Mitochondrial HSP90 Accumulation Promotes Vascular Remodeling in Pulmonary Arterial Hypertension

• DOI: 10.1164/rccm.201708-1751oc
• Publication Date: 2018-02-02T20:42:36Z
• Authors: Olivier Boucherat; Thibaut Peterlini; Alice Bourgeois; Valérie Nadeau; Sandra Breuils-Bo...; Stéphanie Boilet-...; François Potus; Jolyane Meloche; Sophie Chabot; Caroline Lambert; Eve Tremblay; Young Chan Chae; Dario C. Altieri; Gopinath Sutendra; Evangelos D. Mich...; Roxane Paulin; Steeve Provencher; Sébastien Bonnet
• Keywords: Mitochondrial ROS; Immunogold labelling

Pulmonary arterial hypertension (PAH) is a vascular remodeling disease with poor prognosis and limited therapeutic options. Although the mechanisms contributing to in PAH are still unclear, several features, including hyperproliferation resistance apoptosis of pulmonary artery smooth muscle cells (PASMCs), have led emergence cancer-like concept. The molecular chaperone HSP90 (heat shock protein 90) directly associated malignant growth proliferation under stress conditions. In addition being highly expressed cytosol, exists subcellular pool compartmentalized mitochondria (mtHSP90) tumor cells, but not normal where it promotes cell survival.We hypothesized that mtHSP90 PAH-PASMCs represents protective mechanism against stress, promoting their apoptosis.Expression localization were analyzed by Western blot, immunofluorescence, immunogold electron microscopy. vitro, effects inhibition on mitochondrial DNA integrity, bioenergetics, assessed. vivo, potential Gamitrinib, mitochondria-targeted inhibitor, was tested fawn-hooded monocrotaline rats.We demonstrated that, response preferentially accumulates PAH-PASMC (dual immunostaining, immunoblot, microscopy) ensure survival preserving integrity bioenergetic functions. Whereas cytosolic displays lack absolute specificity for PAH-PASMCs, Gamitrinib decreased content repair capacity functions, thus repressing (Ki67 labeling) (Annexin V assay) without affecting control cells. improves two experimental rat models (monocrotaline rat).Our data show first time accumulation feature key regulator homeostasis PAH.