Peroxisome Proliferator-activated Receptor γ and Mitochondria: Drivers or Passengers on the Road to Pulmonary Hypertension?

Peroxisome proliferator-activated receptor g (PPARg) and PPARg coactivator 1a (PGC1a) play central roles in coordinating and driving energy metabolism, fatty acid oxidation, gluconeogenesis, glucose transport, glycogenolysis, peroxisomal remodeling, and oxidative phosphorylation—all of which are believed to be important in the development of pulmonary hypertension (PH), especially that involving hypoxia (1–4). PGC1a is a master regulator of mitochondrial biogenesis, as it integrates and coordinates the activity of multiple transcription factors, such as nuclear respiratory factor 1 (NRF1), NRF2, PPARa, and mitochondrial transcription factor A (TFAM) (5). PGC1a also targets other transcription factors involved in metabolism, including Foxo1, SREBP, Foxa2, and Sox9 (5, 6). Moreover, PGC1a regulates the expression of several enzymes involved in antioxidant defense, including superoxide dismutase 1/2, catalase, and glutathione peroxidase, which detoxify reactive oxygen species (7). These observations, combined with previous reports demonstrating that hypoxia can suppress PPARg expression in lung vascular smooth muscle cells (SMCs), raise the possibility that the mitochondrial abnormalities that are induced by hypoxia-induced suppression of PPARg and PGC1a expression may have wide-ranging effects on pulmonary vascular disease (8–10). The study by Yeligar and colleagues in this issue of the Journal (pp. 648–657) supports the idea that PPARg is a key regulator of normal pulmonary artery SMCs (PASMCs), as its decreased expression drives PASMC proliferation (11). The investigators frame the suppressive effect of hypoxia on PPARg expression as an important mechanism underlying PASMC proliferation in the setting of PH. By performing a series of in vitro lossand gain-of-function experiments targeted at PPARg, Yeligar and colleagues correlated PASMC proliferation with specific alterations of the metabolic and mitochondrial phenotype caused by decreased expression of PPARg. Indeed, genetic or pharmacologic loss-of-function experiments in normal human PASMCs, which recapitulated the effect of hypoxia, showed that decreased PPARg expression or inhibition of PPARg activity led to mitochondrial fission, hyperpolarization, increased oxidative stress, and a shift toward glycolysis, whereas converse effects resulted from experiments with overexpression of PPARg. The study thus further clarifies the molecular pathways that link decreases in PPARg to alterations in cell metabolism and proliferation by showing that hypoxia or decreases in PPARg deplete PGC1a and cause derangements in mitochondrial structure and function that stimulate PASMC proliferation. Collectively, the data from Yeligar and colleagues raise interesting questions about the role of PPARg and its target PGC1a in the regulation of a broad range of SMC functions. However, with regard to potential therapeutic targeting of PPARg (or PGC1a) in PH, several experimental aspects of this study should be considered. In most of their experiments, Yeligar and colleagues used “normal” human PASMCs that were subjected to hypoxia, or genetic or pharmacologic loss-of-function approaches aimed at PPARg. It is also important to consider that there are heterogeneous populations of SMCs that exist in the PAs, and each exhibits distinct responses to hypoxia in vitro and in vivo (12). Further, it is unlikely that a brief exposure to hypoxia would convert a “normal” cell into a “hypertensive” PASMC. Under chronic hypoxic conditions, it takes several weeks for the PH phenotype to develop, and in humans the disease probably develops for years before it is diagnosed (13). Particularly in Group 1 pulmonary arterial hypertension (PAH), the disease is clinically more severe and characteristically associated with more pronounced pulmonary vascular lesions than are found in hypoxic PH. Epigenetic, inflammatory, and molecular processes shape the hypertensive PASMCs (14). It is conceivable that both normal PASMCs subjected to acute hypoxia and PASMCs from disease models or humans have reduced PPARg expression. However, the cellular and molecular contexts of (chronic) PH likely were not significantly captured by the experimental approach employed by the investigative team. The authors’ use of PASMC proliferation as an endpoint to assess the beneficial effects of PPARg activation in PH should also be considered with caution. As mentioned above, PPARg and PGC1a have broad biological actions in metabolism and mitochondrial function, affecting several key cellular processes. Numerous candidates or established therapies for PH, including prostacyclin and its analogs, have been interpreted as targeting PASMC proliferation to explain their potential beneficial effects (15). However, their use does not de-remodel diseased PAs in idiopathic PAH, a finding that can be extended to all presently available therapies for PAH (13). In the context of the paper by Yeligar and colleagues, it may be worth mentioning that early increases in PASMC proliferation often wane in animal models of PH, with little ongoing SMC proliferation even in animals subjected to as little as 4 weeks of hypoxia. In our experience, diseased PASMCs from the lungs of patients with idiopathic or associated PAH do not express markers of proliferation (15); therefore, the paradigm of “apoptosis resistance” may better explain the persistence of PASMCs in PH (16). In line with this hypothesis and consistent with other diseases, it is possible that PASMCs progressively develop a senescence-like phenotype that is apoptosis resistant. Moreover, senescent cells continue to have increased metabolic activities and exhibit a secretory phenotype. In fact, PGC1a-deficient animals exhibit a vascular senescence phenotype that is associated with increased oxidative stress, mitochondrial abnormalities, and reduced telomerase activity (17, 18). Functional PGC1a prevents senescence by enabling transcription of the Foxo1-regulated longevity gene sirtuin 1 (SIRT1). Importantly, ectopic expression of PGC1a, as well as its induction by alpha lipoic acid, increases expression of telomerase reverse transcriptase (TERT), augments the master antioxidant transcription factor Nrf2, and reduces expression of the DNA damage marker p53.