ◽

Cited By ~ 117

Author(s):

Laimute Taraseviciene-Stewart ◽

Mark R. Nicolls ◽

Donatas Kraskauskas ◽

Robertas Scerbavicius ◽

Nana Burns ◽

...

Keyword(s):

T Cells ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Vascular Remodeling ◽

Pulmonary Arterial

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Role of Extracellular Vesicles in Pulmonary Arterial Hypertension

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.120.314152 ◽

2020 ◽

Vol 40 (9) ◽

pp. 2293-2309 ◽

Cited By ~ 1

Author(s):

Avinash Khandagale ◽

Mikael Åberg ◽

Gerhard Wikström ◽

Sara Bergström Lind ◽

Ganna Shevchenko ◽

...

Keyword(s):

Endothelial Cell ◽

Growth Factor ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Extracellular Vesicles ◽

Cell Activation ◽

Cell Activity ◽

Angiogenic Proteins ◽

Pulmonary Arterial

Objective: Extracellular vesicles (EVs) have the potential to act as intercellular communicators. The aims were to characterize circulating EVs in patients with pulmonary arterial hypertension (PAH) and to explore whether these EVs contribute to endothelial activation and angiogenesis. Approach and Results: Patients with PAH (n=70) and healthy controls (HC; n=20) were included in this cross-sectional study. EVs were characterized and human pulmonary endothelial cells (hPAECs) were incubated with purified EVs. Endothelial cell activity and proangiogenic markers were analyzed. Tube formation analysis was performed for hPAECs, and the involvement of PSGL-1 (P-selectin glycoprotein ligand 1) was evaluated. The numbers of CD62P + , CD144 + , and CD235a EVs were higher in blood from PAH compared with HC. Thirteen proteins were differently expressed in PAH and HC EVs, where complement fragment C1q was the most significantly elevated protein ( P =0.0009) in PAH EVs. Upon EVs-internalization in hPAECs, more PAH compared with HC EVs evaded lysosomes ( P <0.01). As oppose to HC, PAH EVs stimulated hPAEC activation and induced transcription and translation of VEGF-A (vascular endothelial growth factor A; P <0.05) and FGF (fibroblast growth factor; P <0.005) which were released in the cell supernatant. These proangiogenic proteins were higher in patient with PAH plasma compered with HC. PAH EVs induced a complex network of angiotubes in vitro, which was abolished by inhibitory PSGL-1antibody. Anti-PSGL-1 also inhibited EV-induced endothelial cell activation and PAH EV dependent increase of VEGF-A. Conclusions: Patients with PAH have higher levels of EVs harboring increased amounts of angiogenic proteins, which induce activation of hPAECs and in vitro angiogenesis. These effects were partly because of platelet-derived EVs evasion of lysosomes upon internalization within hPAEC and through possible involvement of P-selectin-PSGL-1 pathway.

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