Effects of HIV Protease Inhibitors on Progression of Monocrotaline- and Hypoxia-Induced Pulmonary Hypertension in Rats

Gary-Bobo, Guillaume; Houssaïni, Amal; Amsellem, Valérie; Rideau, Dominique; Pacaud, Pierre; Perrin, Aline; Brégeon, Jérémy; Marcos, Élisabeth; Dubois‐Randé, Jean‐Luc; Sitbon, Olivier; Savale, Laurent; Adnot, Serge

doi:10.1161/circulationaha.110.973750

Cited by 46 publications

(36 citation statements)

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“…Activation of mTOR contributes to proliferative lung diseases such as lung cancer and pulmonary hypertension (28)(29)(30)(31), but its potential involvement in degenerative lung diseases such as COPD has not been specifically investigated. Our evidence of mTOR overactivity and increased cell senescence in COPD, combined with the efficacy of rapamycin in decreasing both mTOR activity and cell senescence, point to mTOR activation as a major driver of cell senescence in lungs from patients with COPD.…”

Section: Discussionmentioning

confidence: 99%

mTOR pathway activation drives lung cell senescence and emphysema

et al. 2018

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Section: Discussionmentioning

confidence: 99%

mTOR pathway activation drives lung cell senescence and emphysema

et al. 2018

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“…However, SQV and other first generation HIV-PIs have been shown to reduce immunopathology and tissue damage in several experimental models including sepsis (30), pancreatitis (31) and hypoxia-induced pulmonary arterial hypertension (32). A recent clinical trial showed that a 6-month course of SVQ improves proteinurea in steroid-resistant nephrotic syndrome (33).…”

Section: Discussionmentioning

confidence: 99%

The HIV Protease Inhibitor Saquinavir Inhibits HMGBl-Driven Inflammation by Targeting the Interaction of Cathepsin V with TLR4/MyD88

Pribis

Al‐Abed

Yang

et al. 2015

Mol Med

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Extracellular high-mobility group box 1 (HMGB1) (disulfide form), via activation of toll-like receptor 4 (TLR4)-dependent signaling, is a strong driver of pathologic inflammation in both acute and chronic conditions. Identification of selective inhibitors of HMGB1-TLR4 signaling could offer novel therapies that selectively target proximal endogenous activators of inflammation. A cell-based screening strategy led us to identify first generation HIV-protease inhibitors (PI) as potential inhibitors of HMGB1-TLR4 driven cytokine production. Here we report that the first-generation HIV-PI saquinavir (SQV), as well as a newly identified mammalian protease inhibitor STO33438 (334), potently block disulfide HMGB1-induced TLR4 activation, as assayed by the production of TNF-α by human monocyte-derived macrophages (THP-1). We further report on the identification of mammalian cathepsin V, a protease, as a novel target of these inhibitors. Cellular as well as recombinant protein studies show that the mechanism of action involves a direct interaction between cathepsin V with TLR4 and its adaptor protein MyD88. Treatment with SQV, 334 or the known cathepsin inhibitor SID26681509 (SID) significantly improved survival in murine models of sepsis and reduced liver damage following warm liver ischemia/reperfusion (I/R) models, both characterized by strong HMGB1-TLR4 driven pathology. The current study demonstrates a novel role for cathepsin V in TLR4 signaling and implicates cathepsin V as a novel target for first-generation HIV-PI compounds. The identification of cathepsin V as a target to block HMGB1-TLR4-driven inflammation could allow for a rapid transition of the discovery from the bench to the bedside. Disulfide HMGB1 drives pathologic inflammation in many models by activating signaling through TLR4. Cell-based screening identified the mammalian protease cathepsin V as a novel therapeutic target to inhibit TLR4-mediated inflammation induced by extracellular HMGB1 (disulfide form). We identified two protease inhibitors (PIs) that block cathepsin V and thereby inhibit disulfide HMGB1-induced TLR4 activation: saquinavir (SQV), a firstgeneration PI targeting viral HIV protease and STO33438 (334), targeting mammalian proteases. We discovered that cathepsin V binds TLR4 under basal and HMGB1-stimulated conditions, but dissociates in the presence of SQV over time. Thus cathepsin V is a novel target for first-generation HIV PIs and represents a potential therapeutic target of pathologic inflammation. teraction of the complex with the cognate receptor of the ligand-binding partner (3). Second, the redox status of the three cysteines (C23, C45 and C106) within HMGB1 determines both the efficiency of binding to other ligands as well as the specificity of HMGB1 for certain receptors (5). For example, when in the all-thiol configuration, HMGB1 binds to CXCL12 (SDF1) to amplify the activation of CXCR4 on immune and progenitor cells promoting chemotaxis. In contrast, under mild oxidizing conditions, C23 and C45 can form a disulfide bond an...

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“…11 were associated with cell growth, proliferation, and cell metabolism. Among the new findings was increased expression of chloride intracellular channel 4, a multifunctional protein involved in angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

Pulmonary Hypertension in Circulation and the Circulation Subspecialty Journals

2012

Circulation

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The following articles are being highlighted as part of Circulation's Topic Review series. This series will summarize the most important manuscripts, as selected by the editors, published in Circulation and the Circulation subspecialty journals. The studies included in this article represent the articles related to pulmonary hypertension that were published in Circulation and the Circulation subspecialty journals in . (Circulation. 2012125:e645-e652.) Nitrite Potently Inhibits Hypoxic and Inflammatory Pulmonary Arterial Hypertension and Smooth Muscle Proliferation via Xanthine Oxidoreductase-Dependent Nitric Oxide GenerationSummary: Pulmonary arterial hypertension is a disease of the small pulmonary arteries that is characterized by progressive pulmonary vascular remodeling, vasoconstriction, and thrombosis. These changes lead to increased pulmonary vascular pressures and cause right heart failure, which leads to death. In general, therapies have not been effective in reversing the pathophysiological changes associated with pulmonary arterial hypertension. Our investigations define inhaled nebulized sodium nitrite as a potential therapy for pulmonary arterial hypertension. These data demonstrate that sodium nitrite can prevent or reverse pulmonary arterial hypertension in multiple experimental animal models of this disease process. Furthermore, these data show that nitrite is enzymatically converted to vasoactive nitric oxide in lung tissue and pulmonary artery smooth muscle cells via xanthine oxidoreductase. These findings help to define a therapy that may be useful in the treatment of patients with this insidious disease that to this point has lacked effective pharmacological therapies.Conclusion: These studies reveal a potent effect of inhaled nitrite that limits pathological pulmonary arterial hypertrophy and cellular proliferation in the setting of experimental pulmonary arterial hypertension. 1 Ventricular Geometry, Strain, and Rotational Mechanics in Pulmonary HypertensionSummary: As a result of ventricular interdependence, analysis of concomitant intrinsic left ventricular (LV) diseases (ie, myocardial fibrosis) in patients with significant pulmonary hypertension (PH) is challenging. The farther a region is from the right ventricle (eg, the lateral wall), the less the impact will be that the PH has on LV strain. Furthermore, parameters based on circumferential fibers appear to propagate farther from the right ventricle than longitudinal parameters, likely reflecting continuity of the circumferential fibers from the septum to the lateral wall. Accordingly, a finding of abnormal LV lateral wall longitudinal strain in patients with PH might identify true LV dysfunction that is independent of PH. We further demonstrated that LV torsion correlated negatively with estimated pulmonary artery systolic pressure and with septal flattening. Abnormally reduced LV torsion in PH could represent an advanced stage of PH and geometric alteration. Interestingly, although torsion was reduced, untwisting velocity was s...

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Effects of HIV Protease Inhibitors on Progression of Monocrotaline- and Hypoxia-Induced Pulmonary Hypertension in Rats

Cited by 46 publications

References 29 publications

mTOR pathway activation drives lung cell senescence and emphysema

mTOR pathway activation drives lung cell senescence and emphysema

The HIV Protease Inhibitor Saquinavir Inhibits HMGBl-Driven Inflammation by Targeting the Interaction of Cathepsin V with TLR4/MyD88

Pulmonary Hypertension in Circulation and the Circulation Subspecialty Journals

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