Role of the RhoA/ROCK pathway in high-altitude associated neonatal pulmonary hypertension in lambs

Exposure to high-altitude chronic hypoxia during pregnancy may cause pulmonary hypertension in neonates, as a result of vasoconstriction and vascular remodeling. We hypothesized that susceptibility to pulmonary hypertension, due to an augmented expression and activity of the RhoA/Rho-kinase (ROCK) pathway in these neonates, can be reduced by daily administration of fasudil, a ROCK inhibitor. We studied 10 highland newborn lambs with conception, gestation, and birth at 3,600 m in Putre, Chile. Five highland controls (HLC) were compared with 5 highland lambs treated with fasudil (HL-FAS; 3 mg·kg−1·day−1 iv for 10 days). Ten lowland controls were studied in Lluta (50 m; LLC). During the 10 days of fasudil daily administration, the drug decreased pulmonary arterial pressure (PAP) and resistance (PVR), basally and during a superimposed episode of acute hypoxia. HL-FAS small pulmonary arteries showed diminished muscular area and a reduced contractile response to the thromboxane analog U46619 compared with HLC. Hypoxia, but not fasudil, changed the protein expression pattern of the RhoA/ROCKII pathway. Moreover, HL-FAS lungs expressed less pMYPT1T850 and pMYPT1T696 than HLC, with a potential increase of the myosin light chain phosphatase activity. Finally, hypoxia induced RhoA, ROCKII, and PKG mRNA expression in PASMCs of HLC, but fasudil reduced them (HL-FAS) similarly to LLC. We conclude that fasudil decreases the function of the RhoA/ROCK pathway, reducing the PAP and PVR in chronically hypoxic highland neonatal lambs. The inhibition of ROCKs by fasudil may offer a possible therapeutic tool for the pulmonary hypertension of the neonates.

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2-Aminoethyldiphenylborinate modifies the pulmonary circulation in pulmonary hypertensive newborn lambs partially gestated at high altitude

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00230.2016 ◽

2016 ◽

Vol 311 (4) ◽

pp. L788-L799 ◽

Cited By ~ 7

Author(s):

S. Castillo-Galán ◽

S. Quezada ◽

F. Moraga ◽

G. Ebensperger ◽

E. A. Herrera ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Pulmonary Arterial Pressure ◽

Acute Hypoxia ◽

Pulmonary Arteries ◽

Rho Kinase ◽

Vasoconstrictor Response ◽

End Of Treatment ◽

Vehicle Treatment ◽

Pulmonary Arterial ◽

Phosphodiesterase 5

Calcium signaling through store-operated channels (SOC) is involved in hypoxic pulmonary hypertension. We determined whether a treatment with 2-aminoethyldiphenylborinate (2-APB), a compound with SOC blocker activity, reduces pulmonary hypertension and vascular remodeling. Twelve newborn lambs exposed to perinatal chronic hypoxia were studied, six of them received a 2-APB treatment and the other six received vehicle treatment for 10 days in both cases. Throughout this period, we recorded cardiopulmonary variables and on day 11 we evaluated the response to an acute hypoxic challenge. Additionally, we assessed the vasoconstrictor and vasodilator function in isolated pulmonary arteries as well as their remodeling in lung slices. 2-APB reduced pulmonary arterial pressure between the 3rd and 10th days, cardiac output between the 4th and 8th days, and pulmonary vascular resistance at the 10th day of treatment. The pulmonary vasoconstrictor response to acute hypoxia was reduced by the end of treatment. 2-APB also decreased maximal vasoconstrictor response to the thromboxane mimetic U46619 and endothelin-1 and increased maximal relaxation to 8-bromoguanosine 3′,5′-cyclic monophosphate (8-BrcGMP). The maximal relaxation and potency to phosphodiesterase-5 and Rho-kinase inhibition with sildenafil and fasudil, respectively, were also increased. Finally, 2-APB reduced the medial and adventitial layers' thickness, the expression of α-actin, and the percentage of Ki67-positive nuclei of small pulmonary arteries. Taken together, our results indicate that 2-APB reduces pulmonary hypertension, vasoconstrictor responses, and pathological remodeling in pulmonary hypertensive lambs. We conclude that SOC targeting may be a useful strategy for the treatment of neonatal pulmonary hypertension; however, further testing of specific blockers is needed.

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Increased TMEM16A-encoded calcium-activated chloride channel activity is associated with pulmonary hypertension

AJP Cell Physiology ◽

10.1152/ajpcell.00044.2012 ◽

2012 ◽

Vol 303 (12) ◽

pp. C1229-C1243 ◽

Cited By ~ 74

Author(s):

Abigail S. Forrest ◽

Talia C. Joyce ◽

Marissa L. Huebner ◽

Ramon J. Ayon ◽

Michael Wiwchar ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Electromechanical Coupling ◽

Pulmonary Arteries ◽

Doppler Imaging ◽

Heart Weight ◽

Channel Activity ◽

Cl Channels ◽

Pulmonary Arterial ◽

Pulmonary Artery Smooth Muscle

Pulmonary artery smooth muscle cells (PASMCs) are more depolarized and display higher Ca2+ levels in pulmonary hypertension (PH). Whether the functional properties and expression of Ca2+-activated Cl− channels (ClCa), an important excitatory mechanism in PASMCs, are altered in PH is unknown. The potential role of ClCa channels in PH was investigated using the monocrotaline (MCT)-induced PH model in the rat. Three weeks postinjection with a single dose of MCT (50 mg/kg ip), the animals developed right ventricular hypertrophy (heart weight measurements) and changes in pulmonary arterial flow (pulse-waved Doppler imaging) that were consistent with increased pulmonary arterial pressure and PH. Whole cell patch experiments revealed an increase in niflumic acid (NFA)-sensitive Ca2+-activated Cl− current [ ICl(Ca)] density in PASMCs from large conduit and small intralobar pulmonary arteries of MCT-treated rats vs. aged-matched saline-injected controls. Quantitative RT-PCR and Western blot analysis revealed that the alterations in ICl(Ca) were accompanied by parallel changes in the expression of TMEM16A, a gene recently shown to encode for ClCa channels. The contraction to serotonin of conduit and intralobar pulmonary arteries from MCT-treated rats exhibited greater sensitivity to nifedipine (1 μM), an l-type Ca2+ channel blocker, and NFA (30 or 100 μM, with or without 10 μM indomethacin to inhibit cyclooxygenases) or T16AInh-A01 (10 μM), TMEM16A/ClCa channel inhibitors, than that of control animals. In conclusion, augmented ClCa/TMEM16A channel activity is a major contributor to the changes in electromechanical coupling of PA in this model of PH. TMEM16A-encoded channels may therefore represent a novel therapeutic target in this disease.

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Acute vasodilator effects of Rho-kinase inhibitors in neonatal rats with pulmonary hypertension unresponsive to nitric oxide

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00234.2007 ◽

2008 ◽

Vol 294 (2) ◽

pp. L205-L213 ◽

Cited By ~ 77

Author(s):

Patrick J. McNamara ◽

Prashanth Murthy ◽

Crystal Kantores ◽

Lilian Teixeira ◽

Doreen Engelberts ◽

...

Keyword(s):

Nitric Oxide ◽

Pulmonary Hypertension ◽

Kinase Inhibitors ◽

Pulmonary Arteries ◽

Rho Kinase ◽

Neonatal Rat ◽

Rock Inhibitor ◽

No Donor ◽

Rat Models ◽

Pulmonary Hemodynamic

Pulmonary hypertension (PHT) in neonates is often refractory to the current best therapy, inhaled nitric oxide (NO). The utility of a new class of pulmonary vasodilators, Rho-kinase (ROCK) inhibitors, has not been examined in neonatal animals. Our objective was to examine the activity and expression of RhoA/ROCK in normal and injured pulmonary arteries and to determine the short-term pulmonary hemodynamic (assessed by pulse wave Doppler) effects of ROCK inhibitors (15 mg/kg ip Y-27632 or 30 mg/kg ip fasudil) in two neonatal rat models of chronic PHT with pulmonary vascular remodeling (chronic hypoxia, 0.13 FiO2, or 1 mg·kg−1·day−1 ip chronic bleomycin for 14 days from birth). Activity of the RhoA/ROCK pathway and ROCK expression were increased in hypoxia- and bleomycin-induced PHT. In both models, severe PHT [characterized by raised pulmonary vascular resistance (PVR) and impaired right ventricular (RV) performance] did not respond acutely to inhaled NO (20 ppm for 15 min) or to a single bolus of a NO donor, 3-morpholinosydnonimine hydrochloride (SIN-1; 2 μg/kg ip). In contrast, a single intraperitoneal bolus of either ROCK inhibitor (Y-27632 or fasudil) completely normalized PVR but had no acute effect on RV performance. ROCK-mediated vasoconstriction appears to play a key role in chronic PHT in our two neonatal rat models. Inhibitors of ROCK have potential as a testable therapy in neonates with PHT that is refractory to NO.

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Rescue treatment with a Rho-kinase inhibitor normalizes right ventricular function and reverses remodeling in juvenile rats with chronic pulmonary hypertension

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00595.2010 ◽

2010 ◽

Vol 299 (6) ◽

pp. H1854-H1864 ◽

Cited By ~ 39

Author(s):

Emily Z. Xu ◽

Crystal Kantores ◽

Julijana Ivanovska ◽

Doreen Engelberts ◽

Brian P. Kavanagh ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Smooth Muscle ◽

Right Ventricular ◽

Systolic Function ◽

Rho Kinase ◽

Rock Inhibitor ◽

Rescue Treatment ◽

Right Ventricular Systolic Function ◽

Chronic Pulmonary Hypertension ◽

Pulmonary Arterial

Chronic pulmonary hypertension in infancy and childhood is characterized by a fixed and progressive increase in pulmonary arterial pressure and resistance, pulmonary arterial remodeling, and right ventricular hypertrophy and systolic dysfunction. These abnormalities are replicated in neonatal rats chronically exposed to hypoxia from birth in which increased activity of Rho-kinase (ROCK) is critical to injury, as evidenced by preventive effects of ROCK inhibitors. Our objective in the present study was to examine the reversing effects of a late or rescue approach to treatment with a ROCK inhibitor on the pulmonary and cardiac manifestations of established chronic hypoxic pulmonary hypertension. Rat pups were exposed to air or hypoxia (13% O2) from postnatal day 1 and were treated with Y-27632 (15 mg/kg) or saline vehicle by twice daily subcutaneous injection commencing on day 14, for up to 7 days. Treatment with Y-27632 significantly attenuated right ventricular hypertrophy, reversed arterial wall remodeling, and completely normalized right ventricular systolic function in hypoxia-exposed animals. Reversal of arterial wall remodeling was accompanied by increased apoptosis and attenuated content of endothelin (ET)-1 and ETA receptors. Treatment of primary cultured juvenile rat pulmonary artery smooth muscle cells with Y-27632 attenuated serum-stimulated ROCK activity and proliferation and increased apoptosis. Smooth muscle apoptosis was also induced by short interfering RNA-mediated knockdown of ROCK-II, but not of ROCK-I. We conclude that sustained rescue treatment with a ROCK inhibitor reversed both the hemodynamic and structural abnormalities of chronic hypoxic pulmonary hypertension in juvenile rats and normalized right ventricular systolic function. Attenuated expression and activity of ET-1 and its A-type receptor on pulmonary arterial smooth muscle was a likely contributor to the stimulatory effects of ROCK inhibition on apoptosis. In addition, our data suggest that ROCK-II may be dominant in enhancing survival of pulmonary arterial smooth muscle.

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Treatment with 5-HT potentiates development of pulmonary hypertension in chronically hypoxic rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1997.272.3.h1173 ◽

1997 ◽

Vol 272 (3) ◽

pp. H1173-H1181 ◽

Cited By ~ 12

Author(s):

S. Eddahibi ◽

B. Raffestin ◽

I. Pham ◽

J. M. Launay ◽

P. Aegerter ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Ventricular Hypertrophy ◽

Potential Role ◽

Pressor Response ◽

Acute Hypoxia ◽

Synthesis Inhibitor ◽

Pulmonary Arterial ◽

Isolated Lungs ◽

Dose Dependent

The aim of this study was to investigate the potential role of 5-hydroxytryptamine (5-HT) on development of pulmonary hypertension during chronic exposure to mild (15% O2) and severe (10% O2) hypoxia. In isolated lungs from normoxic rats preconstricted with U-46619, 5-HT (10(-12)-10(-8) M) induced dose-dependent vasodilation (n = 6), which was suppressed by the NO synthesis inhibitor nitro-L-arginine methyl ester (L-NAME, 10(-4) M, n = 5) and reduced by the 5-HT3-receptor antagonist MDL-7222 (10(-5) M, n = 6). The vasoconstriction that was observed with higher concentrations of 5-HT (10(-7)-10(-4) M) was inhibited by ketanserin (10(-5) M) and methiothepin (10(-5) M, n = 6 each). The vasodilator response to 5-HT was suppressed in lungs from rats exposed to 10% O2 but not 15% O2 (n = 6 each). In conscious rats, intravenous administration of 5-HT potentiated the pulmonary pressor response to acute hypoxia (10% O2, n = 5), an effect that remained unchanged after pretreatment with a 5-HT1 and a 5-HT2 antagonist (n = 4) but was attenuated after treatment with the cyclooxygenase inhibitor meclofenamate (n = 4). Treatment with 5-HT (5 nmol/h i.v. by osmotic pumps) for 2 wk in rats simultaneously exposed to 10% O2 increased pulmonary arterial pressure, right ventricular hypertrophy, and muscularization of pulmonary vessels in comparison with their hypoxic controls (n = 12 each). No changes occurred in 15% O2 hypoxic rats (n = 12 each). The present findings show that 5-HT potentiates development of pulmonary hypertension in rats exposed to chronic hypoxia.

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Membrane depolarization is required for pressure-dependent pulmonary arterial tone but not enhanced vasoconstriction to endothelin-1 following chronic hypoxia

Pulmonary Circulation ◽

10.1177/2045894020973559 ◽

2020 ◽

Vol 10 (4) ◽

pp. 204589402097355

Author(s):

Charles E Norton ◽

Nikki L Jernigan ◽

Benjimen R Walker ◽

Thomas C Resta

Keyword(s):

Chronic Hypoxia ◽

Pulmonary Arteries ◽

Rho Kinase ◽

Membrane Depolarization ◽

Src Kinases ◽

Endothelin 1 ◽

Receptor Inhibition ◽

Pulmonary Arterial ◽

Arterial Tone

Enhanced vasoconstriction is increasingly identified as an important contributor to the development of pulmonary hypertension. Chronic hypoxia results in enhanced Rho kinase mediated Ca2+ sensitization contributing to pressure-dependent pulmonary arterial tone as well as augmented vasoconstriction to endothelin-1 and depolarizing stimuli. We sought to investigate the interaction between these vasoconstrictor stimuli in isolated, pressurized, pulmonary arteries. We used the K+ ionophore, valinomycin, to clamp membrane potential (Vm) to investigate the role of membrane depolarization in endothelin-1 and pressure-dependent constriction, and endothelin-1 receptor inhibitors to determine whether membrane depolarization or stretch signal through endothelin-1 receptors. Clamping Vm prevented pressure-dependent tone, but not enhanced vasoconstriction to endothelin-1 following chronic hypoxia. Furthermore, endothelin-1 receptor inhibition had no effect on either pressure-dependent tone or vasoconstriction to KCl. As Src kinases contribute to both pressure-dependent tone and enhanced endothelin-1 vasoconstriction following chronic hypoxia, we further investigated their role in depolarization-induced vasoconstriction. Inhibition of Src kinases attenuated enhanced vasoconstriction to KCl. We conclude that membrane depolarization contributes to pressure-dependent tone but not enhanced vasoconstriction to ET-1, and that Src kinases serve as upstream mediators facilitating enhanced Rho kinase-dependent vasoconstriction following chronic hypoxia.

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Pulmonary hypertension and pulmonary vascular reactivity in beagles at high altitude

Journal of Applied Physiology ◽

10.1152/jappl.1988.65.6.2632 ◽

1988 ◽

Vol 65 (6) ◽

pp. 2632-2640 ◽

Cited By ~ 28

Author(s):

R. F. Grover ◽

R. L. Johnson ◽

R. G. McCullough ◽

R. E. McCullough ◽

S. E. Hofmeister ◽

...

Keyword(s):

Pulmonary Hypertension ◽

High Altitude ◽

Sea Level ◽

Vascular Reactivity ◽

Chronic Hypoxia ◽

Acute Hypoxia ◽

Prostaglandin Synthesis ◽

Inhibition Of Prostaglandin Synthesis ◽

Pulmonary Arterial ◽

Low Altitude

It is unclear whether dogs develop pulmonary hypertension (PH) at high altitude. Beagles from sea level were exposed to an altitude of 3,100 m (PB 525 Torr) for 12-19 mo and compared with age-matched controls remaining at low altitude of 130 m (PB 750 Torr). In beagles taken to high altitude as adults, pulmonary arterial pressures (PAP) at 3,100 m were 21.6 +/- 2.6 vs. 13.2 +/- 1.2 Torr in controls. Likewise, in beagles taken to 3,100 m as puppies 2.5 mo old, PAP was 23.2 +/- 2.1 vs. 13.8 +/- 0.4 Torr in controls. This PH reflected a doubling of pulmonary vascular resistance and showed no progression with time at altitude. Pulmonary vascular reactivity to acute hypoxia was also enhanced at 3,100 m. Inhibition of prostaglandin synthesis did not attenuate the PH or the enhanced reactivity. Once established, the PH was only partially reversed by acute relief of chronic hypoxia, but reversal was virtually complete after return to low altitude. Hence, beagles do develop PH at 3,100 m of a severity comparable to that observed in humans at the same or even higher altitudes.

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Endothelial Dysfunction in Pulmonary Hypertension: Cause or Consequence?

Biomedicines ◽

10.3390/biomedicines9010057 ◽

2021 ◽

Vol 9 (1) ◽

pp. 57

Author(s):

Kondababu Kurakula ◽

Valérie F.E.D. Smolders ◽

Olga Tura-Ceide ◽

J. Wouter Jukema ◽

Paul H. A. Quax ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Therapeutic Potential ◽

Thrombus Formation ◽

Pulmonary Arteries ◽

Mesenchymal Transition ◽

Pulmonary Arterial ◽

Pulmonary Artery Smooth Muscle ◽

Endothelial To Mesenchymal Transition ◽

Molecular Signals

Pulmonary arterial hypertension (PAH) is a rare, complex, and progressive disease that is characterized by the abnormal remodeling of the pulmonary arteries that leads to right ventricular failure and death. Although our understanding of the causes for abnormal vascular remodeling in PAH is limited, accumulating evidence indicates that endothelial cell (EC) dysfunction is one of the first triggers initiating this process. EC dysfunction leads to the activation of several cellular signalling pathways in the endothelium, resulting in the uncontrolled proliferation of ECs, pulmonary artery smooth muscle cells, and fibroblasts, and eventually leads to vascular remodelling and the occlusion of the pulmonary blood vessels. Other factors that are related to EC dysfunction in PAH are an increase in endothelial to mesenchymal transition, inflammation, apoptosis, and thrombus formation. In this review, we outline the latest advances on the role of EC dysfunction in PAH and other forms of pulmonary hypertension. We also elaborate on the molecular signals that orchestrate EC dysfunction in PAH. Understanding the role and mechanisms of EC dysfunction will unravel the therapeutic potential of targeting this process in PAH.

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Endothelial cell premature senescence exacerbates pulmonary arterial hypertension through contact-mediated interaction with vascular smooth muscle cells

European Heart Journal ◽

10.1093/ehjci/ehaa946.2234 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

R Ramadhiani ◽

K Ikeda ◽

K Miyagawa ◽

G.R.T Ryanto ◽

N Tamada ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Smooth Muscle ◽

Endothelial Cell ◽

Pulmonary Arterial Hypertension ◽

Pulmonary Artery ◽

Pulmonary Arteries ◽

Premature Senescence ◽

Pulmonary Arterial ◽

Human Pulmonary Artery

Abstract Introduction Pulmonary arterial hypertension (PAH) is characterized by remodelling and stenosis of the pulmonary arteries, ultimately leading to the right heart failure and death. Endothelial cell (EC) dysfunction is thought to play a central role in the pathogenesis of PAH by mediating the structural changes in pulmonary vasculatures. Various stresses promote premature senescence in EC, which may modify vascular disorders; however, the role of EC senescence in the development of PAH remains poorly understood. Purpose We aimed at investigating the potential role of EC premature senescence in the development of PAH. Methods We recently generated EC-specific progeroid mice in which ECs specifically undergo premature senescence by overexpressing the dominant-negative form of telomere repeat-binding factor 2 (published in Nat Commun 2020). These EC-specific progeroid mice were exposed to hypoxia (10% O2 for three weeks) to induce pulmonary hypertension. Also, we prepared premature senescent ECs using human pulmonary artery ECs (hPAECs) and explored their interaction with human pulmonary artery smooth muscle cells (hPASMCs) in two different conditions; direct and indirect interactions. For indirect coculture, hPASMCs were seeded onto the culture insert, while hPAECs were plated on the culture plate, and they were cocultured in the same well and medium so that secreted factors derived from senescent ECs could access to SMCs through the insert pores. For direct coculture, hPAECs were seeded onto the bottom side of the insert, while hPASMCs were cultured on the top side of the same insert, so that cell-to-cell contact could be made through the pores. Results After chronic hypoxia exposure, the EC-specific progeroid mice showed higher right ventricular systolic pressure and increased right ventricular mass as compared to wild-type (WT) mice, indicating exacerbated pulmonary hypertension. Histological analysis of the lung revealed a significantly enhanced muscularization in the small pulmonary arteries in EC-specific progeroid mice compared to WT mice. Mechanistically, we identified that direct coculture with premature senescent hPAECs enhanced proliferation and migration in hPASMCs, while no such effects were detected in indirect coculture condition. Conclusion To our knowledge, this is the first report that reveals a crucial role of EC premature senescence in the development of PAH. Our in vitro studies suggest that contact-mediated interaction between premature senescent ECs and SMCs is critically involved in its underlying mechanism. Therefore, EC premature senescence is a novel attractive pharmacotherapeutic target for the treatment of PAH. Funding Acknowledgement Type of funding source: None

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Abstract MP155: Oxidized Lipids Diet Causes Pulmonary Hypertension Through T-cell Dependent Endothelial Cell Apoptosis

Circulation Research ◽

10.1161/res.127.suppl_1.mp155 ◽

2020 ◽

Vol 127 (Suppl_1) ◽

Author(s):

Gregoire Ruffenach ◽

Ellen O'connor ◽

Mylene Vaillancourt ◽

JASON HONG ◽

Victor R Grijalva ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Endothelial Cell ◽

T Cell ◽

Antigen Processing ◽

Pulmonary Arteries ◽

Oxidized Lipids ◽

Double Positive ◽

Mimetic Peptide ◽

Pulmonary Arterial

Background: Pulmonary hypertension (PH) is a fatal disease characterized by an increased mean pulmonary arterial pressure above 25mmHg. This increased pressure is, at least in part, due to thickening of the distal pulmonary arteries. Recently, numerous studies demonstrated an increased plasma concentration of oxidized lipids in PH and in diseases where secondary PH developed. Furthermore, 15-hydroxyeicosatetraenoic acid (15-HETE) an oxidized lipid and a major metabolite of arachidonic acid in the lung, has been implicated in dysregulation of major biological pathways in PH. However, the mechanisms involved in the causal role of 15-HETE in pulmonary hypertension development are not known. Methods and Results: To study the role of 15-HETE in PH development, we fed C57BL6/J mice a diet supplemented with 15-HETE for 3 weeks with no other insults. After 3 weeks on the diet with added 15-HETE, C57BL6/J mice had increased concentrations of not only 15-HETE but also of other oxidized lipids (5-, 11- and 12-HETE) in plasma and lung, and they developed PH. RNA-seq analysis revealed the activation of pathways involved in antigen processing and presentation, and with evidence of T cell mediated cytotoxicity in lungs of mice fed 15-HETE. Transcriptomic profiling of lung tissues obtained from patients with pulmonary arterial hypertension (PAH) demonstrated activation of pathways similar to those seen mice. In mice fed a 15-HETE diet, there was an increase in the number of CD8/CD69 double positive cells, as well as an increase in pulmonary arterial endothelial cell (PAEC) apoptosis. Furthermore, PAEC exposed to 15-HETE were more prone to apoptosis when exposed to CD8 cells. Adding Tg6F, an apoA-I mimetic peptide to the 15-HETE diet prevented and rescued PH in C57BL6/J mice, in part, by inhibiting PAEC apoptosis. Conclusions: 15-HETE diet induced PH in C57Bl6/J mice by triggering PAEC death in a T-cell dependent mechanism. The apoA-I mimetic peptide Tg6F was able to prevent and rescue PH induced by 15-HETE.

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