mTOR: A Key to Both Pulmonary Vessel Remodeling and Right Ventricular Function in Pulmonary Arterial Hypertension?

Right ventricular (RV) failure is the ultimate cause of death in patients with severe pulmonary arterial hypertension (PAH) (1, 2). RV dysfunction has long been ascribed primarily to an increase in the RV afterload, and treatments to diminish pulmonary vascular resistance were therefore considered key to improving RV function. However, progressive RV dysfunction despite improvements in pulmonary hemodynamics was reported recently in some patients (3). Moreover, differences in the severity of RV dysfunction have been demonstrated across patients with similar pulmonary hemodynamics (2, 4). For instance, among patients with similar hemodynamics, those with idiopathic PAH usually have better RV function than those with systemic sclerosis, and the prognosis also differs between these two PAH etiologies (1, 4). Thus, differences in the modalities of RV adaptation to pressure overload across PAH types may influence the prognosis. An improved understanding of these modalities would appear to be crucial to prevent loss of RV adaptation leading to RV failure. In this issue of the Journal, Pena and colleagues (pp. 615–625) provide insight into RV adaptation modalities by investigating the mammalian target of rapamycin (mTOR) pathway during SU5416/hypoxia-induced PAH in rats (5). This study builds on a growing body of literature concerning the role of mTOR in experimental and human PAH. An important finding reported previously by this group (6, 7) and others (8–10) is that mTOR activation is involved in pulmonary artery smooth muscle cell proliferation and pulmonary vessel remodeling. In the current study, mTOR signaling, particularly from mTOR complex 1 (mTORC1), was associated with RV dysfunction in SU5416/hypoxic rats, and treatment with the dual mTORC1/mTORC2 inhibitor PP242 improved pulmonary hemodynamics, RV function, and RV structure. The authors concluded that the improvement in RV function resulted in part from direct cardiac mTORC1 inhibition by the drug. This finding suggests that mTOR activation might constitute a shared, targetable cellular process underlying both pulmonary vascular remodeling and RV dysfunction in patients with PAH. This attractive possibility is worth discussing in the light of the results reported by Pena and colleagues. The mechanisms by which mTOR activation could directly alter both the pulmonary arterial tree and RV function deserve discussion. The fact that mTOR activation stimulates vascular cell proliferation during PAH development is consistent with the role of mTOR in protein synthesis, cell growth, and cell survival (Figure 1). The effects of mTOR on cardiac dysfunction, however, are more complex. Thus, mTOR contributes to both embryonic cardiac development and cardiac adaptation to pressure overload with the development of compensatory myocardial hypertrophy, in keeping with the ability of mTOR to increase the synthesis of proteins, including those needed to build striated muscle (Figure 1). However, studies also suggest that prolonged mTOR activation (e.g., as induced genetically in mice) may promote abnormal cardiac hypertrophy with fibrosis, enlargement, and impaired contractility together with increased cellular apoptosis, autophagy, and mitochondrial dysfunction (11, 12). In line with these effects of prolonged mTOR activation is recent evidence that mTOR activation is also involved in cellular senescence (13). In addition, mTOR inhibition by rapamycin was shown to improve cardiac function in mice with decompensated cardiac hypertrophy (11, 14, 15). Thus, the suggestion by Pena and colleagues that mTOR inhibition may improve RV function agrees with the concept that mTOR activation may play a key role in abnormal cardiac hypertrophy (Figure 1). A limitation of this study is the issue of whether the model used by Pena and colleagues is suitable for investigating RV dysfunction. Translating data from experimental PAH models into human applications is difficult given the differences in disease progression and cardiac consequences, which unfold over years in humans and weeks in murine models. Another limitation is that PAH is usually far less severe in murine models than in patients with severe PAH and RV pressure overload. To overcome this limitation, Pena and colleagues studied rats exposed to SU5416 and hypoxia, a combination that induced higher pulmonary artery pressure levels than were observed in rats or mice subjected to hypoxia alone or in transgenic mouse models. The SU5416/hypoxia combination induced some degree of RV dysfunction measurable by echocardiography. The ability of Pena and colleagues to separate a specific effect of the TOR inhibitor on RV function from secondary changes in RV function due to protection against PAH may be in question. PP242 treatment reduced pulmonary vascular remodeling, as was also shown previously with rapamycin, and therefore diminished the RV afterload. Separating this secondary cardiac effect of the drug from a potential primary effect on the heart is not possible using this model. Studies in models such as pulmonary artery banding, designed to specifically assess the effects of mTOR on RV function at different stages of the RV adaptation process, would be useful to clarify this point. Therefore, further studies are needed to determine whether mTOR inhibition directly protects RV function during PAH progression. Inhibition of mTOR as a treatment for PAH could target both mTORC1 and mTORC2 or preferentially mTORC1. Pena and colleagues consider various patterns of mTORC1 and mTORC2 activation in the pulmonary vasculature and right ventricle of rats with SU5416/hypoxia-induced PAH. It is now well established that activation of both mTORC1 and mTORC2 in remodeled pulmonary vessels contributes to vascular cell proliferation in various types of experimental and human PAH (7, 8). In contrast, whether predominant mTORC1 activation in the right ventricle underlies RV dysfunction is still under study. Deregulation of cardiac mTORC1 activation may be a pathophysiological mediator of cardiac hypertrophy and dysfunction in different types of left-sided cardiomyopathy (11). On the other