Pulmonary hypertension (PH) is a severe multifactorial disease characterized by increased pulmonary vascular resistance and pulmonary vascular remodeling with subsequent right heart remodeling and ultimately right heart failure. Mitochondrial dysfunction is suggested to play a key role in PH development. Mitophagy serves for mitochondrial quality control to remove dysfunctional mitochondria. Mitophagy is induced by accumulation of PTEN-induced putative kinase 1 (PINK1) and Parkinson protein 2, E3 ubiquitin protein ligase (PARKIN) at the outer mitochondrial membrane (OMM) of dysfunctional, depolarized mitochondria, while the Presenilins-associated rhomboid-like protein (PARL) degrades PINK1 in healthy mitochondria. Currently, the role of PINK1-dependent mitophagy for development of PH remains unknown. This study thus investigated the role of PINK1/PARKIN-dependent mitophagy in the development of chronic hypoxia-induced PH.Protein expression of PINK1 was increased in precapillary pulmonary arterial smooth muscle cells (PASMC) exposed to 1% O2 for 5 days in vitro and in lung homogenate of mice exposed to 10% O2 for 28 days in vivo. In lung homogenate of patients with idiopathic pulmonary arterial hypertension (IPAH) PINK1 as well as PARL protein expression was increased compared to donor controls. Hypoxia-induced proliferation of Pink1-/- PASMC was attenuated compared to WT PASMC, while their apoptosis was enhanced after in vitro hypoxic incubation compared to WT PASMC. Accordingly, pulmonary vascular remodeling was lower in Pink1-/- mice exposed to 10% O2 for 28 days compared to hypoxic WT mice. In contrast, the chronic hypoxiainduced increase in right ventricular systolic pressure (RVSP) was similar in Pink1-/- and WT mice, however, hypoxia-induced right ventricle (RV) remodeling was also attenuated in Pink1-/- after chronic hypoxic exposure compared to hypoxic WT mice. The PINK1-independent mitophagy pathway regulated by BCL2/Adenovirus E1B 19 KDa protein-interacting protein 3-like (BNIP3L/Nix) was increased in Pink1-/- mice compared to WT mice, possibly attenuating the phenotype of Pink1-/- mice.The data presented in this thesis suggests that PINK1-dependent mitophagy promotes hypoxiainduced pulmonary vascular remodeling by affecting PASMC proliferation and apoptosis. Furthermore, PINK1-dependent mitophagy participates in RV remodeling during chronic hypoxia-induced PH. This finding provides insight into a novel mechanism of hypoxia-induced PH and RV remodeling. Further studies on the role of mitophagy in IPAH and the potential as therapeutic target are necessary.
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