Development of antioxidant peptides that target the pulmonary arteries for the treatment of pulmonary hypertension

Chronic thromboembolic pulmonary hypertension (CTEPH) is defined as a mean pulmonary artery pressure ≥25 mm Hg and pulmonary artery wedge pressure ≤15 mm Hg in the presence of occlusive thrombi within the pulmonary arteries. Surgical pulmonary thromboendarterectomy (PTE) is considered the best treatment option for CTEPH.

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Oxygen-Sensitivity and Pulmonary Selectivity of Vasodilators as Potential Drugs for Pulmonary Hypertension

Antioxidants ◽

10.3390/antiox10020155 ◽

2021 ◽

Vol 10 (2) ◽

pp. 155

Author(s):

Daniel Morales-Cano ◽

Bianca Barreira ◽

Beatriz De Olaiz Navarro ◽

María Callejo ◽

Gema Mondejar-Parreño ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Gas Exchange ◽

Pulmonary Circulation ◽

Pulmonary Arteries ◽

Blood Perfusion ◽

Mesenteric Arteries ◽

Oxygen Sensitivity ◽

Low Oxygen ◽

Oxygen Selectivity

Current approved therapies for pulmonary hypertension (PH) aim to restore the balance between endothelial mediators in the pulmonary circulation. These drugs may exert vasodilator effects on poorly oxygenated vessels. This may lead to the derivation of blood perfusion towards low ventilated alveoli, i.e., producing ventilation-perfusion mismatch, with detrimental effects on gas exchange. The aim of this study is to analyze the oxygen-sensitivity in vitro of 25 drugs currently used or potentially useful for PH. Additionally, the study analyses the effectiveness of these vasodilators in the pulmonary vs. the systemic vessels. Vasodilator responses were recorded in pulmonary arteries (PA) and mesenteric arteries (MA) from rats and in human PA in a wire myograph under different oxygen concentrations. None of the studied drugs showed oxygen selectivity, being equally or more effective as vasodilators under conditions of low oxygen as compared to high oxygen levels. The drugs studied showed low pulmonary selectivity, being equally or more effective as vasodilators in systemic than in PA. A similar behavior was observed for the members within each drug family. In conclusion, none of the drugs showed optimal vasodilator profile, which may limit their therapeutic efficacy in PH.

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The mechanism of ions in pulmonary hypertension

Pulmonary Circulation ◽

10.1177/2045894020987948 ◽

2021 ◽

Vol 11 (1) ◽

pp. 204589402098794

Author(s):

Guogu Liu ◽

Daiyan Fu ◽

Heshen Tian ◽

Aiguo Dai

Keyword(s):

Pulmonary Hypertension ◽

Calcium Ion ◽

Pulmonary Arteries ◽

Chloride Ion ◽

Vasoactive Substances ◽

Pulmonary Vasoconstriction ◽

Concentration Of Ions ◽

Inducing Factors ◽

Effective Drugs ◽

Pathological Manifestation

Pulmonary hypertension（PH）is a kind of hemodynamic and pathophysiological state, in which the pulmonary artery pressure (PAP) rises above a certain threshold. The main pathological manifestation is pulmonary vasoconstriction and remodelling progressively. More and more studies have found that ions play a major role in the pathogenesis of PH. Many vasoactive substances, inflammatory mediators, transcription-inducing factors, apoptosis mediators, redox substances and translation modifiers can control the concentration of ions inside and outside the cell by regulating the activity of ion channels, which can regulate vascular contraction, cell proliferation, migration, apoptosis, inflammation and other functions. We all know that there are no effective drugs to treat PH. Ions are involved in the occurrence and development of PH, so it is necessary to clarify the mechanism of ions in PH as a therapeutic target for PH. The main ions involved in PH are calcium ion (Ca2+), potassium ion (K+), sodium ion (Na+) and chloride ion (Cl–). Here, we mainly discuss the distribution of these ions and their channels in pulmonary arteries and their role in the pathogenesis of PH.

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The Role of JAK/STAT Molecular Pathway in Vascular Remodeling Associated with Pulmonary Hypertension

International Journal of Molecular Sciences ◽

10.3390/ijms22094980 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4980

Author(s):

Inés Roger ◽

Javier Milara ◽

Paula Montero ◽

Julio Cortijo

Keyword(s):

Pulmonary Hypertension ◽

Smooth Muscle ◽

Pulmonary Artery ◽

Vascular Remodeling ◽

Pulmonary Arteries ◽

Clinical Manifestations ◽

Different Types ◽

Artery Remodeling ◽

Stat Pathway ◽

Pulmonary Artery Remodeling

Pulmonary hypertension is defined as a group of diseases characterized by a progressive increase in pulmonary vascular resistance (PVR), which leads to right ventricular failure and premature death. There are multiple clinical manifestations that can be grouped into five different types. Pulmonary artery remodeling is a common feature in pulmonary hypertension (PH) characterized by endothelial dysfunction and smooth muscle pulmonary artery cell proliferation. The current treatments for PH are limited to vasodilatory agents that do not stop the progression of the disease. Therefore, there is a need for new agents that inhibit pulmonary artery remodeling targeting the main genetic, molecular, and cellular processes involved in PH. Chronic inflammation contributes to pulmonary artery remodeling and PH, among other vascular disorders, and many inflammatory mediators signal through the JAK/STAT pathway. Recent evidence indicates that the JAK/STAT pathway is overactivated in the pulmonary arteries of patients with PH of different types. In addition, different profibrotic cytokines such as IL-6, IL-13, and IL-11 and growth factors such as PDGF, VEGF, and TGFβ1 are activators of the JAK/STAT pathway and inducers of pulmonary remodeling, thus participating in the development of PH. The understanding of the participation and modulation of the JAK/STAT pathway in PH could be an attractive strategy for developing future treatments. There have been no studies to date focused on the JAK/STAT pathway and PH. In this review, we focus on the analysis of the expression and distribution of different JAK/STAT isoforms in the pulmonary arteries of patients with different types of PH. Furthermore, molecular canonical and noncanonical JAK/STAT pathway transactivation will be discussed in the context of vascular remodeling and PH. The consequences of JAK/STAT activation for endothelial cells and pulmonary artery smooth muscle cells’ proliferation, migration, senescence, and transformation into mesenchymal/myofibroblast cells will be described and discussed, together with different promising drugs targeting the JAK/STAT pathway in vitro and in vivo.

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Intravascular ultrasound of the elastic pulmonary arteries: a new approach for the evaluation of primary pulmonary hypertension

Heart ◽

10.1136/heart.89.3.311 ◽

2003 ◽

Vol 89 (3) ◽

pp. 311-315 ◽

Cited By ~ 46

Author(s):

J Rodes-Cabau

Keyword(s):

Pulmonary Hypertension ◽

Intravascular Ultrasound ◽

Primary Pulmonary Hypertension ◽

Pulmonary Arteries ◽

New Approach

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Experimental pulmonary hypertension induced by constriction of the pulmonary arteries resulting in rupture or extraordinary dilatation of the right ventricle after administration of a little amount of Na2EDTA

Experimental and Toxicologic Pathology ◽

10.1016/s0940-2993(11)80445-8 ◽

1993 ◽

Vol 45 (1) ◽

pp. 21-27 ◽

Cited By ~ 5

Author(s):

Hisao Yamaguchi ◽

Hirokuni Kaku ◽

Masaru Morisada

Keyword(s):

Pulmonary Hypertension ◽

Right Ventricle ◽

Pulmonary Arteries ◽

The Right

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Dehydroepiandrosterone promotes pulmonary artery relaxation by NADPH oxidation-elicited subunit dimerization of protein kinase G 1α

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00301.2013 ◽

2014 ◽

Vol 306 (4) ◽

pp. L383-L391 ◽

Cited By ~ 17

Author(s):

Dhara Patel ◽

Sharath Kandhi ◽

Melissa Kelly ◽

Boon Hwa Neo ◽

Michael S. Wolin

Keyword(s):

Pulmonary Hypertension ◽

Protein Kinase ◽

Pulmonary Arteries ◽

Activation Mechanism ◽

Protein Kinase G ◽

Beneficial Effects ◽

Vasp Phosphorylation ◽

Vasodilator Activity ◽

Nadph Oxidation ◽

Knockin Mouse

The activity of glucose-6-phosphate dehydrogenase (G6PD) controls a vascular smooth muscle relaxing mechanism promoted by the oxidation of cytosolic NADPH, which has been associated with activation of the 1α form of protein kinase G (PKG-1α) by a thiol oxidation-elicited subunit dimerization. This PKG-1α-activation mechanism appears to contribute to responses of isolated endothelium-removed bovine pulmonary arteries (BPA) elicited by peroxide, cytosolic NADPH oxidation resulting from G6PD inhibition, and hypoxia. Dehydroepiandrosterone (DHEA) is a steroid hormone with pulmonary vasodilator activity, which has beneficial effects in treating pulmonary hypertension. Because multiple mechanisms have been suggested for the vascular effects of DHEA and one of the known actions of DHEA is inhibiting G6PD, we investigated whether it promoted relaxation associated with NADPH oxidation, PKG-1α dimerization, and PKG activation detected by increased vasodilator-stimulated phosphoprotein (VASP) phosphorylation. Relaxation of BPA to DHEA under aerobic or hypoxic conditions was associated with NADPH oxidation, PKG-1α dimerization, and increased VASP phosphorylation. The vasodilator activity of DHEA was markedly attenuated in pulmonary arteries and aorta from a PKG knockin mouse containing a serine in place of a cysteine involved in PKG dimerization. DHEA promoted increased PKG dimerization in lungs from wild-type mice, which was not detected in the PKG knockin mouse model. Thus PKG-1α dimerization is a major contributing factor to the vasodilator actions of DHEA and perhaps its beneficial effects in treating pulmonary hypertension.

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Perspectives on endothelial-to-mesenchymal transition: potential contribution to vascular remodeling in chronic pulmonary hypertension

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00378.2006 ◽

2007 ◽

Vol 293 (1) ◽

pp. L1-L8 ◽

Cited By ~ 202

Author(s):

Enrique Arciniegas ◽

Maria G. Frid ◽

Ivor S. Douglas ◽

Kurt R. Stenmark

Keyword(s):

Pulmonary Hypertension ◽

Smooth Muscle ◽

Vascular Remodeling ◽

Serine Proteases ◽

Structural Changes ◽

Transforming Growth Factor ◽

Pulmonary Arteries ◽

Potential Contribution ◽

Mesenchymal Transition ◽

Endothelial Mesenchymal Transition

All forms of pulmonary hypertension are characterized by structural changes in pulmonary arteries. Increased numbers of cells expressing α-smooth muscle (α-SM) actin is a nearly universal finding in the remodeled artery. Traditionally, it was assumed that resident smooth muscle cells were the exclusive source of these newly appearing α-SM actin-expressing cells. However, rapidly emerging experimental evidence suggests other, alternative cellular sources of these cells. One possibility is that endothelial cells can transition into mesenchymal cells expressing α-SM actin and that this process contributes to the accumulation of SM-like cells in vascular pathologies. We review the evidence that endothelial-mesenchymal transition is an important contributor to cardiac and vascular development as well as to pathophysiological vascular remodeling. Recent work has provided evidence for the role of transforming growth factor-β, Wnt, and Notch signaling in this process. The potential roles of matrix metalloproteinases and serine proteases are also discussed. Importantly, endothelial-mesenchymal transition may be reversible. Thus insights into the mechanisms controlling endothelial-mesenchymal transition are relevant to vascular remodeling and are important as we consider new therapies aimed at reversing pulmonary vascular remodeling.

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Newborn rat response to single vs. combined cGMP-dependent pulmonary vasodilators

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00164.2013 ◽

2014 ◽

Vol 306 (2) ◽

pp. L207-L215 ◽

Cited By ~ 9

Author(s):

Masahiro Enomoto ◽

Amish Jain ◽

Jingyi Pan ◽

Yulia Shifrin ◽

Todd Van Vliet ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Synergistic Effect ◽

Soluble Guanylate Cyclase ◽

Pulmonary Arteries ◽

Small Heat Shock Protein ◽

No Donor ◽

Clinical Exposure ◽

Pulmonary Vasodilators ◽

Pulmonary Vasodilator

Inhaled nitric oxide (NO) and other cGMP- or cAMP-dependent pulmonary vasodilators are often used in combination for the treatment of the persistent pulmonary hypertension of the newborn syndrome. There is in vitro evidence to indicate that NO downregulate the pulmonary vascular response to cGMP-dependent agonists raising concern as to whether a synergistic effect is observed when employing a combined strategy in newborns. Hypothesizing that a synergistic effect is absent, we evaluated newborn and juvenile rat pulmonary arteries to determine the individual and combined vasodilatory effect of cGMP- and cAMP-dependent agonists. In precontracted near-resistance pulmonary arteries, the addition of sildenafil reduced vasorelaxation response to NO donor S-nitroso- N-acetyl penicillamine (SNAP). A similar decrease in SNAP-induced vasodilation was observed in arteries pretreated with BAY 41–2272 (10−9 M), a soluble guanylate cyclase stimulator cGMP, and its downstream protein kinase activator. cGMP also reduced the vasorelaxant response to the cAMP-dependent forskolin. Inhibition of endogenous vascular NO generation enhanced SNAP-induced relaxation. The present data suggest that the mechanism involved in the cGMP desensitization to other relaxant agonists involves downregulation of the small heat shock protein HSP20 and is evident in rat pulmonary and systemic vascular smooth muscle cells. In newborn rats with chronic hypoxia-induced pulmonary hypertension, the combination of sildenafil and inhaled NO resulted in a lesser reduction in pulmonary vascular resistance compared with their individual effect. These data suggest that clinical exposure to one cGMP-dependent pulmonary vasodilator may affect the response to other cGMP- or cAMP-mediated agonists.

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