DNA Damage and Pulmonary Hypertension

Pulmonary hypertension (PH) is defined by a mean pulmonary arterial pressure over 25 mmHg at rest and is diagnosed by right heart catheterization. Among the different groups of PH, pulmonary arterial hypertension (PAH) is characterized by a progressive obstruction of distal pulmonary arteries, related to endothelial cell dysfunction and vascular cell proliferation, which leads to an increased pulmonary vascular resistance, right ventricular hypertrophy, and right heart failure. Although the primary trigger of PAH remains unknown, oxidative stress and inflammation have been shown to play a key role in the development and progression of vascular remodeling. These factors are known to increase DNA damage that might favor the emergence of the proliferative and apoptosis-resistant phenotype observed in PAH vascular cells. High levels of DNA damage were reported to occur in PAH lungs and remodeled arteries as well as in animal models of PH. Moreover, recent studies have demonstrated that impaired DNA-response mechanisms may lead to an increased mutagen sensitivity in PAH patients. Finally, PAH was linked with decreased breast cancer 1 protein (BRCA1) and DNA topoisomerase 2-binding protein 1 (TopBP1) expression, both involved in maintaining genome integrity. This review aims to provide an overview of recent evidence of DNA damage and DNA repair deficiency and their implication in PAH pathogenesis

Les eaux souterraines, un vecteur invisible et pourtant essentiel pour comprendre l'exposition humaine et des écosystèmes à la chlordécone

International audienceL’objectif de cette communication est de présenter les avancées récentes sur la caractérisation de la contamination par la chlordécone (CLD) des eaux souterraines (ESO) qui sont un vecteur clé « invisible » de sa dispersion dans l’environnement. Ce travail se base sur des suivis pluri annuels des ESO des îles de Martinique et Guadeloupe, ainsi que des suivis physico-chimiques de l’Observatoire des Pollutions Agricoles (OPALE). L’analyse des tendances pluri-annuelles montre que contrairement aux points d’eau plus faiblement contaminés avec des tendances à la baisse, des tendances à la hausse ou l’absence de tendance sont détectées pour les points les plus contaminés. Cette variabilité est à rattacher au temps de résidence des aquifères, les concentrations les plus fortes étant généralement observées pour des eaux s’étant infiltrées lors de la phase d’application de la CLD (1970-1990). Un schéma de la contamination des ESO est proposé afin d’identifier les facteurs d’exposition des écosystèmes qui en dépendent

Nebivolol for Improving Endothelial Dysfunction, Pulmonary Vascular Remodeling, and Right Heart Function in Pulmonary Hypertension

International audienceEndothelial cell (EC) dysfunction plays a central role in the pathogenesis of pulmonary arterial hypertension (PAH), promoting vasoconstriction, smooth muscle proliferation, and inflammation

Sirtuin 1 regulates pulmonary artery smooth muscle cell proliferation: role in pulmonary arterial hypertension

International audienceObjective: Energy metabolism shift from oxidative phosphorylation toward glycolysis in pulmonary artery smooth muscle cells (PASMCs) is suggested to be involved in their hyperproliferation in pulmonary arterial hypertension (PAH). Here, we studied the role of the deacetylase sirtuin1 (SIRT1) in energy metabolism regulation in PASMCs via various pathways including activation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), master regulator of mitochondrial biogenesis.Approach and results: Contents of PGC-1α and its downstream targets as well as markers of mitochondrial mass (voltage-dependent anion channel and citrate synthase) were diminished in human PAH PASMCs. These cells and platelet-derived growth factor-stimulated rat PASMCs demonstrated a shift in cellular acetylated/deacetylated state, as evidenced by the increase of the acetylated forms of SIRT1 targets: histone H1 and Forkhead box protein O1. Rat and human PASMC proliferation was potentiated by SIRT1 pharmacological inhibition or specific downregulation via short-interfering RNA. Moreover, after chronic hypoxia exposure, SIRT1 inducible knock out mice displayed a more intense vascular remodeling compared with their control littermates, which was associated with an increase in right ventricle pressure and hypertrophy. SIRT1 activator Stac-3 decreased the acetylation of histone H1 and Forkhead box protein O1 and strongly inhibited rat and human PASMC proliferation without affecting cell mortality. This effect was associated with the activation of mitochondrial biogenesis evidenced by higher expression of mitochondrial markers and downstream targets of PGC-1α.Conclusion: Altered acetylation/deacetylation balance as the result of SIRT1 inactivation is involved in the pathogenesis of PAH, and this enzyme could be a promising therapeutic target for PAH treatment

Chemotherapy-Induced Pulmonary Hypertension: Role of Alkylating Agents

Pulmonary veno-occlusive disease (PVOD) is an uncommon form of pulmonary hypertension (PH) characterized by progressive obstruction of small pulmonary veins and a dismal prognosis. Limited case series have reported a possible association between different chemotherapeutic agents and PVOD. We evaluated the relationship between chemotherapeutic agents and PVOD. Cases of chemotherapy-induced PVOD from the French PH network and literature were reviewed. Consequences of chemotherapy exposure on the pulmonary vasculature and hemodynamics were investigated in three different animal models (mouse, rat, and rabbit). Thirty-seven cases of chemotherapy-associated PVOD were identified in the French PH network and systematic literature analysis. Exposure to alkylating agents was observed in 83.8% of cases, mostly represented by cyclophosphamide (43.2%). In three different animal models, cyclophosphamide was able to induce PH on the basis of hemodynamic, morphological, and biological parameters. In these models, histopathological assessment confirmed significant pulmonary venous involvement highly suggestive of PVOD. Together, clinical data and animal models demonstrated a plausible cause-effect relationship between alkylating agents and PVOD. Clinicians should be aware of this uncommon, but severe, pulmonary vascular complication of alkylating agents.status: publishe