The Role of Nogo and the Mitochondria–Endoplasmic Reticulum Unit in Pulmonary Hypertension

The endoplasmic reticulum stress protein Nogo is a culprit in the mitochondrial defects that characterize pulmonary hypertension, pointing to therapeutic drug targets. From Hypoxia to Lung Hypertension Milkshake lovers know that it takes a lot of force to squeeze liquid through a tiny straw. Similarly, the hearts of patients with pulmonary arterial hypertension (PAH) must work hard to pump blood through the arteries of the lung, which become obstructed by overgrowth of cells within the vessels and by stiffening of their walls. Ultimately, the heart’s right ventricle hypertrophies and failure results. One of the many triggers for PAH—a lethal disease with no cure—is sustained low oxygen (hypoxia) in the blood. By exposing mice to hypoxia and inducing PAH, Sutendra et al. were able to probe the excessive growth of smooth muscle cells in the blood vessel walls and finger a culprit: the Nogo-B protein. Nogo-B is activated by hypoxia only in lung vessels, where it disrupts the close affiliation between the endoplasmic reticulum (ER) and the mitochondria. This structural aberration blocks essential mitochondrial functions and cell death, causing overgrowth of cells—and PAH. The protein Nogo controls the shape of the ER, forming its tubes and tunnels, and acts during vascular remodeling to inhibit apoptosis. These functions make Nogo a promising candidate to mediate the effects of hypoxia on cell proliferation in PAH. Before investigating Nogo’s mechanism of action in mice, the authors established that the amounts of Nogo and its activating transcription factor ATF6 were increased in both lung vessel walls and blood from patients with PAH, but not in carotid vessels. Mice showed a similar increase in Nogo after hypoxia-induced PAH. The authors went on to establish an essential role of Nogo in PAH: After genetic deletion of Nogo, PAH did not develop in hypoxia-exposed mice. In mice with PAH, the relationship between the ER and mitochondria was disrupted. Not only was the distance from the ER to the mitochondria extended, but there was a sharply decreased flow of lipid precursors from one to the other. Even more revealing of the severely altered energy state of these cells were the decreases in metabolic enzymes (pyruvate dehydrogenase and isocitrate dehydrogenase); these changes were mediated by low mitochondrial calcium concentrations and resulted in suppression of glucose oxidation and decreased respiration. These and other mitochondrial abnormalities did not occur when mice without Nogo were exposed to hypoxia. Consistent with this essential role of Nogo in hypertension, both proliferation and apoptosis resistance correlated positively with Nogo protein concentrations in lung arteries. The authors conclude that Nogo is a central player in the pathway that leads from hypoxia to hypertension in the lung, certainly in mice and likely in humans as well. Nogo is an attractive drug target because the type of Nogo that responds to hypoxia is not essential for normal cell function; animals that lack this protein show no apparent lung or other abnormalities. But as a result of this study, other members of the hypoxia-to-PAH pathway are becoming clearer as well; for example, treatment approaches that reverse glycolytic metabolism and the accompanying antiapoptotic state may prove useful in easing the flow of liquid through lungs. Pulmonary arterial hypertension (PAH) is caused by excessive proliferation of vascular cells, which occlude the lumen of pulmonary arteries (PAs) and lead to right ventricular failure. The cause of the vascular remodeling in PAH remains unknown, and the prognosis of PAH remains poor. Abnormal mitochondria in PAH PA smooth muscle cells (SMCs) suppress mitochondria-dependent apoptosis and contribute to the vascular remodeling. We hypothesized that early endoplasmic reticulum (ER) stress, which is associated with clinical triggers of PAH including hypoxia, bone morphogenetic protein receptor II mutations, and HIV/herpes simplex virus infections, explains the mitochondrial abnormalities and has a causal role in PAH. We showed in SMCs from mice that Nogo-B, a regulator of ER structure, was induced by hypoxia in SMCs of the PAs but not the systemic vasculature through activation of the ER stress–sensitive transcription factor ATF6. Nogo-B induction increased the distance between the ER and mitochondria and decreased ER-to-mitochondria phospholipid transfer and intramitochondrial calcium. In addition, we noted inhibition of calcium-sensitive mitochondrial enzymes, increased mitochondrial membrane potential, decreased mitochondrial reactive oxygen species, and decreased mitochondria-dependent apoptosis. Lack of Nogo-B in PASMCs from Nogo-A/B−/− mice prevented these hypoxia-induced changes in vitro and in vivo, resulting in complete resistance to PAH. Nogo-B in the serum and PAs of PAH patients was also increased. Therefore, triggers of PAH may induce Nogo-B, which disrupts the ER-mitochondria unit and suppresses apoptosis. This could rescue PASMCs from death during ER stress but enable the development of PAH through overproliferation. The disruption of the ER-mitochondria unit may be relevant to other diseases in which Nogo is implicated, such as cancer or neurodegeneration.