Mitochondrial HSP90 Accumulation Promotes Vascular Remodeling in Pulmonary Arterial Hypertension

Abstract

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