[The cancer paradigm in pulmonary arterial hypertension: towards anti-remodeling therapies targeting metabolic dysfunction?]
Pulmonary arterial hypertension (PAH) is a rare, complex and multifactorial disease in which pulmonary vascular remodeling plays a major role ending in right heart failure and death. Current specific therapies of PAH that mainly target the vasoconstriction/vasodilatation imbalance are not curative. Bi-pulmonary transplantation remains the only option in patients resistant to current therapies. It is thus crucial to identify novel vascular anti-remodeling therapeutic targets. This remodeling displays several properties of cancer cells, especially overproliferation and apoptosis resistance of pulmonary vascular cells, hallmarks of cancer related to the metabolic shift known as the "Warburg effect". The latter is characterized by a shift of ATP production, from oxidative phosphorylation to low rate aerobic glycolysis. In compensation, the cancer cells exhibit exacerbated glutaminolysis thus resulting in glutamine addiction, necessary to their overproliferation. Glutamine intake results in glutamate production, a molecule at the crossroads of energy metabolism and cancer cell communication, thus contributing to cell proliferation. Accordingly, therapeutic strategies targeting glutamate production, its release into the extracellular space and its membrane receptors have been suggested to treat different types of cancers, not only in the central nervous system but also in the periphery. We propose that similar strategies targeting glutamatergic signaling may be considered in PAH, especially as they could affect not only the vascular remodeling but also the right heart hypertrophy known to involve the glutaminolysis pathway. Ongoing studies aim to characterize the involvement of the glutamate pathway and its receptors in vascular remodeling, and the therapeutic potential of specific molecules targeting this pathway.
INSERM UMR-S 999, Hôpital Marie Lannelongue, 92350 Le Plessis-Robinson, France - Univ. Paris-Sud, Faculté de Médecine, Université Paris-Saclay, 94270 Le Kremlin-Bicêtre, France - AP-HP Assistance Publique-Hôpitaux de Paris, Service de Pneumologie, Hôpital Bicêtre, 94270 Le Kremlin-Bicêtre, France.
Sébastien J
SJ
Dumas
INSERM UMR-S 999, Hôpital Marie Lannelongue, 92350 Le Plessis-Robinson, France - Univ. Paris-Sud, Faculté de Médecine, Université Paris-Saclay, 94270 Le Kremlin-Bicêtre, France - AP-HP Assistance Publique-Hôpitaux de Paris, Service de Pneumologie, Hôpital Bicêtre, 94270 Le Kremlin-Bicêtre, France.
Marc
M
Humbert
INSERM UMR-S 999, Hôpital Marie Lannelongue, 92350 Le Plessis-Robinson, France - Univ. Paris-Sud, Faculté de Médecine, Université Paris-Saclay, 94270 Le Kremlin-Bicêtre, France.
Sylvia
S
Cohen-Kaminsky
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D049109:Cell Proliferation / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008659:Metabolic Diseases / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D058990:Molecular Targeted Therapy / Q000379:methods / Q000639:trends*; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D009369:Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects; D019139:Tumor Escape / Q000187:drug effects; D066253:Vascular Remodeling / Q000187:drug effects*; D014665:Vasodilator Agents / Q000627:therapeutic use
D000970:Antineoplastic Agents; D014665:Vasodilator Agents; D018698:Glutamic Acid